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Emerging Approaches to DNA Data Storage: Challenges and Prospects

  • Andrea Doricchi
    Andrea Doricchi
    Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy
    Dipartimento di Chimica e Chimica Industriale, Università di Genova, via Dodecaneso 31, 16146 Genova, Italy
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  • , 
  • Casey M. Platnich
    Casey M. Platnich
    Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, U.K.
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    Orcidhttps://orcid.org/0000-0002-3634-4580
  • , 
  • Andreas Gimpel
    Andreas Gimpel
    Institute for Chemical and Bioengineering, ETH Zurich, Vladimir-Prelog-Weg 1, 8093 Zurich, Switzerland
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    Orcidhttps://orcid.org/0000-0002-8890-3292
  • , 
  • Friederikee Horn
    Friederikee Horn
    Technical University of Munich, Department of Electrical and Computer Engineering Munchen, Bayern, DE 80333, Germany
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  • , 
  • Max Earle
    Max Earle
    Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, U.K.
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  • , 
  • German Lanzavecchia
    German Lanzavecchia
    Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy
    Dipartimento di Fisica, Università di Genova, via Dodecaneso 33, 16146 Genova, Italy
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  • , 
  • Aitziber L. Cortajarena
    Aitziber L. Cortajarena
    Center for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain
    Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
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    Orcidhttps://orcid.org/0000-0002-5331-114X
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  • Luis M. Liz-Marzán
    Luis M. Liz-Marzán
    Center for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain
    Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
    Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain
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    Orcidhttps://orcid.org/0000-0002-6647-1353
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  • Na Liu
    Na Liu
    Second Physics Institute, University of Stuttgart, 70569 Stuttgart, Germany
    Max Planck Institute for Solid State Research, 70569 Stuttgart, Germany
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  • Reinhard Heckel
    Reinhard Heckel
    Technical University of Munich, Department of Electrical and Computer Engineering Munchen, Bayern, DE 80333, Germany
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  • Robert N. Grass
    Robert N. Grass
    Institute for Chemical and Bioengineering, ETH Zurich, Vladimir-Prelog-Weg 1, 8093 Zurich, Switzerland
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    Orcidhttps://orcid.org/0000-0001-6968-0823
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  • Roman Krahne
    Roman Krahne
    Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy
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    Orcidhttps://orcid.org/0000-0003-0066-7019
  • , 
  • Ulrich F. Keyser*
    Ulrich F. Keyser
    Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, U.K.
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-3188-5414
  • , and 
  • Denis Garoli*
    Denis Garoli
    Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-5418-7494
Cite this: ACS Nano 2022, 16, 11, 17552–17571
Publication Date (Web):October 18, 2022
https://doi.org/10.1021/acsnano.2c06748

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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With the total amount of worldwide data skyrocketing, the global data storage demand is predicted to grow to 1.75 × 1014 GB by 2025. Traditional storage methods have difficulties keeping pace given that current storage media have a maximum density of 103 GB/mm3. As such, data production will far exceed the capacity of currently available storage methods. The costs of maintaining and transferring data, as well as the limited lifespans and significant data losses associated with current technologies also demand advanced solutions for information storage. Nature offers a powerful alternative through the storage of information that defines living organisms in unique orders of four bases (A, T, C, G) located in molecules called deoxyribonucleic acid (DNA). DNA molecules as information carriers have many advantages over traditional storage media. Their high storage density, potentially low maintenance cost, ease of synthesis, and chemical modification make them an ideal alternative for information storage. To this end, rapid progress has been made over the past decade by exploiting user-defined DNA materials to encode information. In this review, we discuss the most recent advances of DNA-based data storage with a major focus on the challenges that remain in this promising field, including the current intrinsic low speed in data writing and reading and the high cost per byte stored. Alternatively, data storage relying on DNA nanostructures (as opposed to DNA sequence) as well as on other combinations of nanomaterials and biomolecules are proposed with promising technological and economic advantages. In summarizing the advances that have been made and underlining the challenges that remain, we provide a roadmap for the ongoing research in this rapidly growing field, which will enable the development of technological solutions to the global demand for superior storage methodologies.

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1. Introduction

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In the present digital era, the quantity of data being produced continues to increase exponentially, with the global demand for data storage expected to grow up to 1.75 × 1014 GB by 2025 and by a further order of magnitude within the end of this decade. (1) The demand for denser and longer-lived information storage devices is also increasing. (2) Current storage technologies, including optical and magnetic devices, are reaching their information density limits and are thus not suitable for long-term (>50 years) storage, which means that valuable information needs to regularly be transferred to newer storage media if it is to be preserved for future generations. Innovative methods are required for long-term information storage to circumvent this laborious and costly process and to combat other pitfalls associated with current storage media (including energy consumption and insufficient data density). (3)
Nature provides an inspiring example of how to encode, transmit, and preserve information by using DNA to store all genetic information in the form of a four nucleotide sequence. As evidenced by DNA’s invaluable role in the perpetuation of genetic information, these molecules are stable for thousands of years under suitable storage conditions; (4) for example, 300 000-year-old mitochondrial DNA from a bear has been successfully sequenced. (5) This DNA sample was preserved in bone, thereby demonstrating that the required power consumption for the archival storage of DNA is very low─another benefit compared with traditional data storage media. In addition to its stability and low cost of storage, DNA presents a major key advantage compared with existing data storage devices: data density. On the basis of its physical dimensions, DNA has a theoretical data density of 6 bits for every 1 nm of polymer, or ∼4.5 × 107 GB/g, (6) which is orders of magnitude higher than the densities achievable using traditional devices. (7,8)
Significant advances have been made in recent years toward using DNA as a digital information storage medium. (9−14) Existing strategies to encode arbitrary information into DNA do so by translating the desired data (i.e., a movie, book, or picture) directly into the nucleotide sequence, which means that to write each data string, chemical DNA synthesis is employed. (15) In sequence-based DNA data storage, the major steps comprise: (1) encoding digital information, (2) data writing (synthesis of new oligonucleotides), (3) storing the DNA in physical or biological conditions, (4) random access, (5) data readout via DNA sequencing, and (6) decoding the DNA sequences back into the original digital code, as represented in Figure 1. (8,12) Over the past decades, substantial advances in biotechnology have significantly bolstered DNA data storage technologies. These include chemical and enzymatic DNA syntheses, (16,17) polymerase chain reaction (PCR) for DNA amplification, (18) and DNA sequencing. (19) Although none of these technologies was initially designed with digital data storage in mind, these considerable developments now enable procedures for writing, random accessing, reading, and editing of data encoded in DNA sequences. (10,11)

Figure 1

Figure 1. General strategy for DNA data storage, wherein the data is stored directly in the sequence of the oligonucleotides. The six main steps─encoding, writing, storage, access, reading, and decoding─are depicted.

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However, each of the procedures involved in DNA data storage─encoding, writing, storage, random access, reading, and decoding─has significant technical limitations that render DNA data storage, at present, not competitive with magnetic and solid-state storage devices. Because the de novo synthesis of long sequences of DNA remains challenging, (20) these sequences must be broken into smaller fragments (∼200 bases), which requires massive numbers of unique DNA sequences to be made. Data readout also presents several challenges: while in theory analogous to the magnetic readout of a hard disk drive, DNA sequencing must be employed to read out the information stored in individual oligonucleotides. Sequencing often relies on fluorescence outputs, which require expensive fluorophores, optical equipment, and trained personnel, as well as substantial amounts of DNA and long reading times (Figure 2a,b). Nanopore methods may present an appealing alternative, as detailed further in this review. With the use of current technologies, DNA storage is estimated to cost 800 million USD per one terabyte of data (by contrast, tape storage costs approximately 15 USD per terabyte). (12) The high price of writing DNA data using existing methods prohibits its mainstream adoption as an information storage material.
One potential strategy to circumvent these pitfalls is to rely on the programmable three-dimensional structure of DNA as opposed to its primary sequence (Figure 2c,d). DNA nanotechnology harnesses the specific base-pairing properties of the nitrogenous bases to create arbitrary two- and three-dimensional shapes. (24) It is possible to generate well-defined, custom objects at the nanoscale using these methods. Information can thus be stored in the 3D structures of these assemblies instead of in the sequence, with readout relying on imaging techniques, such as super resolution imaging, (22) or using single-molecule nanopore measurements. (23,25) The structure-based strategy may reduce the number of DNA sequences that must be synthesized by allowing for the erasing and rewriting of data through simple self-assembly. These structure-based methods also eliminate the need for next-generation sequencing, which remains among the most time-consuming aspects of DNA data storage. Because DNA nanotechnology-based approaches capitalize on the self-assembly of DNA sequences, the resulting structures are inherently reconfigurable, which enables data erasing and rewriting without further synthesis. (26) Moreover, the dynamic nature of these assemblies can be exploited to perform data operations, (13,27) which allows DNA data storage to integrate directly into the field of DNA computation.

Figure 2

Figure 2. Comparison of the main differences between sequence-based (A,B) and structure-based DNA data storage (C,D), as has been presented in the literature to date. (A,B) Sequence-based storage relies on the de novo synthesis of DNA strands and the subsequent sequencing of these entities is performed using next-generation methods. Image adapted with permission from ref (12). Copyright 2019 Springer Nature. (C) By contrast, structure-based methods utilize self-assembly, which means that the information is encoded into their three-dimensional shape. Images adapted with permission: ref (21), copyright 2016 Springer Nature; ref (22), under a Creative Commons Attribution 4.0 License (CC BY), copyright 2021 Springer Nature. (D) These shapes can then be read off using single-molecule methods, including fluorescence, atomic force microscopy, and nanopore techniques. Image adapted from ref (23). Copyright 2019 American Chemical Society.

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In this review, we provide a detailed description of the two aforementioned methods, which we will refer to as “sequence-based” and “structure-based” DNA data storage. A comparison between them that highlights both the similarities and differences in these approaches will provide an overview of the state of the art in DNA data storage. Finally, we also highlight the exciting potential applications of DNA data storage and manipulation, including archival storage, barcoding, cryptography, (11) and DNA computing. Despite the hurdles that must be surmounted to implement DNA data storage, it is important to remember that DNA plays an irreplaceable role in biological systems. As such, DNA will never become obsolete as a data storage medium. We posit that the fundamental nature of DNA, in combination with the high density and low energy cost of DNA data storage, will continue to fuel research in this rapidly growing domain.

2. Sequence-Based DNA Data Storage Methods

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2.1. From Encoding to Data Writing in DNA Data Storage

Any digital data (files of any kind such as text and pictures) can be represented as a sequence of bits (i.e., zeros and ones). One possible data storage approach is to use a set of DNA sequences of 60–200 nt in length. The limitations in sequence length arise from the chemical synthesis of DNA; producing DNA strands longer than a few hundred nucleotides (nt) introduces a significant number of errors into the sequence.
Once properly encoded, data are written on synthetic DNA sequences (Figure 3). Organic chemistry has presented us with a large set of techniques for synthesizing DNA and, as previously mentioned, strands up to 200 nt in length can be readily synthesized. The synthesis is typically performed using phosphoramidite chemistry, which is a four-step cyclic reaction involving the addition of the desired nucleotide to a growing oligonucleotide chain immobilized on a solid support (Figure 3A,B). (28) The use of a solid support enables extensive parallel synthesis, as well as automation of the chemical process, which will be fundamental to the adoption of DNA for data storage applications. (29,30) While there are many advantages to phosphoramidite synthesis, it is worth noting that it requires the use of anhydrous solvents, which produce toxic waste.

Figure 3

Figure 3. An overview of chemical and enzymatic strategies to synthesize custom DNA sequences. (A) Phosphoramidite synthesis─the most widely used chemical strategy for the synthesis of DNA─involves the sequential addition of nucleotides to a growing chain anchored on a solid support. Protecting groups are employed to ensure that no more than one nucleotide is added at each step and are then subsequently removed via chemical deblocking. (B) Deblocking can also be performed by electrochemistry. Reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY-NC) from ref (31). Copyright 2021 AAAS. (C) Enzymatic methods relying on T4rnl ligase or TdT can also be used to specifically add bases to a growing oligonucleotide in aqueous environments, which eliminates the need for organic solvents. Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (32). Copyright 2021 Elsevier B.V.

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An alternative to chemical synthesis is enzyme-based methods, but they are still in their infancy. So far, only tiny amounts of data (hundreds of bits) have been stored using enzymatic synthesis versus data consisting of billions of bits using phosphoramidite synthesis. The concept of enzymatic DNA synthesis arose from the discovery of specific DNA polymerases, and this approach is expected to become both cheaper and faster than phosphoramidite synthesis for data storage applications. (40) A major limitation, however, is DNA polymerase’s need for a template strand. To create a user-defined DNA sequence as in the chemical method, enzymes capable of extending the 3′ end of the ssDNA in a template-independent manner, such as polynucleotide phosphorylase (PNPase), T4 RNA ligase, and terminal deoxynucleotidyl transferase (TdT, Figure 3D), are required. (32) In particular, the use of TdT, a template-independent polymerase, to synthesize DNA oligonucleotides was shown to be a promising alternative to chemical synthesis. (33,16) Among others, Lee et al. (16) reported on a technique for enzymatic synthesis and digital coding that was based on template-independent polymerase TdT and nanopore reading. This strategy allowed the archiving of information in DNA without mandatory single-base precision, as well as cost reduction due to miniaturization and enzyme recycling. Moreover, the synthesis of 1000-nucleotide-long strands with homopolymeric stretches enabled a reduction of the synthesis time (Figure 3D). Palluk et al. (28,33) also described an oligonucleotide synthesis strategy that uses TdT and demonstrated that TdT–dNTP conjugates can quantitatively extend a primer by a single nt in 10–20 s. Crucially, this scheme can be iterated to write a user-defined sequence. Compared with chemical synthesis, which is undertaken in organic solvents, the enzymatic synthesis is compatible with aqueous conditions.
Both chemical and enzymatic syntheses are severely limited by the low speed of these processes. (29,39) Achievement of the necessary parallel writing capabilities while maintaining a realistic infrastructure footprint requires maximization of the number of different sequences that can be synthesized per unit area, simultaneously, on a single platform. The most space-efficient way to increase synthesis density is to reduce the area over which each unique sequence is grown (the feature size), the distance between features (the pitch), or both. To this end, photomask arrays have proven to generate high oligonucleotide densities; (34) however, this technique relies on a series of bespoke photolithographic masks to synthesize a defined set of sequences, that is, masks must be created for each set of desired sequences. An alternative method uses electrode arrays and leverages the scaling and production roadmap of the semiconductor industry, where features as small as 5 nm are now common. For example, Nguyen et al. (35) produced an electrode array and demonstrated independent electrode-specific control of DNA synthesis with electrode sizes and pitches that enabled a synthesis density of 25 million oligonucleotides/cm2 (Figure 3C). Finally, the printing synthesis method has rapidly become the most applied method (also thanks to commercial technological platforms, such as Agilent and Twist).
The sequences to be synthesized are defined by the encoding process, which maps the data to a set of DNA sequences so that a corresponding decoder can reconstruct the information, even though the writing, reading, and storage of the DNA introduces errors. (9,14,36,7,37,29,38,16,39−41)
DNA storage systems overcome these errors without losing data by capitalizing on both physical and logical redundancy. Physical redundancy is achieved by creating many, sometimes inaccurate, copies of each sequence, which enables a consensus to be reached when the data is read. Some errors cannot be resolved using physical redundancy alone. Logical redundancy guarantees reconstruction even when errors occur. While physical redundancy occurs automatically during the synthesis process─many copies of each sequence are always produced─it is fundamental to apply dedicated algorithms to include logical redundancies in the initial encoding. Moreover, encoding and decoding are strictly connected. The algorithms that encode the data to be stored add redundancy in a principled way so that a decoding algorithm can reconstruct the data from noisy reads (Figure 3A).
During the 2010s, extensive innovations in algorithm development have enabled reliable storage of data even under significant errors. Grass et al. (4) used modern error-correcting codes in the context of DNA storage, and a variety of different schemes have been proposed. (4,42−50,36,14) While physical and logical redundancy lower the storage density of DNA, recent works have proposed to raise it by expanding the DNA alphabet using composite natural letters (7,51,52) or chemically modified nucleotides. (53)

2.2. Storage and Degradation Issues

Despite DNA’s long-term stability in well-controlled environments such as ancient bone, with storage durations as long as several hundred thousand years, (54,55) both aqueous solutions and dried DNA only exhibit a half-life on the order of months to a few years under ambient conditions. (56) Therefore, considerations for the physical storage of data-encoding DNA are crucial for realizing its potential for long-term data storage. Without appropriate protection, DNA (and thus the data encoded within) is degraded by multiple mechanisms, including strand breaks, nucleotide mutations, strand cross-linking by UV, oxidation, hydrolysis, alkylation, or mechanical stress, all of which are due to environmental factors. Among those, hydrolysis is the dominating decay pathway in a data storage context. (57,58) Thus, all applicable DNA storage approaches focus on protecting the DNA from moisture and oxygen with either microscopic (i.e., on the level of individual molecules) or macroscopic (i.e., on the level of individual pools) containers. Examples of microscopic containers include encapsulation within silica particles; (56,59−61) embedding in alkaline salt, (62) polymer, (63) sugar, (64) or silk protein (65) matrices; and coprecipitation with calcium phosphates (66) imitating bone. In the latter category, dried or lyophilized DNA is stored on filter paper (64) within hermetically sealed capsules with inert atmosphere (57,58,67,68) or, as is common in biological practice, simply frozen in aqueous solutions and stored at −20 or −80 °C. (69)
Generally, all storage approaches trade long-term stability with a decrease in storage density by 1–3 orders of magnitude, caused by the low loading ratio between DNA and carrier (see Table 1). Additionally, the required time and cost for protection can be a distinguishing factor for DNA data storage systems, albeit less so for long-term storage applications. (69) The size of a single DNA pool is an important consideration for the design of DNA storage media, as index sizes for random access, constraints of PCR, and required physical redundancy for retrieval imply an upper limit on the number of pooled oligos. (69,6) This represents the maximum data that can be stored within a single macroscopic storage container, and has been estimated to lie between a few TB up to a few hundred TB. (56,6,70) We compared the storage densities and half-lives of micro- and macroscopic storage approaches in Table 1 by using the largest model pool size for which random access has been demonstrated at 5.5 TB. (71)
Table 1. Comparison of the DNA loadings (g DNA/g carrier), achieved information density in PB/g, and extrapolated half lives for both macroscopic and microscopic storage approaches, with an assumed pool size of 5.5 TB. (71);a
storage approachτ(10 °C)/ yearsDNA loadingcdensityc/PB/greferences
macroscopic
in solutionb170.005%0.85 (57)
dried7100%17 000 (66)
bone17000.05%8.5 (54,62)
DNAshellc>100 0000.000 02%0.0034 (58,68)
microscopic
trehalose matrix1600.13%2.2 (64)
silica particles5403.4%580 (59,4)
polymer matrixd1100.1%17 (63)
salt matrices75020%3400 (62)
silk matrixeNA0.000 03%0.0051 (65)
calcium phosphate matrix60018%3060 (66)
a

All values are considered at 10 °C and assuming DNA with 150 bp at an information density of 17 EB/g. Temperature corrections were performed using Arrhenius Law using 155 kJ/mol as the activation energy of DNA strand breaks. (57,4)

b

Typical concentration for synthetic DNA is 500 ng/μL.

c

Assumed pool size per DNA shell = 5.5 TB. (71) Weight of the DNA shell is at least 1.3 g. (58)

d

Polymer density was assumed as similar to that of polyethylene glycol at 1.12 g/cm3.

e

Density of filter paper is around 85 kg/m2.

Current approaches towards data encoding in DNA, such as the use of altered DNA topology (23,72) and third-generation sequencing platforms, present new challenges to data storage, as those approaches rely on oligos with multiple hundreds to thousands of nucleotides in length, compared with the few hundreds of nucleotides commonly in use for next-generation sequencing (NGS). (70) While both micro- and macroscopic storage systems are independent of sequence length, DNA decay by hydrolysis scales with the number of nucleotides per oligo and, thus, a proportional increase in the expected number of errors is anticipated. (73) Given that some types of single-site errors, such as strand breaks, may render entire oligos and the data within unreadable, the use of longer sequences further increases the need for durable storage to prevent premature data decay beyond experimental time scales. To this end, systematic studies on decay mechanisms and rates for many approaches to data encoding in DNA are missing, a critical factor regarding approaches that heavily rely on structural integrity for data retrieval.
Currently, long-term storage is only feasible within a protective material and at DNA loadings of only a few percent. Consequently, the need remains for long-term DNA data storage systems closer to DNA’s true storage density. Indeed, further improvements in the coding density toward DNA’s Shannon capacity, for example, by means of improved encoding algorithms or lowering logical redundancy, are largely overshadowed by the general loss of storage density due to the storage matrix. Conversely, the loss in encoding density yielded by encoding approaches relying on DNA topology is rendered less severe by this storage overhead, and the interplay of such approaches with denser storage systems is interesting for further research.

2.3. Random Access

As discussed above, the ability to select only a subset of DNA molecules for readout limits the current data capacity of a single pool of data-encoding DNA. This access to DNA subpools, equivalent to file-level random access, is crucial to scale DNA-based data storage up to large data capacities with no need for costly, complete sequencing of the pool. This has a major implication: an addressing system is needed to select subpools from a complex DNA mixture, with high specificity. Whereas the use of a physical substrate on which DNA can be arrayed may solve this problem, (31) this approach and similar solutions relying on the physical separation of individual oligos or oligo pools render DNA’s density advantage obsolete. Instead, two other major strategies have been developed: PCR-based addressing and direct physical separation (Figure 4). In PCR-based addressing systems, the high specificity of amplification via PCR is leveraged to selectively enrich a subpool over the background by using at least one address-specific primer and corresponding priming regions on the data-encoding oligos. Because of PCR’s exponential nature, a sample of the amplified pool will contain mainly the desired file with its matching priming regions, as well as nonspecific sequences as background. Demonstrated in 2015, (74) this addressing system has now been shown to scale to well above 1010 unique sequences per reaction while only requiring about 10 copies per sequence, which is equivalent to a pool capacity on the order of terabytes. (6,70,71) Either a rigorous design of orthogonal primer sequences (6) or the use of hierarchical addressing systems would be needed to achieve the required high specificity at these scales. (71) Nonetheless, primer-based addressing systems face several constraints. First, the incorporation of random-access priming regions into each oligo decreases the available space for data-encoding bases, thereby also decreasing the storage density (currently by about 15% per address region). (71,75) Second, PCR-based random access irreversibly removes oligos from the pool, which necessitates potentially lossy reamplification of the entire pool after repeated data retrieval. (75,76) Moreover, as pool sizes and, thus, the number of sequences, become larger, the enrichment of a few copies against an ever-increasing background will at some point hit the limitations of PCR regarding processing volumes, required amplification cycles to obtain sufficient enrichment, and nonspecific amplification due to primer–payload similarity. (77,70) Indeed, data retrieval from a hierarchical addressing system of 5.5 TB required additional physical separation of pools via a biotin-based bead extraction between file accesses to fully remove the background carried over from PCR. (71) Lastly, PCR-based addressing is incompatible with common storage approaches, thus necessitating the removal and re-embedding of the encoding DNA into the storage matrix for each random-access operation.

Figure 4

Figure 4. Overview of random access strategies to select a subpool of sequences, usually a file, from a large pool. PCR-based addressing methods leverage the high specificity of primers and the exponential amplification of PCR to enrich target sequences by using either a single or multiple PCR runs. Methods using physical separation as a tool to select sequences also rely on the high specificity of short primers or barcode sequences, but remove the desired sequences using magnetic bead extraction or fluorescence-activated sorting. Images adapted from ref (71) and reproduced with permission from ref (75). Copyright 2019 American Chemical Society and copyright 2021 Springer Nature, respectively.

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As an alternative to PCR, sequence specificity has also been exploited to carry out physical separation of files in pools. As mentioned above, biotin-labeled primers can be used to address and extract specific files via streptavidin magnetic beads on the basis of file-specific random access regions in encoding oligos, similarly to PCR-based addressing. (71,78) This approach has two key advantages: the sample can be reused for subsequent retrievals and nonspecific binding and PCR-induced biases are circumvented. (78) Banal et al. (75) extended this concept to DNA pools encapsulated in silica particles by labeling their surface with DNA barcodes to facilitate random access via fluorescently labeled probes and fluorescence sorting. While this represents a scalable random access scheme compatible with long-term storage, it is likely that the DNA barcodes on silica particles would decay much faster than the data-encoding DNA within so that random access ceases to function even if the data itself may still be intact.
All random access approaches aim at facilitating file-level control in large pools of DNA-encoded files while under the constraints of specificity, scalability, and storage density. Such scaling to large pools is highly desirable because it retains DNA’s high storage density compared with the physical separation of smaller pools using storage approaches (see Section 2.2). Currently, the highest demonstrated data capacity for random access is on the order of terabytes of data. (6,12,71) While this does not appear to be a hard limit, (6) it is likely unpractical to scale random access by PCR-based addressing indefinitely because of the aforementioned difficulty of orthogonal primer design and the requirement for many amplification cycles given the associated impact of PCR bias. (20) Whether any practical limit of PCR-based random access exists in real-life applications remains to be seen, however. As an alternative, hierarchical storage systems combining high-level access to isolated subpools with file-level random access within such subpools appear more suited to allow for random access at the data capacities envisioned for DNA data storage. The first steps in this direction have been taken, such as labeling DNA-embedding polymer disks with QR codes or automated retrieval of individual DNA pools in a digital microfluidic device, (56,63) but the trade-off between storage density, data longevity, and ease of automated data access requires further work.
Beyond random access, other file operations such as encryption with genomic keys, (79) erasure on the basis of obfuscation, (80) and rewriting by chemical modification or PCR (81,82) are also supported by sequence-based DNA data storage. As recently reviewed elsewhere, (83) these approaches highlight the versatility of file operations supported by DNA as a storage medium.

2.4. Reading

While the readout of data encoded in DNA is rarely done in its application as an archival storage system, (69) the complete and error-free retrieval of stored data must be guaranteed within a defined set of storage and sequencing conditions in order for DNA data storage to have any commercial relevance. As a result, the choice of sequencing platform has a marked impact on the design and feasibility of sequence-based DNA data storage. Currently, readout of the DNA sequences needed for data decoding relies heavily on established technologies for DNA sequencing in life science applications, most prominently sequencing-by-synthesis (SBS) as commercialized by Illumina.(Figure 5A,B). (84,85) As an alternative, sequencing using protein nanopores, commercialized by Oxford Nanopore Technologies, has been used because of its ease of implementation, automation, and portability (Figure 5C). (70,81,86) Nanopore sequencing uses electrical readouts rather than fluorescence detection to identify each base of a DNA strand as it moves through a biological nanopore. Contrary to SBS, it is therefore also able to identify modified and unnatural nucleotides such that the readout of data encoded using an expanded molecular alphabet is possible. (53,87)
While nanopore sequencing improves upon several limitations of SBS for DNA data storage, as reviewed by Ceze et al., (12) two key constraints of the technology are its high error rate and the required sequence length. The high error rate of nanopore sequencing (∼10% per nt in the single read), (70,88) compared with the nearly negligible rate of errors introduced by SBS (∼0.5% per nt), (70) necessitates the clustering of sequence information, and thus, higher sequencing coverage and additional postprocessing of sequencing data. (70,86) Moreover, sufficient pore utilization for high sequencing throughput can only be realized for long fragments (>1 kb). (86,88) Therefore, the readily available oligo libraries with a length of only a few hundred nucleotides per sequence must be combined into longer assemblies to be suitable for nanopore sequencing. This process, usually performed via Gibson assembly or overlap extension PCR, (70,81,86) reintroduces several difficult-to-automatize steps into the sequencing workflow, which calls the approach’s claims of improved portability and ease of automation over SBS into question. These constraints currently render nanopore sequencing more challenging and slower than SBS. (12) Accordingly, the largest data size retrieved using the technology is currently about 1.67 MB, compared with around 200 MB for SBS. (70,86)

Figure 5

Figure 5. Overview of next-generation sequencing technologies presently used in DNA data storage. (A) Illumina sequencing generates clusters of identical single-stranded oligonucleotides. As the complement is synthesized using spectrally distinct, fluorescently tagged nucleotides, the identity of each base along the strand can be determined through the color of emission. (B) Oxford Nanopore measurements do not require fluorescent dye molecules. As the oligonucleotide passes through the protein pore, the three-dimensional shape of each base will modulate the ionic current, which results in a current–time trace that corresponds to the specific sequence. Images adapted with permission from ref (85). Copyright 2016 Springer Nature.

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The use of both state-of-the-art SBS and rapidly developing nanopore sequencing for DNA data storage highlights the current trade-off between sequencing accuracy and cost, as well as implications for future scalability. To this end, the development of solid-state nanopores for the determination of DNA structures including their sequence, with the potential of increased accuracy and throughput by avoiding enzymes limiting the translocation rate, holds promise for data storage applications.

2.5. Decoding and Error Correction

In addition to the errors during DNA sequencing discussed in the previous section, errors are also introduced during the synthesis, storage, and amplification steps of DNA data storage, which presents challenges regarding data decoding. While amplification and SBS-based platforms mainly introduce substitution errors (reading a C instead of a G, for example), synthesis dominantly causes deletions (e.g., missing a base) at a final rate of around 0.2–1% per nt. (20,62,70) Insertions (addition of extra bases) are uncommon and usually occur at less than 0.1% per nt, mainly because of synthesis. (20,62) In addition to biases in amplification efficiency, storage mainly contributes to shifts in the copy number distribution of the sequences, which leads to the unrecoverable loss of individual sequences over time, e.g., 8% after 94% of the DNA has decayed (i.e., four half-lives). (20,25) This means that, in general, sequence information is never recovered error-free. As the decoding of the stored data directly depends on this sequence information, both the loss of individual sequences and the introduction of errors into these sequences pose a risk on error-free decoding. While an increase of physical redundancy to cluster sequence information alleviates this problem, doing so is undesirable and inefficient because it drastically lowers the information density. (20) As considerations for cost and automation limit most of the potential for reducing error rates within the data storage workflow, sufficient redundancy must instead be implemented at the sequence level. Therefore, the presence of errors in DNA storage necessitates the use of principled coding/decoding algorithms. The goal of a good encoder/decoder pair is to enable perfect reconstruction from noisy data by introducing a minimal amount of logical redundancy. Error-correcting schemes tailored to DNA data storage consider that the written sequences are relatively short and typically stored in a spatially disordered manner. The optimal coding schemes depend on the noise profile of the storage system. Reliance on logical redundancy introduced by a combination of modern error-correction codes is sufficient for low error rates. However, both for low and large error rates, dominated by deletion errors, one also uses physical redundancy to recover the original information. (42)
An error-correcting code maps an original message to a larger one, which introduces redundancy. If this message is then sent over a noisy channel, thereby introducing random errors, these errors can be detected or corrected. A simple example of an error-correction code was used by Goldman et al., (9) where each part of the information was written on four subsequent DNA sequences. Thus, the loss of sequences could be corrected if fewer than four subsequent sequences were lost. This coding scheme, however, was ill-suited for the used DNA channel because it had a low effective information rate, i.e., number of information bits per total number of encoded bits, and did not recover the whole message. In contrast, good error-correcting codes ensure data recovery with minimal redundancy. The maximal information rate that an error-correcting code can achieve is theoretically bounded. (89) This bound is known as the channel capacity and depends on the characteristics of the noisy channel. This means that the parameters of a good error-correcting code depend on the rates and type of errors. For example, the Reed–Solomon code can correct up to e erasures and s substitutions with 2s + e additional symbols. (90)
In 2015, a DNA data storage that used an error-correcting scheme, which enabled the recovery of full data, was realized by Grass et al. (4) Its encoding/decoding algorithm is explained in Figure 6. It uses an outer code that can correct for the loss of sequences, adds an index for each sequence to be able to retrieve the order of the sequences that are lost during storage, and uses an inner error-correcting code that can correct nucleotide errors within sequences. Following the original introduction of the inner-outer encoding scheme, the vast majority of subsequent works used such a scheme for DNA data storage. (14,42,44,70) In general, the outer code applies on the level of the original information, whereas the inner code protects single sequences or indices. However, different codes were used for the outer and inner codes. A Reed–Solomon code, (4,44,70) Fountain codes, (14) and LDPC (low-density parity check) code were used as an outer code. (91) As an inner code, a Reed–Solomon code was used by Grass et al. and Organick et al. (4,70) Blawat et al. proposed to protect the index separately with a bit-correcting code (BCH) as the inner code. (44) The inner–outer coding scheme works well for moderate error rates of 1–2% and substitutions. However, it cannot correct large error rates that are dominated by insertions and deletions. This is because no inner codes exist that work sufficiently well on short sequences in these noisy setups. (92) Here, the original message can be recovered by additionally exploiting the physical redundancy. For example, in Antkowiak et al., (42) the noisy sequences were first clustered by similarity, then the information on multiple erroneous copies was combined to construct a sequence with fewer errors. This was achieved by an alignment step within the clusters and subsequent majority voting. This resulting sequence could then be sent through the usual decoding steps. Recent works have explored the development of efficient clustering methods tailored to DNA data storage, as well as efficient encoding schemes that allow the recovery of a sequence from multiple noisy reads. (93−96) Such codes could then be used as an inner code. This has led to a better understanding of efficient use of physical redundancy in DNA data storage. However, at this moment an optimal encoding/decoding scheme for long-term DNA storage, or even components of it, remains unknown. For example, the capacity of deletion and insertion channels or reconstruction from multiple reads with the combination of different errors are not fully understood yet. Also, coding for these short unordered sequences remains challenging for very high error rates. Furthermore, different synthesis and sequencing techniques might motivate different approaches. For these reasons, error correction for DNA remains an active topic of research.

Figure 6

Figure 6. Inner–Outer Code. Encoding. The original information is first encoded with an outer code that introduces redundancy and protects against the loss of sequences. In Grass et al. (4) the original information was first grouped into blocks of multiple sequences (light blue). Then, each row was encoded with a Reed–Solomon code that adds redundancy (yellow). The columns correspond to single DNA sequences. These are labeled with a unique index (purple). Each column is then encoded with an inner code that adds logical redundancy on the level of each sequence (green). In general, the inner and outer codes need not add the redundancy separate from the original data, but instead return a modified longer word. Decoding. The original information from the set of noisy sequences (errors marked in red) is retrieved by first decoding the inner code. This removes most errors within the sequences. For large error rates dominated by insertions and deletions, this step may be preceded by a clustering and alignment step that generates sequences with fewer errors from multiple noisy copies. The sequences are ordered by their index. The ordered sequences are then decoded by the outer code. Here, lost sequences correspond to erasures and erroneous sequences to substitutions. These are corrected by the outer code.

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2.6. Limitations of DNA Data Storage

2.6.1. Issues Related to Cost

DNA has become a promising tool for next-generation data storage since it provides high data capacity and storage density (78) and it is possible to store it in multiple ways (37) over significant time periods. (4) However, in order to make DNA data storage standard, some limitations must be overcome. Arguably, the most important limit to the development of DNA data storage is cost, especially in comparison with standard storage processes. Often, synthesis costs for DNA data storage are undisclosed; (12) however, it is possible to draw some conclusions about them. The synthesis of DNA oligos for data storage was column-based and was developed in the 1980s. Since then, this process has been fully automated, and now it allows the synthesis of 96–384 oligos simultaneously. The costs of this procedure range between 0.05 to 0.15 USD per nucleotide. (11) Array-based synthesis processes were developed in the 1990s. They lowered the costs because of their high-throughput nature, with an average price per nucleotide down to 10–4 USD. Thus, if a conservative estimate of 1 bit/nucleotide of encoded data is assumed, each terabyte of digital data would cost 800 million USD, on average. (12,97) In comparison, tape storage costs 7–8 orders of magnitude less, i.e., about 16 USD/TB of data, with prices decreasing by 10% every year (Figures 7A,B). (12,98) Considering this enormous disparity in cost between DNA data storage and magnetic tape, the outlook for DNA storage solutions initially appears dismal. That being said, DNA data storage has the potential to drop significantly in cost over time because of several key features. For example, optimized error-correcting codes could lower the cost (97,14) by increasing the overall efficiency of the storage process by means of accuracy reduction. (12) By capitalizing on error-correcting codes, it may be possible to work with cheaper, albeit less reliable, synthesis processes if it is assumed that any synthetic errors can be identified and corrected for upon readout, thereby leading to an overall reduction in cost. In 2020, Antkowiak et al. proposed that synthesis costs will drop to around 106 USD/TB (i.e., 2–3 orders of magnitude reduction) as a result of improved synthesis strategies, including large parallelization, optimization of reagents, and combination of nonvolatile DNA-based memories with logical operations (Figures 7B–E). (42) In addition, Antkowiak et al. estimated the marginal costs of the chemical synthesis of DNA. With the use of photolithography to synthesize 10 000 copies of each oligo, with a nucleotide reagent cost of 100 USD/g and a logical density equal to 1 bit/nucleotide, the cost of 1 TB of data stored in DNA would be ∼10–2 USD, with a chemical yield of 100%. Even if this chemical yield is impossible to achieve in industrial conditions, DNA data storage will be competitive against tape storage (20 USD/TB cost) even at 0.1% chemical yield. In the latter case, the cost of photolithographic DNA storage would be ∼10 USD/TB, and synthesis conditions would be similar to the one used in surface chemistry (1000× reagent excess), which demonstrates that an optimization of chemical DNA synthesis processes is compatible with DNA data storage applications. Thus, Antkowiak et al. proved that the combination of synthesis processes that produce lower quality DNA oligos (i.e., photolithographic synthesis) and appropriate error-correction codes allows a major cost decrease in DNA data archives. (42) Regarding costs, there is also an important advantage with respect to traditional storage technologies that is worth mentioning. In fact, DNA storage systems’ maintenance costs are expected to be lower than the ones of silicon devices in contemporary data centers. (97)

Figure 7

Figure 7. (A) Cost trend of hard disk drives (HDD), NAND flash-based storage devices, linear tape-open tape cartridges (LTO tape), and optical Blu-ray (BD-RE). Image has been reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (99). Copyright 2018 AIP Publishing LLC. (B) Cost comparison between DNA synthesis for data storage and LTO tape storage. (C–E) Comparison of different DNA synthesis platforms and their characteristic traits. (C) Printing technology is primarily used by Twist and Agilent. (D) Electrochemical synthesis is employed by Custom Array. (E) Antkowiak et al. used light-directed synthesis. (C–E) Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (42). Copyright 2020 Springer Nature.

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A strategy toward decreasing the costs of stored DNA data may be the enzymatic synthesis of DNA strands. (72) This synthesis could, in principle, decrease the costs of reagents even if the required enzymes are still rather expensive. It occurs in aqueous environments and it yields longer strands; however, error rates need to be assessed. A brief review of the principal trends in enzymatic synthesis is provided in section 2.1. The costs of enzymatic synthesis have been estimated by Jensen et al. for a template-independent enzymatic oligonucleotides synthesis (TiEOS) method. (100) The total costs of synthesizing 1000 strands of 1000 nucleotide length would be 136 USD with recycled TdT, 2700 USD by phosphoramidite technique, and 136 000 USD if a fresh stock of TdT was introduced at every cycle. Thus, the costs of the enzymatic synthesis would be 1 order of magnitude lower than the phosphoramidite technique if the TdT was recycled. (100) The combination of advanced error-correcting codes and synchronization algorithms could possibly achieve lower costs of enzymatic DNA synthesis, as recently reported by Tang et al. This strategy allowed the enhancement of the coding rate to more than log23 per unit time and avoidance of deletions. (45) In the future, automation (39) of the reading, writing, and operative procedures, as well as the future developments of microfluidics, may forward DNA data storage toward a reduction of its economic costs. (12)

2.6.2. Issues Related to the Process Time Scales

Besides economic costs, automation could possibly lead to a reduction of the time costs for DNA data storage, as well. Indeed, the time requirements for the process are another limiting factor in the development of DNA data storage. For example, the reading speed is much lower than standard silicon-based storage media. (97) This could be detrimental, especially when the only possible alternative to retrieve a file would be to read the entire database: it would be a very slow process. For these reasons, DNA data storage systems have been proposed for long-term archival purposes (97) that need infrequent reading, while future investigations will be needed to fully realize random access. (78,75,70)
Conversely, in regards to nanopore reads of labeled DNA, each label is read in [10–1; 101] ms. (101,21,102)
The writing speed of DNA data storage is lower than that of standard technologies, too. The current writing speed for DNA archives is in the order of kilobytes/second, thus a reading/writing cycle has a significant cost in terms of time. (8) It is estimated that DNA data storage will need writing speeds in the order of gigabytes/second to be comparable with commercial cloud storage systems in around 10 years. This means DNA data storage must fulfill a gap of 6 orders of magnitude in regard to the writing (i.e., synthesis) and a gap of 2–3 orders of magnitude in regard to the reading (i.e., sequencing). (12)
In order to enhance the read/write speed of DNA data storage, one of the goals should be to make it suitable for frequent data reads and modifications. This is another pivotal reason for the investigations about synthetic polymers as data storage tools, together with the mentioned high cost of DNA. (97)
While writing and reading operations regarding DNA-stored data need to be improved, when it comes to preservation time, DNA is better than current storage technologies. Indeed, the maximum preservation time of information is 50 years for digital memories and 500 years for paper, while it is millennia for inorganic matrix-encapsulated DNA.
In conclusion, DNA data storage presents both advantages and disadvantages with respect to traditional storage methods regarding costs. It is also for this reason that research interest is growing in this field.

3. Structure-Based DNA Data Storage

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3.1. DNA Nanotechnology Versus Synthetic DNA Sequence for Digital Data Storage

DNA nanotechnology may also be employed to overcome the limitations illustrated above in synthesis and reading. Because of the self-assembled nature of DNA nanostructures (Figure 8), it is possible to significantly reduce the synthetic demand and to eliminate the need for next-generation sequencing for DNA data storage. DNA nanotechnology leverages the unparalleled molecular recognition motifs of the nitrogenous bases to create arbitrary two- and three-dimensional structures from the self-assembly of user-defined DNA strands. (24,103) Through careful design of the sequences of these strands, which can be easily synthesized in an automated manner or even purchased from commercial vendors, exquisite control over their final assembly can be realized, thereby enabling the construction of nanoscale shapes and patterns. The main approaches in structural DNA nanotechnology can be divided into three groups: DNA origami, DNA tile assembly, and wireframe DNA structures, (104) all of which have been extensively reviewed elsewhere. (103) Among these, DNA origami is the most widely used method for the construction of DNA-based data storage structures at the nanoscale. Importantly, all of these bottom-up approaches enable the production of asymmetric patterns, which is a key criterion for data storage applications: instead of encoding information directly into the sequence of bases, data may be stored in the three-dimensional shape of these assemblies.

Figure 8

Figure 8. DNA nanostructures are data storage architectures. (A) DNA origami leverages the specific base-pairing motifs of DNA to create arbitrary structures. When a long scaffold strand (several thousand nucleotides in length) is combined with hundreds of short “staple” strands, complementary regions on the different strands will hybridize, thereby folding the scaffold into a desired conformation. These structures can then be examined using (B) atomic force microscopy or (C) electron microscopy, for example. (D) Data can be written onto DNA origami sheets through the site-specific addition of proteins; the data may be read using AFM. (E) Nanoparticles can also be controllably positioned on DNA origami with nanometer-scale resolution, which enables data writing with cryo-EM readout. (A) Image reproduced with permission from ref (108). Copyright Springer Nature 2021. (B) Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (109). Copyright 2019 AAAS. (C) Image reproduced with permission from ref (110). Copyright 2020 Springer Nature. (D) Image reproduced with permission from ref (111). Copyright 2010 Springer Nature. (E) Image reproduced with permission from ref (112). Copyright 2010 Wiley-VCH.

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Because of the noncovalent nature of DNA nanostructures, they can be reconfigured using established strategies, including strand displacement, (26) thermal annealing, (105) and pH changes. (106) The reversible Watson–Crick base pairing means that, unlike data encoded directly into the primary DNA sequence, data storage platforms based on DNA nanostructures can be “erased” and “rewritten” multiple times without requiring any laborious chemical synthesis, which decreases the synthetic demand and cost associated with these methods. (25) Additionally, the reconfigurable nature of these constructs enables their use in data operations and computation, analogous to existing computer memory systems. Because each bit is formed through self-assembly, it is also possible to encrypt information by initially omitting a key element from the assembly mixture; only upon addition of the correct “password” molecule can the DNA-based data be “read.”
Compared with encoding data within the nucleotide sequence itself, data storage based on DNA nanotechnology has one major drawback: data storage density. While data written directly into the DNA sequence theoretically allows 1 exabyte (or 1 billion gigabytes) to be stored in every cubic millimeter of DNA, (107) the data density that has been attained so far using DNA secondary structure is much lower because it requires ∼100 base pairs per bit. (25) That being said, this density is still approximately 3 orders of magnitude higher than current hard drive technologies, with further improvements conceivable through the optimization of the 3D DNA structure. Considering the advantages of encoding information into the secondary structure─including ease of readout, synthetic simplicity, and reconfigurability─this is a minor obstacle and one that may be mitigated through the careful design of DNA nanostructures.

3.2. DNA Nanostructure-Based Information Storage Platforms: Assembly and Readout

When comparing DNA nanostructure data storage to traditional sequence-based methods, the major differences lie in the reading and writing steps. In particular, standard DNA data storage requires slow and costly DNA synthesis, while DNA nanostructures already store molecular data in two- and three-dimensional objects. In fact, the assembly of DNA origami is, itself, a molecular information encoding process, wherein the long scaffold strand is folded with hundreds of short “staples” to form a predetermined structure (Figure 8). The size and morphology of the resulting structures can be assessed using various ensemble and single-molecule characterization methods, thereby enabling the readout of information stored in the shape and structure of these nanoscale assemblies. The use of this suite of techniques (described in detail in the following sections) has two major advantages: (1) Depending on the design and the physical attributes of the data storage structure, it may be possible to perform more than one type of characterization. Comparing the results of different readout methodologies may allow for the identification of systematic biases in each modality, which generates a feedback cycle wherein structures may be improved upon and recharacterized. (2) The identification of larger structures (on the order of approximately tens of nanometers) de facto requires lower resolution than the differentiation of single bases, thereby facilitating the use of less precise techniques without sacrificing accuracy. Additionally, because the single-molecule readout methods used for the assessment of DNA nanostructures are also used in DNA sequencing, these techniques are constantly improving: in this way, the advancement of sequence-based DNA data storage also supports the growth of alternative, structure-based approaches.

3.2.1. Gel Electrophoresis

A first and very simple method to read data is the use of gel electrophoresis, which remains one of the key methods to differentiate DNA nanostructures of different shapes and sizes, as well as to assess their yield. Through the formation of DNA nanostructures with prescribed differences in size, it is possible to encode information and then read this out using the discrete bands formed on a gel. To this end, simple structures involving hairpins, loops, or G-quadruplexes placed along linear DNA backbones can also be used to store digital data. For example, Halvorsen and Wong used the change between a closed loop structure (“1”) to a linear structure (“0”)─which have different elution times by gel electrophoresis─as a binary switch. The authors used electrophoresis to demonstrate the readout of an 11 byte ASCII message. (113) The creation of many loops of different sizes, each distinguishable by gel electrophoresis, offers a greater number of possible bits in each lane (Figure 9A). (114) The formation of loop structures is not the only operation of DNA nanostructures that can be directly probed using gel electrophoresis. In an alternative approach, five single-stranded nucleotides were annealed together to form an assembly with three addressable overhangs; when complementary strands to each of these overhangs were introduced, the site changed from a “0” (single-stranded) to a “1” (double-stranded) state, which could then be reversed using strand displacement. (115) These examples highlight the simple and inexpensive nature of gel electrophoresis as a readout platform, especially when compared with optical, electrochemical, and AFM-based methods. However, the relatively long read times and low data capacity of these methodologies limit their applicability. Gel electrophoresis, being a bulk measurement, also requires substantial quantities of DNA for readout relative to single-molecule methods like AFM, electron microscopies, and nanopore techniques.

Figure 9

Figure 9. Examples of DNA nanostructures for digital information storage. (A) The folding of DNA origami into loop structures upon binding of a biomolecule target generates a shift in the assembly’s electrophoretic mobility. Image adapted with permission under a Creative Commons Attribution 4.0 license (CC BY) from ref (114). Copyright 2017 Oxford University Press. (B) The association of different DNA sequences to carbon nanotubes produces an array of morphologies and, therefore, can be used to produce barcodes. Image adapted from ref (116). Copyright 2019 American Chemical Society. (C). Data strings based on regions of varying fluorescence intensities along a DNA nanotube can be read out using single-molecule fluorescence microscopy. Image adapted from ref (117). Copyright 2021 American Chemical Society.

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3.2.2. Fluorescence

Bulk fluorescence measurements can read out data encoded into DNA nanostructures. In an early example, DNA strands were used as “molecular memory” by transitioning thermally between a hairpin structure (unwritten state) and a duplex structure (written state). (118) The oligonucleotides were appended with fluorophore/quencher pairs; as the thermal cycling occurs, the fluorescence output reversibly switches between two defined states to produce a binary signal. Unfortunately, because this process is performed in solution, the whole memory is erased simultaneously, which highlights the need for alternative strategies that enable spatial addressability. To this end, single-molecule fluorescence methods may be used instead to read out DNA origami breadboards appended with fluorophores. In one approach, termed “polychromic address multiplexing,” DNA origami was separated into spatially resolved “cells,” each of which contained a set of fluorophores appended to DNA. Some of these linkers contain photocleavable groups, which enables the disruption of energy transfer processes between adjacent dyes, thus resulting in a fluorescence change. The switch between two possible intensity values provides the binary logic in this system. (119) Through the use of single-molecule total internal reflection fluorescence (TIRF) microscopy, it is possible to decode fluorescent barcodes assembled on DNA nanostructures. (120) Pan et al. utilized this diffraction-limited imaging technique to devise a method to group fluorophores into bright (“on”) lengths along a DNA origami rod. (121) Such bright spots were separated by dark (“off”) regions to create geometric barcodes using only one color of emitter (Figure 9C). Another tactic used a DNA origami “breadboard,” which was divided into a grid of pixels or an “indexed matrix of digital information.” Each specific location on the origami represents a bit, with the presence (“1”) or absence (“0”) of a docking site for a fluorophore encoding binary information. (22) Docking sites are located using DNA points accumulation for imaging in nanoscale topography (DNA-PAINT), a form of super resolution fluorescence imaging that relies on transient binding of short DNA strands to prepositioned sites on an origami structure. (122) In this example, unique data patterns are created by selecting which staple strands within the origami possess data domains. This approach also uses error-correction algorithms that enable message recovery even when individual docking sites are missing. Unlike DNA sequencing, which requires multiple reads to reach a consensus, this tactic can read 750 origami to reach a 100% probability of full data retrieval, which means that only femtomoles of material are needed.

3.2.3. Atomic Force Microscopy

Early examples of DNA origami were reported in the mid 2000s and involved the assembly of 2D arrays to form various images, including the letters of the alphabet, (123) a nanoscale Mona Lisa, (124) and a map of the Americas. (125) Atomic force microscopy (AFM) was used to “read-out” images formed by DNA origami, and this remains a key technique for the study of DNA-based nanomaterials. (126) AFM measurements detect differences in height over a sample surface, without affecting the sample, thus rendering this method ideally suited to reading out three-dimensional patterns on DNA origami. Binary information can be written by precisely placing nanoparticles or proteins at defined positions on a DNA breadboard. In the context of DNA data storage, Zhang et al. demonstrated in 2019 (127) a “DNA braille” system, which was prepared by patterning biotinylated overhangs onto DNA origami. The data in this system are encrypted; only when streptavidin is added and binds to biotin does the pattern become readable by AFM. The decryption time for this method is 1–2 h, including sample processing, imaging, and readout─this time could be reduced by using high-speed AFM methods and fully automated image analysis algorithms. Similarly, Fan et al. used AFM to decode information stored in DNA domino arrays. (127) The use of DNA overhangs bearing streptavidin enables the use of strand displacement reactions to controllably erase and rewrite data on the DNA origami surface, (128) thereby underlining the advantages of DNA nanotechnology as an information storage platform. AFM is also suitable to look at DNA positioned on other types of nanomaterials; for example, it was found that condensing DNA strands onto carbon nanotubes creates height differences that were observable by AFM (Figure 9B). Control of the patterning of these protrusions, which interestingly do not rely on DNA hybridization, may allow for the production of two-dimensional barcodes on carbon nanotubes. (116)

3.2.4. Electron Microscopy

Relying on similar principles, the decoding of DNA nanostructures can also be achieved using electron microscopy (EM). DNA itself can be difficult to visualize using EM because of insufficient electron density-related contrast, and therefore, often requires staining. As such, EM is better suited to the examination of hybrid structures, wherein the DNA is used to create “barcodes” made of gold nanoparticles, (129) for example. Different barcodes can then be used to track the cellular uptake of various nanostructures because EM allows for the identification of subcellular compartments. EM exhibits some of the same advantages and pitfalls of AFM: while these techniques allow for high-resolution two- and three-dimensional images to be formed of DNA nanostructures, they are time-consuming and expensive, as well as relatively low-throughput. As cryo-EM and liquid-cell EM techniques continue to improve, the direct imaging of biomolecules might offer an alternative in the future with better resolution on the single-molecule level even without the use of staining or nanoparticles.

3.2.5. Nanopore Measurements

More recently, through the use of long DNA backbones as in DNA origami, the organization of DNA protrusions has been used to produce three-dimensional DNA barcodes (21) or hard drives that may be read using solid-state nanopores. Nanopore methods require no labeling for readout, which makes them an attractive alternative to fluorescence. Briefly, an electric field is applied across a nanoscale hole (made from glass or Si3N4, for example), which causes molecules to translocate through this nanopore. As the analyte passes, it modulates the ionic current signal because of its 3D shape blocking the pore─in this way, the structure of the DNA nanoconstruct is translated directly into an electrical signal (Figure 10). The resulting current–time traces can then be analyzed using automated methods, which allows for rapid data decoding.

Figure 10

Figure 10. DNA data storage structures relying on nanopore readout. (A) An encrypted “DNA hard drive,” wherein readout may only occur once the correct molecular “keywords” have been added. Streptavidin molecules (gray circle in inset) partially block the nanopore as they translocate, which causes a momentary decrease in the current. Image reproduced from ref (25). Copyright 2020 American Chemical Society. (B) Multilevel barcoding is achievable by exploiting DNA junctions with different sizes, which create current drops of variable magnitude. Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (102). Copyright 2021 Wiley-VCH. (C) A DNA barcode with “structural colors” can also be formed by closely packing structural units, which therefore read as one protrusion. These units may be based on either monovalent streptavidin or a DNA cuboid. (D) Nanopore microscope can be used to detect up to 10 structural colors within the same DNA data string. The correct identification of the “color” was verified using fluorescence microscopy, wherein fluorescently labeled (5′-fluorescein) structural units were used. (C,D) Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (130). Copyright 2022 Springer Nature.

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The use of nanopores to read out digital information encoded in DNA nanostructures was demonstrated by Bell and Keyser, who fabricated “DNA barcodes” to capture proteins. (21) The authors used conical quartz nanopores with diameters of ∼14 nm for a 3-bit barcode that could be assigned with 94% accuracy. Now, these quartz nanopores can read out DNA hairpins along a carrier strand with a density of approximately 1 bit per 30 nm─ca. 3 times the data density of conventional hard drives. (25) One of the major benefits of this method is their high speed: a single “DNA hard drive” can be read out on the millisecond time scale using a quartz nanopore because of the superior signal-to-noise ratio when compared with DNA sequencing. Solid-state nanopores combined with DNA nanotechnology have since been used to save and encrypt a grayscale image. (102) Streptavidin-labeled scaffolds can also be used to create a secure data storage system that requires the correct molecular “keywords” to decode the data within the structure (Figure 10A). Multilevel storage architectures have been achieved using different DNA junction sizes to create a quaternary encoding system (Figure 10B). (102) Increased storage density beyond binary barcodes can also be achieved by creating blocks of repeating structural units that appear as a single protrusion within the nanopore, which creates “structural colors” to generate up to 10 data levels. (130) Compared with fluorescence, sequencing, or gel electrophoresis-based strategies, single-molecule nanopore measurements require less material and enable faster data reading; through a combination of this technology with deep learning methods, (131) real-time nanopore data analysis is attainable.
Another important feature is random access, as demonstrated in 2021 by Bošković et al. (101) In their work, random access of DNA barcodes was performed by exploiting a modified PCR method to increase the number of the target DNA nanostructures. Indeed, DNA structural barcodes were annealed as short oligonucleotides containing protrusions on single-stranded DNA (ssDNA) scaffolds to form digital bits at precise locations. In these structures, DNA nicks were ligated to favor the copy of the barcode by PCR. Each of these structures had a noncomplementary end, which acted as a barcode-specific primer template for the random access of data.

3.2.6. Alternative Approaches and Polymer Chemistries

The use of double-stranded DNA as a storage medium was also exploited in recent work by Tabatabaei et al. (72) on DNA punch cards. This macromolecular storage technology was used to encode the information in the sequence of bases of the DNA strands by using their sugar–phosphate backbone, i.e., topologically. Indeed, a pattern of nicking positions was precisely realized on the backbone of native dsDNA, and here, information was encoded by means of absence (i.e., 0) or presence (i.e., 1) of nicks. On the basis of enzymatic modification of DNA, nicks enable adding several functionalities to the storage system, for example, single-bit random access, pooling, and in-memory computation. However, the DNA punch cards system was able to store only up to 14 kB of digital information. Therefore, additional research is foreseen toward scaling its costs.
DNA as a natural polymer is not the only solution for data storage technologies. Therefore, researchers started to look for alternative molecular storage platforms based on synthetic polymers. Synthetic polymers can be used to increase stability against chemical degradation while offering a wide range of base modifications. Although alternative DNA bases have been introduced, synthetic polymers could be prepared using a set of monomers with a wider set of codes which expands the alphabet for data encoding. (97) First experiments reading single-stranded synthetic biopolymers indicate that the reading step can be performed with biological nanopores without the use of an enzyme slowing down the translocation. (132) As an example, Cao et al. used informational biopolymers composed of a backbone of poly(phosphodiesters) with dideoxyadenosine at both ends, and engineered-aerolysin nanopores. The results suggest a path to single-bit resolution at least in short polymers, however machine learning and training are needed for the successful readout. The study suggests an alternative way to store information with high density. The idea to use the backbone of an organic polymer to store digital information is similar to the approach discussed for DNA nanostructures.
Apart from DNA, other organic molecules have been recently proposed. (133,134) Two interesting examples are the use of peptide sequences for data storage, as reported by Ng et al. (133) and the use of urethanes as reported by Dahlhauser et al. (134) Unfortunately in both these cases, reading required the use of mass spectroscopy, with the consequent limitation in terms of costs and speed. Recent advances in nanopore-based readout of short peptide sequences (135) may speed up developments in this area. (53)

3.3. DNA Nanotechnology for Molecular Computation

The storage of data in DNA is undoubtedly an exciting possible solution to our ever-expanding data storage needs. This technology may lead to future hybrid electronic–biomolecular computing systems in which some portion of the burden of data storage is supported by DNA encoding, which raises the question: “Can more of the computer system’s functions be carried out using DNA?” By reducing the time overhead of conversion to a digital format and directly undertaking data processing tasks with DNA-based computation, it may be possible to create molecular computing systems that are more efficient than conventional electronic analogues. Because of the noncovalent nature of DNA nanostructures, these materials are primed for use in molecular computation. A working prototype for a DNA computer was developed by Adleman in 1994, (136) wherein he used a separation-based approach to calculate a Hamiltonian path in a graph with seven summits. This problem was particularly suited to a molecular computing approach because it is an NP-complete problem; while verification of a putative solution has a complexity that is linear with respect to the number of nodes, the path space search is exponential in complexity with respect to the same. In a DNA computer, however, each DNA molecule plays the part of a separate processor, which enables many parallel operations to be carried out in a small reaction volume. This strategy greatly accelerates the initial path search, as statistics predict that DNA constructs corresponding to every possible path should be produced upon mixing. The task is then reduced to one of selection and filtering by removing invalid paths. The Adleman experiment acted as a proof of concept: in practice, the process was more time- and labor-intensive than a conventional digital approach. Nonetheless, the possibility of a DNA-based computer inspired researchers to further develop Adleman’s method and to devise advanced and powerful general DNA computing solutions. Early experimental and theoretical work examining the possibilities of DNA computation was focused on this parallelization and the benefits that it offered with regard to efficiently solving other NP-complete problems. (137,138) Recent work on DNA computation has moved away from such problems toward recreating deterministic logical operations, for example, addition (139) and multiplication, (140) with definite outcomes. Su et al. produced DNA logic cascades, which allows the buildup of a full adder, a 4:1 multiplexer, and then, they combined these with other logic circuits to produce a DNA arithmetic logic unit (ALU): the foundation of general-purpose processors. (139) These applications demonstrate the methods that can be used to mitigate error in DNA computation, which arise from the leeway and tolerance of mismatch inherent in sequence-specific DNA hybridization.
Larger engineered DNA nanostructures show great promise for use in biomolecular computation as well as small origami structures. Robust, rigid DNA tiles with programmable “sticky ends” have been made using double-crossover (DX), (141) triple-crossover (TX), (142) and single-stranded tile (SST) (143) motifs and used for a variety of algorithmic self-assembly experiments. This is facilitated by the logical equivalence of these tiles with Wang tiles, which are theoretical constructs with specified interactions that can simulate a Turing machine. A correctly designed, self-assembling set of these tiles is theoretically able to perform any computation that can be carried out by a conventional computer. Past applications of this idea include the design of a set of TX tiles that carry out a cumulative XOR operation, a set of DX tiles that self-assemble into a Sierpinski triangle, and impressively, a set of 355 SSTs that can be used to produce a variety of cellular automata capable of carrying out a number of computational tasks (Figure 11). (144) Particularly interesting in the latter example is the ability to controllably reintroduce indeterminism by including a plurality of tiles that could fill a given niche and leaving the ultimately realized pattern up to competition. This brings about a marriage of the benefits of deterministic logic and the power of indeterministic computing to solve combinatorial problems, thereby highlighting the utility of DNA nanotechnology not only for data storage but also for molecular computation.

Figure 11

Figure 11. Tile-based computations and algorithmic self-assembly. (A) Self-assembly by SSTs. From a seed, tiles attach to the frontier of a growing SST lattice according to interaction rules determined by their exposed recognition sequences. (B) An iterated Boolean circuit mimicking the function of a computation to determine whether or not a binary number is a multiple of 310. A long enough lattice will settle into one or another fixed pattern corresponding to the calculation result. (C) The result of four “multiple of 3” tilings. The numbers at the left mark the experiment number. The tilings correctly determine which input numbers have a factor of 3. (A–C) Images adapted with permission from ref (144). Copyright 2019 Springer Nature. (D) A Sierpinski triangle created by a cumulative XOR computation performed by DNA tiles. Sierpinski’s triangle is a fractal pattern, and the self-assembly rule that creates it is Turing complete. Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (145). Copyright 2004 PLoS Biology.

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4. Conclusions and Outlook

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DNA data storage─both the sequence- and structure-based versions─offers the possibility of storing digital information at very high data density. This promise has led a large number of actors (public and private institutions, corporations, etc.) to invest on the quest for advanced methods and experiments. Although great advances have been made toward DNA data storage, it is not yet competitive against conventional storage technologies. Significant challenges need to be overcome, in particular regarding writing speed and, hence, cost. While stored data size has been markedly increased, the current record for DNA digital data storage is still around 200 MB, with single synthesis runs lasting about 24 h. (8,12) Achieving the storage of TBs of data at a low cost is unattainable with the current techniques. Toward this goal, great efforts on the development of encoding schemes, writing and reading processes, and storage procedures are presently being made. (146,9,81,44,74,14)
As the chemical and enzymatic processes for making sequence-defined nucleic acids continue to improve, the cost and time associated with writing DNA-based information is continually decreasing. These improvements are particularly important for sequence-based storage, but they importantly reduce costs for structure-based approaches, as well. Additionally, as alternative chemistries emerge, including unnatural nucleotides (147) and small molecules that can modulate the structure of DNA, (148) the parameter space for structure- and sequence-based DNA data storage is continually expanding. Importantly, these chemistries not only widen the breadth of materials that can be produced, but also may further extend the lifetime of DNA sequences, as these modifications render DNA less recognizable to enzymes.
For data readout, DNA sequencing is rapidly advancing, but current methods would be incompatible with unnatural monomer units, which limits the scope of the methods. Furthermore, all current DNA sequencing techniques require molecular machines like polymerases, which set fundamental limits for the throughput per enzyme, thereby meaning there is an upper threshold on the rate of sequencing even with massive parallelization. Emerging, rapid approaches to establish polymer sequence or three-dimensional structure one molecule at the time will improve the competitiveness of DNA data storage. Both natural and chemically modified oligonucleotides, as well as hybrid nanostructures involving DNA and quantum dots or nanoparticles, may be read out using solid-state nanopores. The versatility of this methodology, which hinges on the possibility of finely tuning nanopore size, makes this an attractive avenue for the future characterization of both pure DNA and composite materials. Through the use of quantum dots or fluorescent dyes, nanopore readout may be also combined with optical techniques to reduce the readout error rate without requiring enzymes to slow translocation. (149) While the use of higher order nanostructures or composite nanomaterials does sacrifice data density, the advantages of these methods are expected to outweigh this drawback. In terms of synthesis, DNA nanotechnology greatly simplifies assembly procedures and produces structures that can easily be reconfigured. Indeed, computation is a natural extension for DNA nanotechnology, especially considering the vast library of naturally evolved enzymes that nature uses to copy, change, and repair genetic information. The interface between these natural systems and DNA nanotechnology is an active area of research, which generates other possibilities for DNA data storage that leverage nature’s evolved machinery. We foresee that DNA nanostructures made for information storage will find audiences in cryptography, steganography, and other fields (4,58,116) and that combining DNA data storage with data analysis techniques such as neural networks will afford opportunities in a growing number of sectors. (127)
Because of the long-term stability of DNA under appropriate storage conditions, we predict that archival storage will be the most valuable application for DNA data storage. In this cold storage setting, information would be infrequently accessed from a relatively static DNA database. Considering that long-term, archival storage (97) operates over long time scales─decades, centuries, and possibly millennia─this application requires only infrequent access to the stored information, which substantially reduces the impact of reading costs and long read times associated with DNA data storage. While the long-term stability of DNA, itself, is firmly established, further studies on the lifetimes of noncovalently assembled DNA nanostructures will need to be conducted to ensure that data stored in these formats are not compromised over time. Specifically, encapsulation and retrieval of DNA nanostructures in silica beads and other matrices should be examined, as well as the readability of DNA nanomaterials after prolonged freezing. It is also important to mention that the preservation of DNA digital archives can be implemented using not only in vitro substrates but also in vivo approaches. (150−153) As three-dimensional nucleic acid nanostructures have also successfully been produced inside cells, (154) there is potentially important synergy between in vitro/in vivo DNA nanotechnology and data storage, which remains, as of yet, unexplored.
Even in the context of archival storage, a DNA database, like its electronic analogues, would benefit greatly from dynamic properties that allow data to be erased, rewritten, and updated. For example, in-storage file operations and computations, as well as the ability to repeatedly access DNA databases, would reduce DNA synthesis costs and abrogate the need to store multiple copies of archives. In this area, DNA nanostructures may present advantages over traditional sequence-based storage methods, as the reconfiguration of these supramolecular moieties is firmly established, though rarely in the context of information storage. The implementation of dynamic properties and a full characterization of the kinetics of these processes would bring DNA-based storage systems one step closer to practical viability. (78)
A combination of sequence- and structure-based approaches could represent a significant advancement to overcome the various hurdles associated with DNA data storage. For this field to reach its full potential, cooperation between scientists from a range of research areas will be essential to produce the advanced chemical techniques, instrumentation, characterization methods, and automated analysis tools that are required. As the wide range of topics, from mathematics to polymer chemistry, shows, data storage based on polymers will demand multidisciplinary consortia that ideally design the whole process from data encoding to decoding with a bottom-up approach.

Author Information

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  • Corresponding Authors
  • Authors
    • Andrea Doricchi - Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy;  Dipartimento di Chimica e Chimica Industriale, Università di Genova, via Dodecaneso 31, 16146 Genova, Italy
    • Casey M. Platnich - Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, U.K.;  Orcidhttps://orcid.org/0000-0002-3634-4580
    • Andreas Gimpel - Institute for Chemical and Bioengineering, ETH Zurich, Vladimir-Prelog-Weg 1, 8093 Zurich, Switzerland;  Orcidhttps://orcid.org/0000-0002-8890-3292
    • Friederikee Horn - Technical University of Munich, Department of Electrical and Computer Engineering Munchen, Bayern, DE 80333, Germany
    • Max Earle - Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, U.K.
    • German Lanzavecchia - Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy;  Dipartimento di Fisica, Università di Genova, via Dodecaneso 33, 16146 Genova, Italy
    • Aitziber L. Cortajarena - Center for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain;  Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain;  Orcidhttps://orcid.org/0000-0002-5331-114X
    • Luis M. Liz-Marzán - Center for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain;  Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain;  Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain;  Orcidhttps://orcid.org/0000-0002-6647-1353
    • Na Liu - Second Physics Institute, University of Stuttgart, 70569 Stuttgart, Germany;  Max Planck Institute for Solid State Research, 70569 Stuttgart, Germany
    • Reinhard Heckel - Technical University of Munich, Department of Electrical and Computer Engineering Munchen, Bayern, DE 80333, Germany
    • Robert N. Grass - Institute for Chemical and Bioengineering, ETH Zurich, Vladimir-Prelog-Weg 1, 8093 Zurich, Switzerland;  Orcidhttps://orcid.org/0000-0001-6968-0823
    • Roman Krahne - Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy;  Orcidhttps://orcid.org/0000-0003-0066-7019
  • Author Contributions

    The authors contributed equally to this work.

  • Funding

    The research leading to these results has received funding from the European Union under the Horizon 2020 Program, FET-Open: DNA-FAIRYLIGHTS, Grant Agreement No. 964995.

  • Notes
    The authors declare no competing financial interest.

Vocabulary

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sequence-based DNA data storage

storage approach in which information is stored in the nucleotide sequence of many individual DNA strands

structure-based DNA data storage

storage approach in which DNA is designed in a way that allows information to be stored in its structural features, e.g., 2D and 3D shape

data encoding with error-correcting codes

conversion from digital, binary data into the primary sequence (sequence-based) or 2D/3D structure (structure-based) of DNA by adding redundancy to counteract errors and partial data loss

random access

process by which a certain subset of information is selected (e.g., a single file) from a large pool of information

reading

process by which the data encoded in DNA are read; this process varies according to if the DNA data storage is sequence-based or storage-based

decoding

conversion of the information that was read from DNA into binary data; this conversion happens both in sequence-based and in structure-based DNA data storage

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    Goldman, Nick; Bertone, Paul; Chen, Siyuan; Dessimoz, Christophe; LeProust, Emily M.; Sipos, Botond; Birney, Ewan
    Nature (London, United Kingdom) (2013), 494 (7435), 77-80CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Digital prodn., transmission and storage have revolutionized how we access and use information but have also made archiving an increasingly complex task that requires active, continuing maintenance of digital media. This challenge has focused some interest on DNA as an attractive target for information storage because of its capacity for high-d. information encoding, longevity under easily achieved conditions and proven track record as an information bearer. Previous DNA-based information storage approaches have encoded only trivial amts. of information or were not amenable to scaling-up, and used no robust error-correction and lacked examn. of their cost-efficiency for large-scale information archival. Here we describe a scalable method that can reliably store more information than has been handled before. We encoded computer files totalling 739 kilobytes of hard-disk storage and with an estd. Shannon information of 5.2 × 106 bits into a DNA code, synthesized this DNA, sequenced it and reconstructed the original files with 100% accuracy. Theor. anal. indicates that our DNA-based storage scheme could be scaled far beyond current global information vols. and offers a realistic technol. for large-scale, long-term and infrequently accessed digital archiving. In fact, current trends in technol. advances are reducing DNA synthesis costs at a pace that should make our scheme cost-effective for sub-50-yr archiving within a decade.
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  10. 10
    Meiser, L. C.; Nguyen, B. H.; Chen, Y. J.; Nivala, J.; Strauss, K.; Ceze, L.; Grass, R. N. Synthetic DNA Applications in Information Technology. Nat. Commun. 2022, 13 (1), 1– 13,  DOI: 10.1038/s41467-021-27846-9
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  11. 11
    Meiser, L. C.; Antkowiak, P. L.; Koch, J.; Chen, W. D.; Kohll, A. X.; Stark, W. J.; Heckel, R.; Grass, R. N. Reading and Writing Digital Data in DNA. Nat. Protoc 2020, 15 (1), 86– 101,  DOI: 10.1038/s41596-019-0244-5
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    11
    Reading and writing digital data in DNA
    Meiser, Linda C.; Antkowiak, Philipp L.; Koch, Julian; Chen, Weida D.; Kohll, A. Xavier; Stark, Wendelin J.; Heckel, Reinhard; Grass, Robert N.
    Nature Protocols (2020), 15 (1), 86-101CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
    In this work, we provide instructions for archiving digital information in the form of DNA and for subsequently retrieving it from the DNA. In principle, information can be represented in DNA by simply mapping the digital information to DNA and synthesizing it. However, imperfections in synthesis, sequencing, storage and handling of the DNA induce errors within the mols., making error-free information storage challenging. Along with the protocol, we provide computer code that automatically encodes digital information to DNA sequences and decodes the information back from DNA to a digital file. The required software is provided on a Github repository. The protocol relies on com. DNA synthesis and DNA sequencing via Illumina dye sequencing, and requires 1-2 h of prepn. time, 1/2 d for sequencing prepn. and 2-4 h for data anal. This protocol focuses on storage scales of ~ 100 kB to 15 MB, offering an ideal starting point for small expts. It can be augmented to enable higher data vols. and random access to the data and also allows for future sequencing and synthesis technologies, by changing the parameters of the encoder/decoder to account for the corresponding error rates.
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  12. 12
    Ceze, L.; Nivala, J.; Strauss, K. Molecular Digital Data Storage Using DNA. Nat. Rev. Genet 2019, 20 (8), 456– 466,  DOI: 10.1038/s41576-019-0125-3
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    12
    Molecular digital data storage using DNA
    Ceze, Luis; Nivala, Jeff; Strauss, Karin
    Nature Reviews Genetics (2019), 20 (8), 456-466CODEN: NRGAAM; ISSN:1471-0056. (Nature Research)
    A review. Mol. data storage is an attractive alternative for dense and durable information storage, which is sorely needed to deal with the growing gap between information prodn. and the ability to store data. DNA is a clear example of effective archival data storage in mol. form. In this Review, we provide an overview of the process, the state of the art in this area and challenges for mainstream adoption. We also survey the field of in vivo mol. memory systems that record and store information within the DNA of living cells, which, together with in vitro DNA data storage, lie at the growing intersection of computer systems and biotechnol.
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    Song, X.; Reif, J. Nucleic Acid Databases and Molecular-Scale Computing. ACS Nano 2019, 13 (6), 6256– 6268,  DOI: 10.1021/acsnano.9b02562
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    13
    Nucleic Acid Databases and Molecular-Scale Computing
    Song, Xin; Reif, John
    ACS Nano (2019), 13 (6), 6256-6268CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. DNA outperforms most conventional storage media in terms of information retention time, phys. d., and volumetric coding capacity. Advances in synthesis and sequencing technologies have enabled implementations of large synthetic DNA databases with impressive storage capacity and reliable data recovery. Several robust DNA storage architectures featuring random access, error correction, and content rewritability have been constructed with the potential for scalability and cost redn. We survey these recent achievements and discuss alternative routes for overcoming the hurdles of engineering practical DNA storage systems. We also review recent exciting work on in vivo DNA memory including intracellular recorders constructed by programmable genome editing tools. Besides information storage, DNA could serve as a versatile mol. computing substrate. We highlight several state-of-the-art DNA computing techniques such as strand displacement, localized hybridization chain reactions, and enzymic reaction networks. We summarize how these simple primitives have facilitated rational designs and implementations of in vitro DNA reaction networks that emulate digital/analog circuits, artificial neural networks, or nonlinear dynamic systems. We envision these modular primitives could be strategically adapted for sophisticated database operations and massively parallel computations on DNA databases. We also highlight in vivo DNA computing modules such as CRISPR logic gates for building scalable genetic circuits in living cells. To conclude, we discuss various implications and challenges of DNA-based storage and computing, and we particularly encourage innovative work on bridging these two areas of research to further explore mol. parallelism and near-data processing. Such integrated mol. systems could lead to far-reaching applications in biocomputing, security, and medicine.
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  14. 14
    Erlich, Y.; Zielinski, D. DNA Fountain Enables a Robust and Efficient Storage Architecture. Science 2017, 355 (6328), 950– 954,  DOI: 10.1126/science.aaj2038
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    14
    DNA Fountain enables a robust and efficient storage architecture
    Erlich, Yaniv; Zielinski, Dina
    Science (Washington, DC, United States) (2017), 355 (6328), 950-954CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    DNA is an attractive medium to store digital information. Here the authors report a storage strategy, called DNA Fountain, that is highly robust and approaches the information capacity per nucleotide. Using the approach, the authors stored a full computer operating system, movie, and other files with a total of 2.14 × 106 bytes in DNA oligonucleotides and perfectly retrieved the information from a sequencing coverage equiv. to a single tile of Illumina sequencing. The authors also tested a process that can allow 2.18 × 1015 retrievals using the original DNA sample and were able to perfectly decode the data. Finally, the authors explored the limit of the architecture in terms of bytes per mol. and obtained a perfect retrieval from a d. of 215 petabytes per g of DNA, orders of magnitude higher than previous reports.
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    Caruthers, M. H. A Brief Review of DNA and RNA Chemical Synthesis. Biochem. Soc. Trans. 2011, 39 (2), 575– 580,  DOI: 10.1042/BST0390575
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    15
    A brief review of DNA and RNA chemical synthesis
    Caruthers, Marvin H.
    Biochemical Society Transactions (2011), 39 (2), 575-580CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)
    A review. Current methodologies used to synthesize DNA and RNA are reviewed. These focus on using controlled pore glass and microarrays on glass slides.
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  16. 16
    Lee, H. H.; Kalhor, R.; Goela, N.; Bolot, J.; Church, G. M. Terminator-Free Template-Independent Enzymatic DNA Synthesis for Digital Information Storage. Nat. Commun. 2019, 10, 2383,  DOI: 10.1038/s41467-019-10258-1
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    16
    Terminator-free template-independent enzymatic DNA synthesis for digital information storage
    Lee Henry H; Kalhor Reza; Church George M; Lee Henry H; Kalhor Reza; Church George M; Goela Naveen; Bolot Jean
    Nature communications (2019), 10 (1), 2383 ISSN:.
    DNA is an emerging medium for digital data and its adoption can be accelerated by synthesis processes specialized for storage applications. Here, we describe a de novo enzymatic synthesis strategy designed for data storage which harnesses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT) in kinetically controlled conditions. Information is stored in transitions between non-identical nucleotides of DNA strands. To produce strands representing user-defined content, nucleotide substrates are added iteratively, yielding short homopolymeric extensions whose lengths are controlled by apyrase-mediated substrate degradation. With this scheme, we synthesize DNA strands carrying 144 bits, including addressing, and demonstrate retrieval with streaming nanopore sequencing. We further devise a digital codec to reduce requirements for synthesis accuracy and sequencing coverage, and experimentally show robust data retrieval from imperfectly synthesized strands. This work provides distributive enzymatic synthesis and information-theoretic approaches to advance digital information storage in DNA.
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    Lee, H.; Wiegand, D. J.; Griswold, K.; Punthambaker, S.; Chun, H.; Kohman, R. E.; Church, G. M. Photon-Directed Multiplexed Enzymatic DNA Synthesis for Molecular Digital Data Storage. Nat. Commun. 2020, 11, 5246,  DOI: 10.1038/s41467-020-18681-5
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    17
    Photon-directed multiplexed enzymatic DNA synthesis for molecular digital data storage
    Lee, Howon; Wiegand, Daniel J.; Griswold, Kettner; Punthambaker, Sukanya; Chun, Honggu; Kohman, Richie E.; Church, George M.
    Nature Communications (2020), 11 (1), 5246CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: New storage technologies are needed to keep up with the global demands of data generation. DNA is an ideal storage medium due to its stability, information d. and ease-of-readout with advanced sequencing techniques. However, progress in writing DNA is stifled by the continued reliance on chem. synthesis methods. The enzymic synthesis of DNA is a promising alternative, but thus far has not been well demonstrated in a parallelized manner. Here, we report a multiplexed enzymic DNA synthesis method using maskless photolithog. Rapid uncaging of Co2+ ions by patterned UV light activates Terminal deoxynucleotidyl Transferase (TdT) for spatially-selective synthesis on an array surface. Spontaneous quenching of reactions by the diffusion of excess caging mols. confines synthesis to light patterns and controls the extension length. We show that our multiplexed synthesis method can be used to store digital data by encoding 12 unique DNA oligonucleotide sequences with video game music, which is equiv. to 84 trits or 110 bits of data.
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  18. 18
    Kubista, M.; Andrade, J. M.; Bengtsson, M.; Forootan, A.; Jonák, J.; Lind, K.; Sindelka, R.; Sjöback, R.; Sjögreen, B.; Strömbom, L.; Ståhlberg, A.; Zoric, N. The Real-Time Polymerase Chain Reaction. Mol. Aspects Med. 2006, 27 (2–3), 95– 125,  DOI: 10.1016/j.mam.2005.12.007
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    18
    The real-time polymerase chain reaction
    Kubista, Mikael; Andrade, Jose Manuel; Bengtsson, Martin; Forootan, Amin; Jonak, Jiri; Lind, Kristina; Sindelka, Radek; Sjoeback, Robert; Sjoegreen, Bjoern; Stroembom, Linda; Stahlberg, Anders; Zoric, Neven
    Molecular Aspects of Medicine (2006), 27 (2-3), 95-125CODEN: MAMED5; ISSN:0098-2997. (Elsevier B.V.)
    A review. The scientific, medical, and diagnostic communities have been presented the most powerful tool for quant. nucleic acids anal.: real-time PCR [Bustin, S.A., 2004. A-Z of Quant. PCR. IUL Press, San Diego, CA]. This new technique is a refinement of the original Polymerase Chain Reaction (PCR) developed by Kary Mullis and coworkers in the mid-80s, for which Kary Mullis was awarded the 1993 Nobel prize in Chem. By PCR essentially any nucleic acid sequence present in a complex sample can be amplified in a cyclic process to generate a large no. of identical copies that can readily be analyzed. This made it possible, for example, to manipulate DNA for cloning purposes, genetic engineering, and sequencing. But as an anal. technique the original PCR method had some serious limitations. By first amplifying the DNA sequence and then analyzing the product, quantification was exceedingly difficult since the PCR gave rise to essentially the same amt. of product independently of the initial amt. of DNA template mols. that were present. This limitation was resolved in 1992 by the development of real-time PCR by Higuchi et al. In real-time PCR the amt. of product formed is monitored during the course of the reaction by monitoring the fluorescence of dyes or probes introduced into the reaction that is proportional to the amt. of product formed, and the no. of amplification cycles required to obtain a particular amt. of DNA mols. is registered. Assuming a certain amplification efficiency, which typically is close to a doubling of the no. of mols. per amplification cycle, it is possible to calc. the no. of DNA mols. of the amplified sequence that were initially present in the sample. With the highly efficient detection chemistries, sensitive instrumentation, and optimized assays that are available today the no. of DNA mols. of a particular sequence in a complex sample can be detd. with unprecedented accuracy and sensitivity sufficient to detect a single mol. Typical uses of real-time PCR include pathogen detection, gene expression anal., single nucleotide polymorphism (SNP) anal., anal. of chromosome aberrations, and most recently also protein detection by real-time immuno PCR.
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    Shendure, J.; Balasubramanian, S.; Church, G. M.; Gilbert, W.; Rogers, J.; Schloss, J. A.; Waterston, R. H. DNA Sequencing at 40: Past, Present and Future. Nature 2017, 550 (7676), 345,  DOI: 10.1038/nature24286
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    19
    DNA sequencing at 40: past, present and future
    Shendure, Jay; Balasubramanian, Shankar; Church, George M.; Gilbert, Walter; Rogers, Jane; Schloss, Jeffery A.; Waterston, Robert H.
    Nature (London, United Kingdom) (2017), 550 (7676), 345-353CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    This review commemorates the 40th anniversary of DNA sequencing, a period in which we have already witnessed multiple technol. revolutions and a growth in scale from a few kilobases to the first human genome, and now to millions of human and a myriad of other genomes. DNA sequencing has been extensively and creatively repurposed, including as a 'counter' for a vast range of mol. phenomena. We predict that in the long view of history, the impact of DNA sequencing will be on a par with that of the microscope.
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  20. 20
    Heckel, R.; Mikutis, G.; Grass, R. N. A Characterization of the DNA Data Storage Channel. Sci. Rep 2019, 9 (1), 1– 12,  DOI: 10.1038/s41598-019-45832-6
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    20
    The MyoRobot technology discloses a premature biomechanical decay of skeletal muscle fiber bundles derived from R349P desminopathy mice
    Haug, Michael; Meyer, Charlotte; Reischl, Barbara; Proelss, Gerhard; Vetter, Kristina; Iberl, Julian; Nuebler, Stefanie; Schuermann, Sebastian; Rupitsch, Stefan J.; Heckel, Michael; Poeschel, Thorsten; Winter, Lilli; Herrmann, Harald; Clemen, Christoph S.; Schroeder, Rolf; Friedrich, Oliver
    Scientific Reports (2019), 9 (1), 1-10CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Mutations in the Des gene coding for the muscle-specific intermediate filament protein desmin lead to myopathies and cardiomyopathies. We previously generated a R349P desmin knock-in mouse strain as a patient-mimicking model for the corresponding most frequent human desmin mutation R350P. Since nothing is known about the age-dependent changes in the biomechanics of affected muscles, we investigated the passive and active biomechanics of small fiber bundles from young (17-23 wks), adult (25-45 wks) and aged (>60 wks) heterozygous and homozygous R349P desmin knock-in mice in comparison to wild-type littermates. We used a novel automated biomechatronics platform, the MyoRobot, to perform coherent quant. recordings of passive (resting length-tension curves, visco-elasticity) and active (caffeine-induced force transients, pCa-force, 'slack-tests') parameters to det. age-dependent effects of the R349P desmin mutation in slow-twitch soleus and fast-twitch extensor digitorum longus small fiber bundles. We demonstrate that active force properties are not affected by this mutation while passive steady-state elasticity is vastly altered in R349P desmin fiber bundles compatible with a pre-aged phenotype exhibiting stiffer muscle prepns. Visco-elasticity on the other hand, was not altered. Our study represents the first systematic age-related characterization of small muscle fiber bundle prepn. biomechanics in conjunction with inherited desminopathy.
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    Bell, N. A. W.; Keyser, U. F. Digitally Encoded DNA Nanostructures for Multiplexed, Single-Molecule Protein Sensing with Nanopores. Nat. Nanotechnol 2016, 11 (7), 645– 651,  DOI: 10.1038/nnano.2016.50
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    21
    Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores
    Bell, Nicholas A. W.; Keyser, Ulrich F.
    Nature Nanotechnology (2016), 11 (7), 645-651CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    The simultaneous detection of a large no. of different analytes is important in bionanotechnol. research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, highly multiplexed sensing of single mols. can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, the authors designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signaled by the presence or absence of multiple DNA dumbbell hairpins. A 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows the authors to simultaneously detect four different antibodies of the same isotype at nanomolar concn. levels.
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  22. 22
    Dickinson, G. D.; Mortuza, G. M.; Clay, W.; Piantanida, L.; Green, C. M.; Watson, C.; Hayden, E. J.; Andersen, T.; Kuang, W.; Graugnard, E.; Zadegan, R.; Hughes, W. L. An Alternative Approach to Nucleic Acid Memory. Nat. Commun. 2021, 12 (1), 2371,  DOI: 10.1038/s41467-021-22277-y
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    An alternative approach to nucleic acid memory
    Dickinson, George D.; Mortuza, Golam Md; Clay, William; Piantanida, Luca; Green, Christopher M.; Watson, Chad; Hayden, Eric J.; Andersen, Tim; Kuang, Wan; Graugnard, Elton; Zadegan, Reza; Hughes, William L.
    Nature Communications (2021), 12 (1), 2371CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    DNA is a compelling alternative to non-volatile information storage technologies due to its information d., stability, and energy efficiency. Previous studies have used artificially synthesized DNA to store data and automated next-generation sequencing to read it back. Here, we report digital Nucleic Acid Memory (dNAM) for applications that require a limited amt. of data to have high information d., redundancy, and copy no. In dNAM, data is encoded by selecting combinations of single-stranded DNA with (1) or without (0) docking-site domains. When self-assembled with scaffold DNA, staple strands form DNA origami breadboards. Information encoded into the breadboards is read by monitoring the binding of fluorescent imager probes using DNA-PAINT super-resoln. microscopy. To enhance data retention, a multi-layer error correction scheme that combines fountain and bi-level parity codes is used. As a prototype, fifteen origami encoded with Data is in our DNA!\n are analyzed. Each origami encodes unique data-droplet, index, orientation, and error-correction information. The error-correction algorithms fully recover the message when individual docking sites, or entire origami, are missing. Unlike other approaches to DNA-based data storage, reading dNAM does not require sequencing. As such, it offers an addnl. path to explore the advantages and disadvantages of DNA as an emerging memory material.
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    Chen, K.; Kong, J.; Zhu, J.; Ermann, N.; Predki, P.; Keyser, U. F. Digital Data Storage Using DNA Nanostructures and Solid-State Nanopores. Nano Lett. 2019, 19 (2), 1210– 1215,  DOI: 10.1021/acs.nanolett.8b04715
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    Digital Data Storage Using DNA Nanostructures and Solid-State Nanopores
    Chen, Kaikai; Kong, Jinglin; Zhu, Jinbo; Ermann, Niklas; Predki, Paul; Keyser, Ulrich F.
    Nano Letters (2019), 19 (2), 1210-1215CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Solid-state nanopores are powerful tools for reading the three-dimensional shape of mols., allowing for the translation of mol. structure information into elec. signals. Here, we show a high-resoln. integrated nanopore system for identifying DNA nanostructures that has the capability of distinguishing attached short DNA hairpins with only a stem length difference of 8 bp along a DNA double strand named the DNA carrier. Using our platform, we can read up to 112 DNA hairpins with a sepg. distance of 114 bp attached on a DNA carrier that carries digital information. Our encoding strategy allows for the creation of a library of mols. with a size of up to 5 × 1033 (2112) that is only built from a few hundred types of base mols. for data storage and has the potential to be extended by linking multiple DNA carriers. Our platform provides a nanopore- and DNA nanostructure-based data storage method with convenient access and the potential for miniature-scale integration.
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    Seeman, N. C.; Sleiman, H. F. DNA Nanotechnology. Nat. Rev. Mater. 2018, 3, 17068,  DOI: 10.1038/natrevmats.2017.68
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    DNA nanotechnology
    Seeman, Nadrian C.; Sleiman, Hanadi F.
    Nature Reviews Materials (2018), 3 (1), 17068CODEN: NRMADL; ISSN:2058-8437. (Nature Research)
    DNA is the mol. that stores and transmits genetic information in biol. systems. The field of DNA nanotechnol. takes this mol. out of its biol. context and uses its information to assemble structural motifs and then to connect them together. This field has had a remarkable impact on nanoscience and nanotechnol., and has been revolutionary in our ability to control mol. self-assembly. In this Review, we summarize the approaches used to assemble DNA nanostructures and examine their emerging applications in areas such as biophysics, diagnostics, nanoparticle and protein assembly, biomol. structure detn., drug delivery and synthetic biol. The introduction of orthogonal interactions into DNA nanostructures is discussed, and finally, a perspective on the future directions of this field is presented.
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    Chen, K.; Zhu, J.; Bošković, F.; Keyser, U. F. Nanopore-Based Dna Hard Drives for Rewritable and Secure Data Storage. Nano Lett. 2020, 20 (5), 3754– 3760,  DOI: 10.1021/acs.nanolett.0c00755
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    Nanopore-Based DNA Hard Drives for Rewritable and Secure Data Storage
    Chen, Kaikai; Zhu, Jinbo; Boskovic, Filip; Keyser, Ulrich F.
    Nano Letters (2020), 20 (5), 3754-3760CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Nanopores are powerful single-mol. tools for label-free sensing of nanoscale mols. including DNA that can be used for building designed nanostructures and performing computations. Here, DNA hard drives (DNA-HDs) are introduced based on DNA nanotechnol. and nanopore sensing as a rewritable mol. memory system, allowing for storing, operating, and reading data in the changeable three-dimensional structure of DNA. Writing and erasing data are significantly improved compared to previous mol. storage systems by employing controllable attachment and removal of mols. on a long double-stranded DNA. Data reading is achieved by detecting the single mols. at the millisecond time scale using nanopores. The DNA-HD also ensures secure data storage where the data can only be read after providing the correct phys. mol. keys. The approach allows for easy-writing and easy-reading, rewritable, and secure data storage toward a promising miniature scale integration for mol. data storage and computation.
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    Zhang, D. Y.; Seelig, G. Dynamic DNA Nanotechnology Using Strand-Displacement Reactions. Nat. Chem. 2011, 3 (2), 103– 113,  DOI: 10.1038/nchem.957
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    Dynamic DNA nanotechnology using strand-displacement reactions
    Zhang, David Yu; Seelig, Georg
    Nature Chemistry (2011), 3 (2), 103-113CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    A review. The specificity and predictability of Watson-Crick base pairing make DNA a powerful and versatile material for engineering at the nanoscale. This has enabled the construction of a diverse and rapidly growing set of DNA nanostructures and nanodevices through the programmed hybridization of complementary strands. Although it had initially focused on the self-assembly of static structures, DNA nanotechnol. is now also becoming increasingly attractive for engineering systems with interesting dynamic properties. Various devices, including circuits, catalytic amplifiers, autonomous mol. motors and reconfigurable nanostructures, have recently been rationally designed to use DNA strand-displacement reactions, in which two strands with partial or full complementarity hybridize, displacing in the process one or more pre-hybridized strands. This mechanism allows for the kinetic control of reaction pathways. Here, the authors review DNA strand-displacement-based devices, and look at how this relatively simple mechanism can lead to a surprising diversity of dynamic behavior.
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  27. 27
    Song, T.; Eshra, A.; Shah, S.; Bui, H.; Fu, D.; Yang, M.; Mokhtar, R.; Reif, J. Fast and Compact DNA Logic Circuits Based on Single-Stranded Gates Using Strand-Displacing Polymerase. Nat. Nanotechnol 2019, 14 (11), 1075– 1081,  DOI: 10.1038/s41565-019-0544-5
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    27
    Fast and compact DNA logic circuits based on single-stranded gates using strand-displacing polymerase
    Song, Tianqi; Eshra, Abeer; Shah, Shalin; Bui, Hieu; Fu, Daniel; Yang, Ming; Mokhtar, Reem; Reif, John
    Nature Nanotechnology (2019), 14 (11), 1075-1081CODEN: NNAABX; ISSN:1748-3387. (Nature Research)
    DNA is a reliable biomol. with which to build mol. computation systems. In particular, DNA logic circuits (diffusion-based) have shown good performance regarding scalability and correctness of computation. However, previous architectures of DNA logic circuits have two limitations. First, the speed of computation is slow, often requiring hours to compute a simple function. Second, the circuits are of high complexity regarding the no. of DNA strands. Here, the authors introduce an architecture of DNA logic circuits based on single-stranded logic gates using strand-displacing DNA polymerase. The logic gates consist of only single DNA strands, which largely reduces leakage reactions and signal restoration steps such that the circuits are improved in regard to both speed of computation and the no. of DNA strands needed. Large-scale logic circuits can be constructed from the gates by simple cascading strategies. In particular, the authors have demonstrated a fast and compact logic circuit that computes the square-root function of four-bit input nos.
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  28. 28
    Palluk, S.; Arlow, D. H.; de Rond, T.; Barthel, S.; Kang, J. S.; Bector, R.; Baghdassarian, H. M.; Truong, A. N.; Kim, P. W.; Singh, A. K.; Hillson, N. J.; Keasling, J. D. De Novo DNA Synthesis Using Polymerasenucleotide Conjugates. Nat. Biotechnol. 2018, 36 (7), 645– 650,  DOI: 10.1038/nbt.4173
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    28
    De novo DNA synthesis using polymerase-nucleotide conjugates
    Palluk, Sebastian; Arlow, Daniel H.; de Rond, Tristan; Barthel, Sebastian; Kang, Justine S.; Bector, Rathin; Baghdassarian, Hratch M.; Truong, Alisa N.; Kim, Peter W.; Singh, Anup K.; Hillson, Nathan J.; Keasling, Jay D.
    Nature Biotechnology (2018), 36 (7), 645-650CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
    Oligonucleotides are almost exclusively synthesized using the nucleoside phosphoramidite method, even though it is limited to the direct synthesis of ∼200 mers and produces hazardous waste. Here, we describe an oligonucleotide synthesis strategy that uses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT). Each TdT mol. is conjugated to a single deoxyribonucleoside triphosphate (dNTP) mol. that it can incorporate into a primer. After incorporation of the tethered dNTP, the 3' end of the primer remains covalently bound to TdT and is inaccessible to other TdT-dNTP mols. Cleaving the linkage between TdT and the incorporated nucleotide releases the primer and allows subsequent extension. We demonstrate that TdT-dNTP conjugates can quant. extend a primer by a single nucleotide in 10-20 s, and that the scheme can be iterated to write a defined sequence. This approach may form the basis of an enzymic oligonucleotide synthesizer.
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  29. 29
    Kosuri, S.; Church, G. M. Large-Scale de Novo DNA Synthesis: Technologies and Applications. Nat. Methods 2014, 11 (5), 499– 507,  DOI: 10.1038/nmeth.2918
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    29
    Large-scale de novo DNA synthesis: technologies and applications
    Kosuri, Sriram; Church, George M.
    Nature Methods (2014), 11 (5), 499-507CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    A review. For over 60 years, the synthetic prodn. of new DNA sequences has helped researchers understand and engineer biol. Here we summarize methods and caveats for the de novo synthesis of DNA, with particular emphasis on recent technologies that allow for large-scale and low-cost prodn. In addn., we discuss emerging applications enabled by large-scale de novo DNA constructs, as well as the challenges and opportunities that lie ahead.
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  30. 30
    LeProust, E. M.; Peck, B. J.; Spirin, K.; McCuen, H. B.; Moore, B.; Namsaraev, E.; Caruthers, M. H. Synthesis of High-Quality Libraries of Long (150mer) Oligonucleotides by a Novel Depurination Controlled Process. Nucleic Acids Res. 2010, 38 (8), 2522– 2540,  DOI: 10.1093/nar/gkq163
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    30
    Synthesis of high-quality libraries of long (150mer) oligonucleotides by a novel depurination controlled process
    LeProust Emily M; Peck Bill J; Spirin Konstantin; McCuen Heather Brummel; Moore Bridget; Namsaraev Eugeni; Caruthers Marvin H
    Nucleic acids research (2010), 38 (8), 2522-40 ISSN:.
    We have achieved the ability to synthesize thousands of unique, long oligonucleotides (150mers) in fmol amounts using parallel synthesis of DNA on microarrays. The sequence accuracy of the oligonucleotides in such large-scale syntheses has been limited by the yields and side reactions of the DNA synthesis process used. While there has been significant demand for libraries of long oligos (150mer and more), the yields in conventional DNA synthesis and the associated side reactions have previously limited the availability of oligonucleotide pools to lengths <100 nt. Using novel array based depurination assays, we show that the depurination side reaction is the limiting factor for the synthesis of libraries of long oligonucleotides on Agilent Technologies' SurePrint DNA microarray platform. We also demonstrate how depurination can be controlled and reduced by a novel detritylation process to enable the synthesis of high quality, long (150mer) oligonucleotide libraries and we report the characterization of synthesis efficiency for such libraries. Oligonucleotide libraries prepared with this method have changed the economics and availability of several existing applications (e.g. targeted resequencing, preparation of shRNA libraries, site-directed mutagenesis), and have the potential to enable even more novel applications (e.g. high-complexity synthetic biology).
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  31. 31
    Xu, C.; Ma, B.; Gao, Z.; Dong, X.; Zhao, C.; Liu, H. Electrochemical DNA Synthesis and Sequencing on a Single Electrode with Scalability for Integrated Data Storage. Sci. Adv. 2021, 7, abk0100,  DOI: 10.1126/sciadv.abk0100
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    Yoo, E.; Choe, D.; Shin, J.; Cho, S.; Cho, B. K. Mini Review: Enzyme-Based DNA Synthesis and Selective Retrieval for Data Storage. Comput. Struct Biotechnol J. 2021, 19, 2468– 2476,  DOI: 10.1016/j.csbj.2021.04.057
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    32
    Mini review: Enzyme-based DNA synthesis and selective retrieval for data storage
    Yoo, Eojin; Choe, Donghui; Shin, Jongoh; Cho, Suhyung; Cho, Byung-Kwan
    Computational and Structural Biotechnology Journal (2021), 19 (), 2468-2476CODEN: CSBJAC; ISSN:2001-0370. (Elsevier B.V.)
    A review. The market for using and storing digital data is growing, with DNA synthesis emerging as an efficient way to store massive amts. of data. Storing information in DNA mainly consists of two steps: data writing and reading. The writing step requires encoding data in DNA, building one nucleotide at a time as a form of single-stranded DNA (ssDNA). Once the data needs to be read, the target DNA is selectively retrieved and sequenced, which will also be in the form of an ssDNA. Recently, enzyme-based DNA synthesis is emerging as a new method to be a breakthrough on behalf of decades-old chem. synthesis. A few enzymic methods have been presented for data memory, including the use of terminal deoxynucleotidyl transferase. Besides, enzyme-based amplification or denaturation of the target strand into ssDNA provides selective access to the desired dataset. In this review, we summarize diverse enzymic methods for either synthesizing ssDNA or retrieving the data-contg. DNA.
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  33. 33
    Barthel, S.; Palluk, S.; Hillson, N. J.; Keasling, J. D.; Arlow, D. H. Enhancing Terminal Deoxynucleotidyl Transferase Activity on Substrates with 3′ Terminal Structures for Enzymatic De Novo DNA Synthesis. Genes (Basel) 2020, 11 (1), 102,  DOI: 10.3390/genes11010102
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    Pawloski, A. R.; McGall, G.; Kuimelis, R. G.; Barone, D.; Cuppoletti, A.; Ciccolella, P.; Spence, E.; Afroz, F.; Bury, P.; Chen, C.; Chen, C.; Pao, D.; Le, M.; McGee, B.; Harkins, E.; Savage, M.; Narasimhan, S.; Goldberg, M.; Rava, R.; Fodor, S. P. A. Photolithographic Synthesis of High-Density DNA Probe Arrays: Challenges and Opportunities. Journal of Vacuum Science & Technology B: Microelectronics and Nanometer Structures 2007, 25 (6), 2537,  DOI: 10.1116/1.2794325
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    Photolithographic synthesis of high-density DNA probe arrays: Challenges and opportunities
    Pawloski, Adam R.; McGall, Glenn; Kuimelis, Robert G.; Barone, Dale; Cuppoletti, Andrea; Ciccolella, Paul; Spence, Eric; Afroz, Farhana; Bury, Paul; Chen, Christy; Chen, Chuan; Pao, Dexter; Le, Mary; McGee, Becky; Harkins, Elizabeth; Savage, Michael; Narasimhan, Sim; Goldberg, Martin; Rava, Richard; Fodor, Stephen P. A.
    Journal of Vacuum Science & Technology, B: Microelectronics and Nanometer Structures--Processing, Measurement, and Phenomena (2007), 25 (6), 2537-2546CODEN: JVSTBM; ISSN:1071-1023. (American Institute of Physics)
    The continual need for increased manufg. capacity in the prodn. of GeneChip DNA probe arrays, and the expanding use of these arrays into new areas of application such as mol. medicine, has stimulated the development of new chemistries and prodn. methods with higher efficiency and resoln. For current prodn. methods based on contact photolithog., modifications in substrate materials and photoactivated synthesis reagents have provided significant improvements in array performance and information content (≥4 × 106 sequences/cm2). An alternative next-generation manufg. process is also in development, which utilizes photoacid generating polymer films, and automated projection lithog. systems. This process has the ability to fabricate arrays with 1 μ feature pitch and smaller, providing an unprecedented sequence d. of 108/cm2 and greater. (c) 2007 American Institute of Physics.
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  35. 35
    Nguyen, B. H.; Takahashi, C. N.; Gupta, G.; Smith, J. A.; Rouse, R.; Berndt, P.; Yekhanin, S.; Ward, D. P.; Ang, S. D.; Garvan, P.; Parker, H. Y.; Carlson, R.; Carmean, D.; Ceze, L.; Strauss, K. Scaling DNA Data Storage with Nanoscale Electrode Wells. Sci. Adv. 2021, 7 (48), 1– 7,  DOI: 10.1126/sciadv.abi6714
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    Zhang, Y.; Kong, L.; Wang, F.; Li, B.; Ma, C.; Chen, D.; Liu, K.; Fan, C.; Zhang, H. Information Stored in Nanoscale: Encoding Data in a Single DNA Strand with Base64. Nano Today 2020, 33, 100871,  DOI: 10.1016/j.nantod.2020.100871
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    Information stored in nanoscale: Encoding data in a single DNA strand with Base64
    Zhang, Yi; Kong, Linlin; Wang, Fei; Li, Bo; Ma, Chao; Chen, Dong; Liu, Kai; Fan, Chunhai; Zhang, Hongjie
    Nano Today (2020), 33 (), 100871CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
    DNA as a storage medium has enormous potential because of its high storage d., but the produced redundancy limits this potential. The introduction of less error corrections to fully increase the storage d. in DNA remains a major challenge. To address this, an optimized Base64 method is developed and accordingly we realized a high specific storage d. of 1.77 bits/nucleotide in a DNA single strand. In this strategy, by Base64 encoding, code reshaping and balancing, and data mapping, some random text information was encoded into a DNA sequence and the corresponding DNA mol. was synthesized. It was then inserted into a circular plasmid for long-term information storage. This is also particularly suitable for information replication at an exponential rate when it is transformed in a bacterium. The introduction of balance codes during the transcoding process effectively controlled the GC content and continuous base repeat, which is important to reduce the error rates in the encoded DNA synthesis and sequencing. Moreover, the circular plasmid platform enhanced the storage stability and sequencing accuracy. Therefore, our approach achieved a robust and high efficient storage and an accurate readout of digital data.
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  37. 37
    Newman, S.; Stephenson, A. P.; Willsey, M.; Nguyen, B. H.; Takahashi, C. N.; Strauss, K.; Ceze, L. High Density DNA Data Storage Library via Dehydration with Digital Microfluidic Retrieval. Nat. Commun. 2019, 10 (1), 1706,  DOI: 10.1038/s41467-019-09517-y
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    High density DNA data storage library via dehydration with digital microfluidic retrieval
    Newman, Sharon; Stephenson, Ashley P.; Willsey, Max; Nguyen, Bichlien H.; Takahashi, Christopher N.; Strauss, Karin; Ceze, Luis
    Nature Communications (2019), 10 (1), 1706CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    DNA promises to be a high d. data storage medium, but phys. storage poses a challenge. To store large amts. of data, pools must be phys. isolated so they can share the same addressing scheme. We propose the storage of dehydrated DNA spots on glass as an approach for scalable DNA data storage. The dried spots can then be retrieved by a water droplet using a digital microfluidic device. Here we show that this storage schema works with varying spot organization, spotted masses of DNA, and droplet retrieval dwell times. In all cases, the majority of the DNA was retrieved and successfully sequenced. We demonstrate that the spots can be densely arranged on a microfluidic device without significant contamination of the retrieval. We also demonstrate that 1 TB of data could be stored in a single spot of DNA and successfully retrieved using this method.
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    Erlich, Y. A Vision for Ubiquitous Sequencing. Genome Res. 2015, 25 (10), 1411– 1416,  DOI: 10.1101/gr.191692.115
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    A vision for ubiquitous sequencing
    Erlich, Yaniv
    Genome Research (2015), 25 (10), 1411-1416CODEN: GEREFS; ISSN:1088-9051. (Cold Spring Harbor Laboratory Press)
    A review. Genomics has recently celebrated reaching the $1000 genome milestone, making affordable DNA sequencing a reality. This goal of the sequencing revolution has been successfully completed. Looking forward, the next goal of the revolution can be ushered in by the advent of sequencing sensors -miniaturized sequencing devices that are manufd. for real time applications and deployed in large quantities at low costs. The first part of this manuscript envisions applications that will benefit from moving the sequencers to the samples in a range of domains. In the second part, the manuscript outlines the crit. barriers that need to be addressed in order to reach the goal of ubiquitous sequencing sensors.
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    Takahashi, C. N.; Nguyen, B. H.; Strauss, K.; Ceze, L. Demonstration of End-to-End Automation of DNA Data Storage. Sci. Rep 2019, 9 (1), 1– 6,  DOI: 10.1038/s41598-019-41228-8
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    Eurotium Cristatum Fermented Okara as a Potential Food Ingredient to Combat Diabetes
    Chan, Li Yan; Takahashi, Masaki; Lim, Pei Jean; Aoyama, Shinya; Makino, Saneyuki; Ferdinandus, Ferdinandus; Ng, Shi Ya Clara; Arai, Satoshi; Fujita, Hideaki; Tan, Hong Chang; Shibata, Shigenobu; Lee, Chi-Lik Ken
    Scientific Reports (2019), 9 (1), 1-9CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Type 2 diabetes mellitus (T2DM) is a chronic disease, and dietary modification is a crucial part of disease management. Okara is a sustainable source of fiber-rich food. Most of the valorization research on okara focused more on the phys. attributes instead of the possible health attributes. The fermn. of okara using microbes originated from food source, such as tea, sake, sufu and yoghurt, were explored here. The aim of this study is to investigate fermented okara as a functional food ingredient to reduce blood glucose levels. Fermented and non-fermented okara exts. were analyzed using the metabolomic approach with UHPLC-QTof-MSE. Statistical anal. demonstrated that the anthraquinones, emodin and physcion, served as potential markers and differentiated Eurotium cristatum fermented okara (ECO) over other choices of microbes. The in-vitro αglucosidase activity assays and in-vivo mice studies showed that ECO can reduce postprandial blood glucose levels. A 20% ECO loading crispy snack prototype revealed a good nutrition compn. and could serve as a fundamental formulation for future antidiabetes recipe development, strengthening the hypothesis that ECO can be used as a novel food ingredient for diabetic management.
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    Choi, H.; Choi, Y.; Choi, J.; Lee, A. C.; Yeom, H.; Hyun, J.; Ryu, T.; Kwon, S. Purification of Multiplex Oligonucleotide Libraries by Synthesis and Selection. Nat. Biotechnol. 2022, 40 (1), 47– 53,  DOI: 10.1038/s41587-021-00988-3
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    40
    Purification of multiplex oligonucleotide libraries by synthesis and selection
    Choi, Hansol; Choi, Yeongjae; Choi, Jaewon; Lee, Amos Chungwon; Yeom, Huiran; Hyun, Jinwoo; Ryu, Taehoon; Kwon, Sunghoon
    Nature Biotechnology (2022), 40 (1), 47-53CODEN: NABIF9; ISSN:1087-0156. (Nature Portfolio)
    Complex oligonucleotide (oligo) libraries are essential materials for diverse applications in synthetic biol., pharmaceutical prodn., nanotechnol. and DNA-based data storage. However, the error rates in synthesizing complex oligo libraries can be substantial, leading to increment in cost and labor for the applications. As most synthesis errors arise from faulty insertions and deletions, we developed a length-based method with single-base resoln. for purifn. of complex libraries contg. oligos of identical or different lengths. Our method-purifn. of multiplex oligonucleotide libraries by synthesis and selection-can be performed either step-by-step manually or using a next-generation sequencer. When applied to a digital data-encoded library contg. oligos of identical length, the method increased the purity of full-length oligos from 83% to 97%. We also show that libraries encoding the complementarity-detg. region H3 with three different lengths (with an empirically achieved diversity >106) can be simultaneously purified in one pot, increasing the in-frame oligo fraction from 49.6% to 83.5%.
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    Wang, Y.; Wang, M.; Wang, J.; Liu, J. An Adaptive Data Redundancy Strategy in Cloud Storage. In 2019 IEEE 2nd International Conference on Electronic Information and Communication Technology (ICEICT); IEEE, 2019; pp 40– 45.
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    Antkowiak, P. L.; Lietard, J.; Darestani, M. Z.; Somoza, M. M.; Stark, W. J.; Heckel, R.; Grass, R. N. Low Cost DNA Data Storage Using Photolithographic Synthesis and Advanced Information Reconstruction and Error Correction. Nat. Commun. 2020, 11, 5345,  DOI: 10.1038/s41467-020-19148-3
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    Low cost DNA data storage using photolithographic synthesis and advanced information reconstruction and error correction
    Antkowiak, Philipp L.; Lietard, Jory; Darestani, Mohammad Zalbagi; Somoza, Mark M.; Stark, Wendelin J.; Heckel, Reinhard; Grass, Robert N.
    Nature Communications (2020), 11 (1), 5345CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Due to its longevity and enormous information d., DNA is an attractive medium for archival storage. The current hamstring of DNA data storage systems-both in cost and speed-is synthesis. The key idea for breaking this bottleneck pursued in this work is to move beyond the low-error and expensive synthesis employed almost exclusively in today's systems, towards cheaper, potentially faster, but high-error synthesis technologies. Here, we demonstrate a DNA storage system that relies on massively parallel light-directed synthesis, which is considerably cheaper than conventional solid-phase synthesis. However, this technol. has a high sequence error rate when optimized for speed. We demonstrate that even in this high-error regime, reliable storage of information is possible, by developing a pipeline of algorithms for encoding and reconstruction of the information. In our expts., we store a file contg. sheet music of Mozart, and show perfect data recovery from low synthesis fidelity DNA.
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    Nguyen, T. T.; Cai, K.; Schouhamer Immink, K. A.; Kiah, H. M. Capacity-Approaching Constrained Codes With Error Correction for DNA-Based Data Storage. IEEE Trans Inf Theory 2021, 67 (8), 5602– 5613,  DOI: 10.1109/TIT.2021.3066430
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    Blawat, M.; Gaedke, K.; Hütter, I.; Chen, X.-M.; Turczyk, B.; Inverso, S.; Pruitt, B. W.; Church, G. M. Forward Error Correction for DNA Data Storage. Procedia Comput. Sci. 2016, 80, 1011– 1022,  DOI: 10.1016/j.procs.2016.05.398
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    Tang, Y.; Farnoud, F. Correcting Deletion Errors in DNA Data Storage with Enzymatic Synthesis. In 2021 IEEE Information Theory Workshop (ITW); IEEE, 2021; pp 1– 6.
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    Lu, X.; Kim, S. Design of Nonbinary Error Correction Codes with a Maximum Run-Length Constraint to Correct a Single Insertion or Deletion Error for DNA Storage. IEEE Access 2021, 9, 135354– 135363,  DOI: 10.1109/ACCESS.2021.3116245
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    Press, W. H.; Hawkins, J. A.; Jones, S. K.; Schaub, J. M.; Finkelstein, I. J. HEDGES Error-Correcting Code for DNA Storage Corrects Indels and Allows Sequence Constraints. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (31), 18489– 18496,  DOI: 10.1073/pnas.2004821117
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    47
    HEDGES error-correcting code for DNA storage corrects indels and allows sequence constraints
    Press, William H.; Hawkins, John A.; Jones, Stephen Jr. K.; Schaub, Jeffrey M.; Finkelstein, Ilya J.
    Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (31), 18489-18496CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Synthetic DNA is rapidly emerging as a durable, high-d. information storage platform. A major challenge for DNA-based information encoding strategies is the high rate of errors that arise during DNA synthesis and sequencing. Here, we describe the HEDGES (Hash Encoded, Decoded by Greedy Exhaustive Search) error-correcting code that repairs all three basic types of DNA errors: insertions, deletions, and substitutions. HEDGES also converts unresolved or compd. errors into substitutions, restoring synchronization for correction via a std. Reed-Solomon outer code that is interleaved across strands. Moreover, HEDGES can incorporate a broad class of user-defined sequence constraints, such as avoiding excess repeats, or too high or too low windowed guanine-cytosine (GC) content. We test our code both via in silico simulations and with synthesized DNA. From its measured performance, we develop a statistical model applicable to much larger datasets. Predicted performance indicates the possibility of error-free recovery of petabyte- and exabyte-scale data from DNA degraded with as much as 10% errors. As the cost of DNA synthesis and sequencing continues to drop, we anticipate that HEDGES will find applications in large-scale error-free information encoding.
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    Dong, Y.; Sun, F.; Ping, Z.; Ouyang, Q.; Qian, L. DNA Storage: Research Landscape and Future Prospects. Natl. Sci. Rev. 2020, 7 (6), 1092– 1107,  DOI: 10.1093/nsr/nwaa007
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    DNA storage: research landscape and future prospects
    Dong, Yiming; Sun, Fajia; Ping, Zhi; Ouyang, Qi; Qian, Long
    National Science Review (2020), 7 (6), 1092-1107CODEN: NSRACI; ISSN:2053-714X. (Oxford University Press)
    The global demand for data storage is currently o utpacing the world's storage capabilities. DNA, the carrier of natural genetic information, offrs a stable, resource- and energy-effient and sustainable data storage soln. In this review, we summarize the fundamental theory, r esearch h istory, and tech. challenges of DNA s torage. From a quant. perspective, we evaluate the prospect of DNA, and org. polymers in general, as a novel class of data storage medium.
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    Hosseini, M.; Pratas, D.; Pinho, A. A Survey on Data Compression Methods for Biological Sequences. Information 2016, 7 (4), 56,  DOI: 10.3390/info7040056
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    Vishwakarma, R. High Density Data Storage In Dna Using An Efficient Message Encoding Scheme. International Journal of Information Technology Convergence and Services 2012, 2 (2), 41– 46,  DOI: 10.5121/ijitcs.2012.2204
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    Choi, Y.; Ryu, T.; Lee, A. C.; Choi, H.; Lee, H.; Park, J.; Song, S. H.; Kim, S.; Kim, H.; Park, W.; Kwon, S. High Information Capacity DNA-Based Data Storage with Augmented Encoding Characters Using Degenerate Bases. Sci. Rep 2019, 9, 6582,  DOI: 10.1038/s41598-019-43105-w
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    51
    High information capacity DNA-based data storage with augmented encoding characters using degenerate bases
    Choi Yeongjae; Ryu Taehoon; Choi Hansol; Lee Hansaem; Park Jaejun; Kwon Sunghoon; Ryu Taehoon; Park Jaejun; Lee Amos C; Kwon Sunghoon; Song Suk-Heung; Kim Seojoo; Kim Hyeli; Park Wook; Kwon Sunghoon; Kwon Sunghoon
    Scientific reports (2019), 9 (1), 6582 ISSN:.
    DNA-based data storage has emerged as a promising method to satisfy the exponentially increasing demand for information storage. However, practical implementation of DNA-based data storage remains a challenge because of the high cost of data writing through DNA synthesis. Here, we propose the use of degenerate bases as encoding characters in addition to A, C, G, and T, which augments the amount of data that can be stored per length of DNA sequence designed (information capacity) and lowering the amount of DNA synthesis per storing unit data. Using the proposed method, we experimentally achieved an information capacity of 3.37 bits/character. The demonstrated information capacity is more than twice when compared to the highest information capacity previously achieved. The proposed method can be integrated with synthetic technologies in the future to reduce the cost of DNA-based data storage by 50%.
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  52. 52
    Ren, Y.; Zhang, Y.; Liu, Y.; Wu, Q.; Su, J.; Wang, F.; Chen, D.; Fan, C.; Liu, K.; Zhang, H. DNA-Based Concatenated Encoding System for High-Reliability and High-Density Data Storage. Small Methods 2022, 6 (4), 2101335,  DOI: 10.1002/smtd.202101335
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    DNA-Based Concatenated Encoding System for High-Reliability and High-Density Data Storage
    Ren, Yubin; Zhang, Yi; Liu, Yawei; Wu, Qinglin; Su, Juanjuan; Wang, Fan; Chen, Dong; Fan, Chunhai; Liu, Kai; Zhang, Hongjie
    Small Methods (2022), 6 (4), 2101335CODEN: SMMECI; ISSN:2366-9608. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Information storage based on DNA mols. provides a promising soln. with advantages of low-energy consumption, high storage efficiency, and long lifespan. However, there are only four natural nucleotides and DNA storage is thus limited by 2 bits per nucleotide. Here, artificial nucleotides into DNA data storage to achieve higher coding efficiency than 2 bits per nucleotide is introduced. To accommodate the characteristics of DNA synthesis and sequencing, two high-reliability encoding systems suitable for four, six, and eight nucleotides, i.e., the RaptorQ-Arithmetic-LZW-RS (RALR) and RaptorQ-Arithmetic-Base64-RS (RABR) systems, are developed. The two concatenated encoding systems realize the advantages of correcting DNA sequence losses, correcting errors within DNA sequences, reducing homopolymers, and controlling specific nucleotide contents. The av. coding efficiencies with error correction and without arithmetic compression by the RALR system using four, six, and eight nucleotides reach 1.27, 1.61, and 1.85 bits per nucleotide, resp. While the av. coding efficiencies by the RABR system are up to 1.50, 2.00, and 2.35 bits per nucleotide, resp. The coding efficiency, versatility, and tunability of the developed artificial DNA systems might provide significant guidance for high-reliability and high-d. data storage.
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  53. 53
    Tabatabaei, S. K.; Pham, B.; Pan, C.; Liu, J.; Chandak, S.; Shorkey, S. A.; Hernandez, A. G.; Aksimentiev, A.; Chen, M.; Schroeder, C. M.; Milenkovic, O. Expanding the Molecular Alphabet of DNA-Based Data Storage Systems with Neural Network Nanopore Readout Processing. Nano Lett. 2022, 22 (5), 1905– 1914,  DOI: 10.1021/acs.nanolett.1c04203
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    53
    Expanding the Molecular Alphabet of DNA-Based Data Storage Systems with Neural Network Nanopore Readout Processing
    Tabatabaei S Kasra; Liu Jingqian; Aksimentiev Aleksei; Schroeder Charles M; Tabatabaei S Kasra; Schroeder Charles M; Pham Bach; Shorkey Spencer A; Chen Min; Pan Chao; Milenkovic Olgica; Chandak Shubham; Hernandez Alvaro G; Aksimentiev Aleksei; Schroeder Charles M; Schroeder Charles M
    Nano letters (2022), 22 (5), 1905-1914 ISSN:.
    DNA is a promising next-generation data storage medium, but challenges remain with synthesis costs and recording latency. Here, we describe a prototype of a DNA data storage system that uses an extended molecular alphabet combining natural and chemically modified nucleotides. Our results show that MspA nanopores can discriminate different combinations and ordered sequences of natural and chemically modified nucleotides in custom-designed oligomers. We further demonstrate single-molecule sequencing of the extended alphabet using a neural network architecture that classifies raw current signals generated by Oxford Nanopore sequencers with an average accuracy exceeding 60% (39× larger than random guessing). Molecular dynamics simulations show that the majority of modified nucleotides lead to only minor perturbations of the DNA double helix. Overall, the extended molecular alphabet may potentially offer a nearly 2-fold increase in storage density and potentially the same order of reduction in the recording latency, thereby enabling new implementations of molecular recorders.
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  54. 54
    Allentoft, M. E.; Collins, M.; Harker, D.; Haile, J.; Oskam, C. L.; Hale, M. L.; Campos, P. F.; Samaniego, J. A.; Gilbert, T. P. M.; Willerslev, E.; Zhang, G.; Scofield, R. P.; Holdaway, R. N.; Bunce, M. The Half-Life of DNA in Bone: Measuring Decay Kinetics in 158 Dated Fossils. Proceedings of the Royal Society B: Biological Sciences 2012, 279 (1748), 4724– 4733,  DOI: 10.1098/rspb.2012.1745
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    54
    The half-life of DNA in bone: measuring decay kinetics in 158 dated fossils
    Allentoft, Morten E.; Collins, Matthew; Harker, David; Haile, James; Oskam, Charlotte L.; Hale, Marie L.; Campos, Paula F.; Samaniego, Jose A.; Gilbert, M. Thomas P.; Willerslev, Eske; Zhang, Guojie; Scofield, R. Paul; Holdaway, Richard N.; Bunce, Michael
    Proceedings of the Royal Society B: Biological Sciences (2012), 279 (1748), 4724-4733CODEN: PRSBC7 ISSN:. (Royal Society)
    Claims of extreme survival of DNA have emphasized the need for reliable models of DNA degrdn. through time. By analyzing mitochondrial DNA (mtDNA) from 158 radiocarbon-dated bones of the extinct New Zealand moa, we confirm empirically a long-hypothesized exponential decay relationship. The av. DNA half-life within this geog. constrained fossil assemblage was estd. to be 521 years for a 242 bp mtDNA sequence, corresponding to a per nucleotide fragmentation rate (k) of 5.50 × 10-6 per yr. With an effective burial temp. of 13.1°C, the rate is almost 400 times slower than predicted from published kinetic data of in vitro DNA depurination at pH 5. Although best described by an exponential model (R2 = 0.39), considerable sample-to-sample variance in DNA preservation could not be accounted for by geol. age. This variation likely derives from differences in taphonomy and bone diagenesis, which have confounded previous, less spatially constrained attempts to study DNA decay kinetics. Lastly, by calcg. DNA fragmentation rates on Illumina HiSeq data, we show that nuclear DNA has degraded at least twice as fast as mtDNA. These results provide a baseline for predicting long-term DNA survival in bone.
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  55. 55
    van der Valk, T.; Pečnerová, P.; Díez-del-Molino, D.; Bergström, A.; Oppenheimer, J.; Hartmann, S.; Xenikoudakis, G.; Thomas, J. A.; Dehasque, M.; Sağlıcan, E.; Fidan, F. R.; Barnes, I.; Liu, S.; Somel, M.; Heintzman, P. D.; Nikolskiy, P.; Shapiro, B.; Skoglund, P.; Hofreiter, M.; Lister, A. M.; Götherström, A.; Dalén, L. Million-Year-Old DNA Sheds Light on the Genomic History of Mammoths. Nature 2021, 591 (7849), 265– 269,  DOI: 10.1038/s41586-021-03224-9
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    Million-year-old DNA sheds light on the genomic history of mammoths
    van der Valk, Tom; Pecnerova, Patricia; Diez-del-Molino, David; Bergstroem, Anders; Oppenheimer, Jonas; Hartmann, Stefanie; Xenikoudakis, Georgios; Thomas, Jessica A.; Dehasque, Marianne; Saglican, Ekin; Fidan, Fatma Rabia; Barnes, Ian; Liu, Shanlin; Somel, Mehmet; Heintzman, Peter D.; Nikolskiy, Pavel; Shapiro, Beth; Skoglund, Pontus; Hofreiter, Michael; Lister, Adrian M.; Goetherstroem, Anders; Dalen, Love
    Nature (London, United Kingdom) (2021), 591 (7849), 265-269CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Temporal genomic data hold great potential for studying evolutionary processes such as speciation. However, sampling across speciation events would, in many cases, require genomic time series that stretch well back into the Early Pleistocene subepoch. Although theor. models suggest that DNA should survive on this timescale1, the oldest genomic data recovered so far are from a horse specimen dated to 780-560 thousand years ago2. Here we report the recovery of genome-wide data from three mammoth specimens dating to the Early and Middle Pleistocene subepochs, two of which are more than one million years old. We find that two distinct mammoth lineages were present in eastern Siberia during the Early Pleistocene. One of these lineages gave rise to the woolly mammoth and the other represents a previously unrecognized lineage that was ancestral to the first mammoths to colonize North America. Our analyses reveal that the Columbian mammoth of North America traces its ancestry to a Middle Pleistocene hybridization between these two lineages, with roughly equal admixt. proportions. Finally, we show that the majority of protein-coding changes assocd. with cold adaptation in woolly mammoths were already present one million years ago. These findings highlight the potential of deep-time palaeogenomics to expand our understanding of speciation and long-term adaptive evolution.
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  56. 56
    Antkowiak, P. L.; Koch, J.; Nguyen, B. H.; Stark, W. J.; Strauss, K.; Ceze, L.; Grass, R. N. Integrating DNA Encapsulates and Digital Microfluidics for Automated Data Storage in DNA. Small 2022, 18, 2107381,  DOI: 10.1002/smll.202107381
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    56
    Integrating DNA Encapsulates and Digital Microfluidics for Automated Data Storage in DNA
    Antkowiak, Philipp L.; Koch, Julian; Nguyen, Bichlien H.; Stark, Wendelin J.; Strauss, Karin; Ceze, Luis; Grass, Robert N.
    Small (2022), 18 (15), 2107381CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Using DNA as a durable, high-d. storage medium with eternal format relevance can address a future data storage deficiency. The proposed storage format incorporates dehydrated particle spots on glass, at a theor. capacity of more than 20 TB per spot, which can be efficiently retrieved without significant loss of DNA. The authors measure the rapid decay of dried DNA at room temp. and present the synthesis of encapsulated DNA in silica nanoparticles as a possible soln. In this form, the protected DNA can be readily applied to digital microfluidics (DMF) used to handle retrieval operations amenable to full automation. A storage architecture is demonstrated, which can increase the storage capacity of today's archival storage systems by more than three orders of magnitude: A DNA library contg. 7373 unique sequences is encapsulated and stored under accelerated aging conditions (4 days at 70°C, 50% RH) corresponding to 116 years at room temp. and the stored information is successfully recovered.
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  57. 57
    Bonnet, J.; Colotte, M.; Coudy, D.; Couallier, V.; Portier, J.; Morin, B.; Tuffet, S. Chain and Conformation Stability of Solid-State DNA: Implications for Room Temperature Storage. Nucleic Acids Res. 2010, 38 (5), 1531– 1546,  DOI: 10.1093/nar/gkp1060
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    Chain and conformation stability of solid-state DNA: implications for room temperature storage
    Bonnet, Jacques; Colotte, Marthe; Coudy, Delphine; Couallier, Vincent; Portier, Joseph; Morin, Benedicte; Tuffet, Sophie
    Nucleic Acids Research (2010), 38 (5), 1531-1546CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Currently, a wide interest exists in room temp. storage of dehydrated DNA. However, there is no sufficient knowledge about its chem. and structural stability. Here we show that solid-state DNA degrdn. is greatly affected by atm. water and oxygen at room temp. In these conditions DNA can even be lost by aggregation. These are major concerns since lab. plastic ware is not airtight. Chain-breaking rates measured between 70° and 140° seemed to follow Arrhenius' law. Extrapolation to 25° gave a degrdn. rate of about 1-40 cuts/105 nucleotides/century. However, these figures are to be taken as very tentative since they depend on the validity of the extrapolation and the pos. or neg. effect of contaminants, buffers or additives. Regarding the secondary structure, denaturation expts. showed that DNA secondary structure could be preserved or fully restored upon rehydration, except possibly for small fragments. Indeed, below about 500 bp, DNA fragments underwent a very slow evolution (almost suppressed in the presence of trehalose) which could end in an irreversible denaturation. Thus, this work validates using room temp. for storage of DNA if completely protected from water and oxygen.
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  58. 58
    Coudy, D.; Colotte, M.; Luis, A.; Tuffet, S.; Bonnet, J. Long Term Conservation of DNA at Ambient Temperature. Implications for DNA Data Storage. PLoS One 2021, 16 (11), e0259868,  DOI: 10.1371/journal.pone.0259868
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    58
    Long term conservation of DNA at ambient temperature. Implications for DNA data storage
    Coudy, Delphine; Colotte, Marthe; Luis, Aurelie; Tuffet, Sophie; Bonnet, Jacques
    PLoS One (2021), 16 (11), e0259868CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    DNA conservation is central to many applications. This leads to an ever-increasing no. of samples which are more and more difficult and costly to store or transport. A way to alleviate this problem is to develop procedures for storing samples at room temp. while maintaining their stability. A variety of com. systems have been proposed but they fail to completely protect DNA from deleterious factors, mainly water. On the other side, Imagene company has developed a procedure for long-term conservation of biospecimen at room temp. based on the confinement of the samples under an anhyd. and anoxic atm. maintained inside hermetic capsules. The procedure has been validated by us and others for purified RNA, and for DNA in buffy coat or white blood cells lysates, but a precise detn. of purified DNA stability is still lacking. We used the Arrhenius law to det. the DNA degrdn. rate at room temp. We found that extrapolation to 25°C gave a degrdn. rate const. equiv. to about 1 cut/century/100 000 nucleotides, a stability several orders of magnitude larger than the current commercialized processes. Such a stability is fundamental for many applications such as the preservation of very large DNA mols. (particularly interesting in the context of genome sequencing) or oligonucleotides for DNA data storage. Capsules are also well suited for this latter application because of their high capacity. One can calc. that the 64 zettabytes of data produced in 2020 could be stored, standalone, for centuries, in about 20 kg of capsules.
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  59. 59
    Chen, W. D.; Kohll, A. X.; Nguyen, B. H.; Koch, J.; Heckel, R.; Stark, W. J.; Ceze, L.; Strauss, K.; Grass, R. N. Combining Data Longevity with High Storage Capacity─Layer-by-Layer DNA Encapsulated in Magnetic Nanoparticles. Adv. Funct. Mater. 2019, 29, 1901672,  DOI: 10.1002/adfm.201901672
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    Paunescu, D.; Puddu, M.; Soellner, J. O. B.; Stoessel, P. R.; Grass, R. N. Reversible DNA Encapsulation in Silica to Produce ROS-Resistant and Heat-Resistant Synthetic DNA “Fossils. Nat. Protoc 2013, 8 (12), 2440– 2448,  DOI: 10.1038/nprot.2013.154
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    60
    Reversible DNA encapsulation in silica to produce ROS-resistant and heat-resistant synthetic DNA 'fossils'
    Paunescu, Daniela; Puddu, Michela; Soellner, Justus O. B.; Stoessel, Philipp R.; Grass, Robert N.
    Nature Protocols (2013), 8 (12), 2440-2448CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    This protocol describes a method for encapsulating DNA into amorphous silica (glass) spheres, mimicking the protection of nucleic acids within ancient fossils. In this approach, DNA encapsulation is achieved after the ammonium functionalization of silica nanoparticles. Within the glass spheres, the nucleic acid mols. are hermetically sealed and protected from chem. attack, thereby withstanding high temps. and aggressive radical oxygen species (ROS). The encapsulates can be used as inert taggants to trace chem. and biol. entities. The present protocol is applicable to short double-stranded (ds) and single-stranded (ss) DNA fragments, genomic DNA and plasmids. The nucleic acids can be recovered from the glass spheres without harm by using fluoride-contg. buffered oxide etch solns. Special emphasis is placed in this protocol on the safe handling of these buffered hydrogen fluoride solns. After dissoln. of the spheres and subsequent purifn., the nucleic acids can be analyzed by std. techniques (gel electrophoresis, quant. PCRR (qPCR) and sequencing). The protocol requires 6 d for completion with a total hands-on time of 4 h.
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  61. 61
    Koch, J.; Gantenbein, S.; Masania, K.; Stark, W. J.; Erlich, Y.; Grass, R. N. A DNA-of-Things Storage Architecture to Create Materials with Embedded Memory. Nat. Biotechnol. 2020, 38 (1), 39– 43,  DOI: 10.1038/s41587-019-0356-z
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    61
    A DNA-of-things storage architecture to create materials with embedded memory
    Koch, Julian; Gantenbein, Silvan; Masania, Kunal; Stark, Wendelin J.; Erlich, Yaniv; Grass, Robert N.
    Nature Biotechnology (2020), 38 (1), 39-43CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
    DNA storage offers substantial information d.1-7 and exceptional half-life3. We devised a 'DNA-of-things' (DoT) storage architecture to produce materials with immutable memory. In a DoT framework, DNA mols. record the data, and these mols. are then encapsulated in nanometer silica beads8, which are fused into various materials that are used to print or cast objects in any shape. First, we applied DoT to three-dimensionally print a Stanford Bunny9 that contained a 45 kB digital DNA blueprint for its synthesis. We synthesized five generations of the bunny, each from the memory of the previous generation without addnl. DNA synthesis or degrdn. of information. To test the scalability of DoT, we stored a 1.4 MB video in DNA in plexiglass spectacle lenses and retrieved it by excising a tiny piece of the plexiglass and sequencing the embedded DNA. DoT could be applied to store electronic health records in medical implants, to hide data in everyday objects (steganog.) and to manuf. objects contg. their own blueprint. It may also facilitate the development of self-replicating machines.
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  62. 62
    Kohll, A. X.; Antkowiak, P. L.; Chen, W. D.; Nguyen, B. H.; Stark, W. J.; Ceze, L.; Strauss, K.; Grass, R. N. Stabilizing Synthetic DNA for Long-Term Data Storage with Earth Alkaline Salts. Chem. Commun. 2020, 56 (25), 3613– 3616,  DOI: 10.1039/D0CC00222D
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    Stabilizing synthetic DNA for long-term data storage with earth alkaline salts
    Kohll, A. Xavier; Antkowiak, Philipp L.; Chen, Weida D.; Nguyen, Bichlien H.; Stark, Wendelin J.; Ceze, Luis; Strauss, Karin; Grass, Robert N.
    Chemical Communications (Cambridge, United Kingdom) (2020), 56 (25), 3613-3616CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Rapid aging tests (70°C, 50% RH) of solid state DNA dried in the presence of various salt formulations, showed the strong stabilizing effect of calcium phosphate, calcium chloride and magnesium chloride, even at high DNA loadings (>20 wt%). A DNA-based digital information storage system utilizing the stabilizing effect of MgCl2 was tested by storing a DNA file, encoding 115 kB of digital data, and the successful readout of the file by sequencing after accelerated aging.
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  63. 63
    Choi, Y.; Bae, H. J.; Lee, A. C.; Choi, H.; Lee, D.; Ryu, T.; Hyun, J.; Kim, S.; Kim, H.; Song, S. H.; Kim, K.; Park, W.; Kwon, S. DNA Micro-Disks for the Management of DNA-Based Data Storage with Index and Write-Once–Read-Many (WORM) Memory Features. Adv. Mater. 2020, 32 (37), 2001249,  DOI: 10.1002/adma.202001249
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    63
    DNA Micro-Disks for the Management of DNA-Based Data Storage with Index and Write-Once-Read-Many (WORM) Memory Features
    Choi, Yeongjae; Bae, Hyung Jong; Lee, Amos C.; Choi, Hansol; Lee, Daewon; Ryu, Taehoon; Hyun, Jinwoo; Kim, Seojoo; Kim, Hyeli; Song, Suk-Heung; Kim, Kibeom; Park, Wook; Kwon, Sunghoon
    Advanced Materials (Weinheim, Germany) (2020), 32 (37), 2001249CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    DNA-based data storage has attracted attention because of its higher phys. d. of the data and longer retention time than those of conventional digital data storage. However, previous DNA-based data storage lacked index features and the data quality of storage after a single access was not preserved, obstructing its industrial use. Here, DNA micro-disks, QR-coded micro-sized disks that harbor data-encoded DNA mols. for the efficient management of DNA-based data storage, are proposed. The two major features that previous DNA-based data-storage studies could not achieve are demonstrated. One feature is accessing data items efficiently by indexing the data-encoded DNA library. Another is achieving write-once-read-many (WORM) memory through the immobilization of DNA mols. on the disk and their enrichment through in situ DNA prodn. Through these features, the reliability of DNA-based data storage is increased by allowing selective and multiple accession of data-encoded DNA with lower data loss than previous DNA-based data storage methods.
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  64. 64
    Organick, L.; Nguyen, B. H.; McAmis, R.; Chen, W. D.; Kohll, A. X.; Ang, S. D.; Grass, R. N.; Ceze, L.; Strauss, K. An Empirical Comparison of Preservation Methods for Synthetic DNA Data Storage. Small Methods 2021, 5 (5), 2001094,  DOI: 10.1002/smtd.202001094
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    64
    An Empirical Comparison of Preservation Methods for Synthetic DNA Data Storage
    Organick, Lee; Nguyen, Bichlien H.; McAmis, Rachel; Chen, Weida D.; Kohll, A. Xavier; Ang, Siena Dumas; Grass, Robert N.; Ceze, Luis; Strauss, Karin
    Small Methods (2021), 5 (5), 2001094CODEN: SMMECI; ISSN:2366-9608. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Synthetic DNA has recently risen as a viable alternative for long-term digital data storage. To ensure that information is safely recovered after storage, it is essential to appropriately preserve the phys. DNA mols. encoding the data. While preservation of biol. DNA has been studied previously, synthetic DNA differs in that it is typically much shorter in length, it has different sequence profiles with fewer, if any, repeats (or homopolymers), and it has different contaminants. In this paper, nine different methods used to preserve data files encoded in synthetic DNA are evaluated by accelerated aging of nearly 29 000 DNA sequences. In addn. to a mol. count comparison, the DNA is also sequenced and analyzed after aging. These findings show that errors and erasures are stochastic and show no practical distribution difference between preservation methods. Finally, the phys. d. of these methods is compared and a stability vs. d. trade-offs discussion provided.
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    Liu, Y.; Zheng, Z.; Gong, H.; Liu, M.; Guo, S.; Li, G.; Wang, X.; Kaplan, D. L. DNA Preservation in Silk. Biomater Sci. 2017, 5 (7), 1279– 1292,  DOI: 10.1039/C6BM00741D
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    65
    DNA preservation in silk
    Liu, Yawen; Zheng, Zhaozhu; Gong, He; Liu, Meng; Guo, Shaozhe; Li, Gang; Wang, Xiaoqin; Kaplan, David L.
    Biomaterials Science (2017), 5 (7), 1279-1292CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
    The structure of DNA is susceptible to alterations at high temp. and on changing pH, irradn. and exposure to DNase. In the present study, the stability of total DNA purified from human dermal fibroblast cells, as well as that of plasmid DNA, was studied in silk protein materials. The DNA/silk mixts. were stabilized on filter paper (silk/DNA + filter) or filter paper pre-coated with silk and treated with methanol (silk/DNA + PT-filter) as a route to practical utility. After air-drying and water extn., 50-70% of the DNA and silk could be retrieved and showed a single band on electrophoretic gels. 6% silk/DNA + PT-filter samples provided improved stability in comparison with 3% silk/DNA + filter samples and DNA + filter samples for DNA preservation, with ~ 40% of the band intensity remaining at 37°C after 40 days and ~ 10% after exposure to UV light for 10 h. Quant. anal. using the PicoGreen assay confirmed the results. The use of Tris/borate/EDTA (TBE) buffer enhanced the preservation and/or extn. of the DNA. The high mol. wt. and high content of a cryst. beta-sheet structure formed on the coated surfaces likely accounted for the preservation effects obsd. for the silk/DNA + PT-filter samples. Although similar preservation effects were also obtained for lyophilized silk/DNA samples, the rapid and simple processing available with the silk-DNA-filter membrane system makes it appealing for future applications.
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  66. 66
    Antkowiak, P. L.; Koch, J.; Rzepka, P.; Nguyen, B. H.; Strauss, K.; Stark, W. J.; Grass, R. N. Anhydrous Calcium Phosphate Crystals Stabilize DNA for Dry Storage. Chem. Commun. 2022, 58 (19), 3174– 3177,  DOI: 10.1039/D2CC00414C
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    66
    Anhydrous calcium phosphate crystals stabilize DNA for dry storage
    Antkowiak, Philipp L.; Koch, Julian; Rzepka, Przemyslaw; Nguyen, Bichlien H.; Strauss, Karin; Stark, Wendelin J.; Grass, Robert N.
    Chemical Communications (Cambridge, United Kingdom) (2022), 58 (19), 3174-3177CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The resilience of ancient DNA (aDNA) in bone gives rise to the preservation of synthetic DNA with bioinorg. materials such as calcium phosphate (CaP). Accelerated aging expts. at elevated temp. and humidity displayed a pos. effect of co-pptd., cryst. dicalcium phosphate on the stability of synthetic DNA in contrast to amorphous CaP. Quant. PXRD in combination with SEM and EDX measurements revealed distinct CaP phase transformations of calcium phosphate dihydrate (brushite) to anhyd. dicalcium phosphate (monetite) influencing DNA stability.
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  67. 67
    Clermont, D.; Santoni, S.; Saker, S.; Gomard, M.; Gardais, E.; Bizet, C. Assessment of DNA Encapsulation, a New Room-Temperature DNA Storage Method. Biopreserv Biobank 2014, 12 (3), 176– 183,  DOI: 10.1089/bio.2013.0082
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    67
    Assessment of DNA encapsulation, a new room-temperature DNA storage method
    Clermont Dominique; Santoni Sylvain; Saker Safa; Gomard Maite; Gardais Eliane; Bizet Chantal
    Biopreservation and biobanking (2014), 12 (3), 176-83 ISSN:.
    A new procedure for room-temperature storage of DNA was evaluated whereby DNA samples from human tissue, bacteria, and plants were stored under an anoxic and anhydrous atmosphere in small glass vials fitted in stainless-steel, laser-sealed capsules (DNAshells(®)). Samples were stored in DNAshells(®) at room temperature for various periods of time to assess any degradation and compare it to frozen control samples and those stored in GenTegra® tubes. The study included analysis of the effect of accelerated aging by using a high temperature (76°C) at 50% relative humidity. No detectable DNA degradation was seen in samples stored in DNAshells(®) at room temperature for 18 months. Polymerase chain reaction experiments, pulsed field gel electrophoresis, and amplified fragment length polymorphism analyses also demonstrated that the protective properties of DNAshells(®) are not affected by storage under extreme conditions (76°C, 50% humidity) for 30 hours, guaranteeing 100 years without DNA sample degradation. However, after 30 hours of storage at 76°C, it was necessary to include adjustments to the process in order to avoid DNA loss. Successful protection of DNA was obtained for 1 week and even 1 month of storage at high temperature by adding trehalose, which provides a protective matrix. This study demonstrates the many advantages of using DNAshells(®) for room-temperature storage, particularly in terms of long-term stability, safety, transport, and applications for molecular biology research.
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  68. 68
    Fabre, A. L.; Luis, A.; Colotte, M.; Tuffet, S.; Bonnet, J. High DNA Stability in White Blood Cells and Buffy Coat Lysates Stored at Ambient Temperature under Anoxic and Anhydrous Atmosphere. PLoS One 2017, 12 (11), e0188547,  DOI: 10.1371/journal.pone.0188547
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    68
    High DNA stability in white blood cells and buffy coat lysates stored at ambient temperature under anoxic and anhydrous atmosphere
    Fabre, Anne-Lise; Luis, Aurelie; Colotte, Marthe; Tuffet, Sophie; Bonnet, Jacques
    PLoS One (2017), 12 (11), e0188547/1-e0188547/23CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Conventional storage of blood-derived fractions relies on cold. However, lately, ambient temp. preservation has been evaluated by several independent institutions that see economic and logistic advantages in getting rid of the cold chain. Here we validated a novel procedure for ambient temp. preservation of DNA in white blood cell and buffy coat lysates based on the confinement of the desiccated biospecimens under anoxic and anhyd. atm. in original hermetic minicapsules. For this validation we stored encapsulated samples either at ambient temp. or at several elevated temps. to accelerate aging. We found that DNA extd. from stored samples was of good quality with a yield of extn. as expected. Degrdn. rates were estd. from the av. fragment size of denatured DNA run on agarose gels and from qPCR reactions. At ambient temp., these rates were too low to be measured but the degrdn. rate dependence on temp. followed Arrhenius' law, making it possible to extrapolate degrdn. rates at 25°C. According to these values, the DNA stored in the encapsulated blood products would remain larger than 20 kb after one century at ambient temp. At last, qPCR expts. demonstrated the compatibility of extd. DNA with routine DNA downstream analyses. Altogether, these results showed that this novel storage method provides an adequate environment for ambient temp. long term storage of high mol. wt. DNA in dehydrated lysates of white blood cells and buffy coats.
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  69. 69
    Matange, K.; Tuck, J. M.; Keung, A. J. DNA Stability: A Central Design Consideration for DNA Data Storage Systems. Nat. Commun. 2021, 12 (1), 1358,  DOI: 10.1038/s41467-021-21587-5
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    69
    DNA stability: a central design consideration for DNA data storage systems
    Matange, Karishma; Tuck, James M.; Keung, Albert J.
    Nature Communications (2021), 12 (1), 1358CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    A review. Abstr.: Data storage in DNA is a rapidly evolving technol. that could be a transformative soln. for the rising energy, materials, and space needs of modern information storage. Given that the information medium is DNA itself, its stability under different storage and processing conditions will fundamentally impact and constrain design considerations and data system capabilities. Here we analyze the storage conditions, mol. mechanisms, and stabilization strategies influencing DNA stability and pose specific design configurations and scenarios for future systems that best leverage the considerable advantages of DNA storage.
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  70. 70
    Organick, L.; Ang, S. D.; Chen, Y. J.; Lopez, R.; Yekhanin, S.; Makarychev, K.; Racz, M. Z.; Kamath, G.; Gopalan, P.; Nguyen, B.; Takahashi, C. N.; Newman, S.; Parker, H. Y.; Rashtchian, C.; Stewart, K.; Gupta, G.; Carlson, R.; Mulligan, J.; Carmean, D.; Seelig, G.; Ceze, L.; Strauss, K. Random Access in Large-Scale DNA Data Storage. Nat. Biotechnol. 2018, 36 (3), 242– 248,  DOI: 10.1038/nbt.4079
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    70
    Random access in large-scale DNA data storage
    Organick, Lee; Ang, Siena Dumas; Chen, Yuan-Jyue; Lopez, Randolph; Yekhanin, Sergey; Makarychev, Konstantin; Racz, Miklos Z.; Kamath, Govinda; Gopalan, Parikshit; Nguyen, Bichlien; Takahashi, Christopher N.; Newman, Sharon; Parker, Hsing-Yeh; Rashtchian, Cyrus; Stewart, Kendall; Gupta, Gagan; Carlson, Robert; Mulligan, John; Carmean, Douglas; Seelig, Georg; Ceze, Luis; Strauss, Karin
    Nature Biotechnology (2018), 36 (3), 242-248CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
    Synthetic DNA is durable and can encode digital data with high d., making it an attractive medium for data storage. However, recovering stored data on a large-scale currently requires all the DNA in a pool to be sequenced, even if only a subset of the information needs to be extd. Here, we encode and store 35 distinct files (over 200 MB of data), in more than 13 million DNA oligonucleotides, and show that we can recover each file individually and with no errors, using a random access approach. We design and validate a large library of primers that enable individual recovery of all files stored within the DNA. We also develop an algorithm that greatly reduces the sequencing read coverage required for error-free decoding by maximizing information from all sequence reads. These advances demonstrate a viable, large-scale system for DNA data storage and retrieval.
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    Tomek, K. J.; Volkel, K.; Simpson, A.; Hass, A. G.; Indermaur, E. W.; Tuck, J. M.; Keung, A. J. Driving the Scalability of DNA-Based Information Storage Systems. ACS Synth. Biol. 2019, 8 (6), 1241– 1248,  DOI: 10.1021/acssynbio.9b00100
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    71
    Driving the Scalability of DNA-Based Information Storage Systems
    Tomek, Kyle J.; Volkel, Kevin; Simpson, Alexander; Hass, Austin G.; Indermaur, Elaine W.; Tuck, James M.; Keung, Albert J.
    ACS Synthetic Biology (2019), 8 (6), 1241-1248CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    The extreme d. of DNA presents a compelling advantage over current storage media; however, to reach practical capacities, new systems for organizing and accessing information are needed. Here, the authors use chem. handles to selectively ext. unique files from a complex database of DNA mimicking 5 TB of data and design and implement a nested file address system that increases the theor. max. capacity of DNA storage systems by five orders of magnitude. These advancements enable the development and future scaling of DNA-based data storage systems with modern capacities and file access capabilities.
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  72. 72
    Tabatabaei, S. K.; Wang, B.; Athreya, N. B. M.; Enghiad, B.; Hernandez, A. G.; Fields, C. J.; Leburton, J.-P.; Soloveichik, D.; Zhao, H.; Milenkovic, O. DNA Punch Cards for Storing Data on Native DNA Sequences via Enzymatic Nicking. Nat. Commun. 2020, 11 (1), 1742,  DOI: 10.1038/s41467-020-15588-z
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    72
    DNA punch cards for storing data on native DNA sequences via enzymatic nicking
    Tabatabaei, S. Kasra; Wang, Boya; Athreya, Nagendra Bala Murali; Enghiad, Behnam; Hernandez, Alvaro Gonzalo; Fields, Christopher J.; Leburton, Jean-Pierre; Soloveichik, David; Zhao, Huimin; Milenkovic, Olgica
    Nature Communications (2020), 11 (1), 1742CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Synthetic DNA-based data storage systems have received significant attention due to the promise of ultrahigh storage d. and long-term stability. However, all known platforms suffer from high cost, read-write latency and error-rates that render them noncompetitive with modern storage devices. One means to avoid the above problems is using readily available native DNA. As the sequence content of native DNA is fixed, one can modify the topol. instead to encode information. Here, we introduce DNA punch cards, a macromol. storage mechanism in which data is written in the form of nicks at predetd. positions on the backbone of native double-stranded DNA. The platform accommodates parallel nicking on orthogonal DNA fragments and enzymic toehold creation that enables single-bit random-access and in-memory computations. We use Pyrococcus furiosus Argonaute to punch files into the PCR products of Escherichia coli genomic DNA and accurately reconstruct the encoded data through high-throughput sequencing and read alignment.
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    Mikutis, G.; Schmid, L.; Stark, W. J.; Grass, R. N. Length-Dependent DNA Degradation Kinetic Model: Decay Compensation in DNA Tracer Concentration Measurements. AIChE J. 2019, 65 (1), 40– 48,  DOI: 10.1002/aic.16433
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    73
    Length-dependent DNA degradation kinetic model: Decay compensation in DNA tracer concentration measurements
    Mikutis, Gediminas; Schmid, Lucius; Stark, Wendelin J.; Grass, Robert N.
    AIChE Journal (2019), 65 (1), 40-48CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)
    DNA is often used as a tracer in both environmental fluid flow characterization and in material tracking to avoid counterfeiting and ensure transparency in product value chains. The main drawback of DNA as a tracer is its limited stability, making quant. anal. difficult. Here, we study length-dependent DNA decay at elevated temps. and under sunlight by quant. PCR and show that the stability of randomly generated DNA sequences is inversely proportional to the sequence length. By quantifying the remaining DNA length distribution, we present a method to det. the extent of decay and to account for it. We propose a correction factor based on the ratio of measured concns. of two different length sequences. Multiplying the measured DNA concn. by this length-dependent correction factor enables precise DNA tracer quantification, even if DNA mols. have undergone more than 100-fold degrdn. © 2018 American Institute of Chem. Engineers AIChE J, 2018.
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    Hossein Tabatabaei Yazdi, S. M.; Gabrys, R.; Milenkovic, O. Portable and Error-Free DNA-Based Data Storage. Sci. Rep 2017, 7, 5011,  DOI: 10.1038/s41598-017-05188-1
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    Banal, J. L.; Shepherd, T. R.; Berleant, J.; Huang, H.; Reyes, M.; Ackerman, C. M.; Blainey, P. C.; Bathe, M. Random Access DNA Memory Using Boolean Search in an Archival File Storage System. Nat. Mater. 2021, 20 (9), 1272– 1280,  DOI: 10.1038/s41563-021-01021-3
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    75
    Random access DNA memory using Boolean search in an archival file storage system
    Banal, James L.; Shepherd, Tyson R.; Berleant, Joseph; Huang, Hellen; Reyes, Miguel; Ackerman, Cheri M.; Blainey, Paul C.; Bathe, Mark
    Nature Materials (2021), 20 (9), 1272-1280CODEN: NMAACR; ISSN:1476-1122. (Nature Portfolio)
    DNA is an ultrahigh-d. storage medium that could meet exponentially growing worldwide demand for archival data storage if DNA synthesis costs declined sufficiently and if random access of files within exabyte-to-yottabyte-scale DNA data pools were feasible. Here, we demonstrate a path to overcome the second barrier by encapsulating data-encoding DNA file sequences within impervious silica capsules that are surface labeled with single-stranded DNA barcodes. Barcodes are chosen to represent file metadata, enabling selection of sets of files with Boolean logic directly, without use of amplification. We demonstrate random access of image files from a prototypical 2-kilobyte image database using fluorescence sorting with selection sensitivity of one in 106 files, which thereby enables one in 106N selection capability using N optical channels. Our strategy thereby offers a scalable concept for random access of archival files in large-scale mol. datasets.
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  76. 76
    Chen, Y. J.; Takahashi, C. N.; Organick, L.; Bee, C.; Ang, S. D.; Weiss, P.; Peck, B.; Seelig, G.; Ceze, L.; Strauss, K. Quantifying Molecular Bias in DNA Data Storage. Nat. Commun. 2020, 11, 3264,  DOI: 10.1038/s41467-020-16958-3
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    76
    Quantifying molecular bias in DNA data storage
    Chen, Yuan-Jyue; Takahashi, Christopher N.; Organick, Lee; Bee, Callista; Ang, Siena Dumas; Weiss, Patrick; Peck, Bill; Seelig, Georg; Ceze, Luis; Strauss, Karin
    Nature Communications (2020), 11 (1), 3264CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: DNA has recently emerged as an attractive medium for archival data storage. Recent work has demonstrated proof-of-principle prototype systems; however, very uneven (biased) sequencing coverage has been reported, which indicates inefficiencies in the storage process. Deviations from the av. coverage in the sequence copy distribution can either cause wasteful provisioning in sequencing or excessive no. of missing sequences. Here, we use millions of unique sequences from a DNA-based digital data archival system to study the oligonucleotide copy unevenness problem and show that the two paramount sources of bias are the synthesis and amplification (PCR) processes. Based on these findings, we develop a statistical model for each mol. process as well as the overall process. We further use our model to explore the trade-offs between synthesis bias, storage phys. d., logical redundancy, and sequencing redundancy, providing insights for engineering efficient, robust DNA data storage systems.
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    Winston, C.; Organick, L.; Ward, D.; Ceze, L.; Strauss, K.; Chen, Y.-J. Combinatorial PCR Method for Efficient, Selective Oligo Retrieval from Complex Oligo Pools. ACS Synth. Biol. 2022, 11 (5), 1727– 1734,  DOI: 10.1021/acssynbio.1c00482
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    77
    Combinatorial PCR Method for Efficient, Selective Oligo Retrieval from Complex Oligo Pools
    Winston, Claris; Organick, Lee; Ward, David; Ceze, Luis; Strauss, Karin; Chen, Yuan-Jyue
    ACS Synthetic Biology (2022), 11 (5), 1727-1734CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    With the rapidly decreasing cost of array-based oligo synthesis, large-scale oligo pools offer significant benefits for advanced applications including gene synthesis, CRISPR-based gene editing, and DNA data storage. The selective retrieval of specific oligos from these complex pools traditionally uses polymerase chain reaction (PCR). Designing a large no. of primers to use in PCR presents a serious challenge, particularly for DNA data storage, where the size of an oligo pool is orders of magnitude larger than other applications. Although a nested primer address system was recently developed to increase the no. of accessible files for DNA storage, it requires more complicated lab protocols and more expensive reagents to achieve high specificity, as well as more DNA address space. Here, we present a new combinatorial PCR method that has none of those drawbacks and outperforms in retrieval specificity. In expts., we accessed three files that each comprised 1% of a DNA prototype database that contained 81 different files and enriched them to over 99.9% using our combinatorial primer method. Our method provides a viable path for scaling up DNA data storage systems and has broader utility whenever one must access a specific target oligo and can design their own primer regions.
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  78. 78
    Lin, K. N.; Volkel, K.; Tuck, J. M.; Keung, A. J. Dynamic and Scalable DNA-Based Information Storage. Nat. Commun. 2020, 11 (1), 2981,  DOI: 10.1038/s41467-020-16797-2
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    Dynamic and scalable DNA-based information storage
    Lin, Kevin N.; Volkel, Kevin; Tuck, James M.; Keung, Albert J.
    Nature Communications (2020), 11 (1), 2981CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The phys. architectures of information storage systems often dictate how information is encoded, databases are organized, and files are accessed. Here we show that a simple architecture comprised of a T7 promoter and a single-stranded overhang domain (ss-dsDNA), can unlock dynamic DNA-based information storage with powerful capabilities and advantages. The overhang provides a phys. address for accessing specific DNA strands as well as implementing a range of in-storage file operations. It increases theor. storage densities and capacities by expanding the encodable sequence space and simplifies the computational burden in designing sets of orthogonal file addresses. Meanwhile, the T7 promoter enables repeatable information access by transcribing information from DNA without destroying it. Furthermore, satn. mutagenesis around the T7 promoter and systematic analyses of environmental conditions reveal design criteria that can be used to optimize information access. This simple but powerful ss-dsDNA architecture lays the foundation for information storage with versatile capabilities.
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    Grass, R. N.; Heckel, R.; Dessimoz, C.; Stark, W. J. Genomic Encryption of Digital Data Stored in Synthetic DNA. Angew. Chem., Int. Ed. 2020, 59 (22), 8476– 8480,  DOI: 10.1002/anie.202001162
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    79
    Genomic Encryption of Digital Data Stored in Synthetic DNA
    Grass, Robert N.; Heckel, Reinhard; Dessimoz, Christophe; Stark, Wendelin J.
    Angewandte Chemie, International Edition (2020), 59 (22), 8476-8480CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Today, we can read human genomes and store digital data robustly in synthetic DNA. Herein, we report a strategy to intertwine these two technologies to enable the secure storage of valuable information in synthetic DNA, protected with personalized keys. We show that genetic short tandem repeats (STRs) contain sufficient entropy to generate strong encryption keys, and that only one technol., DNA sequencing, is required to simultaneously read the key and the data. Using this approach, we exptl. generated 80 bit strong keys from human DNA, and used such a key to encrypt 17 kB of digital information stored in synthetic DNA. Finally, the decrypted information was recovered perfectly from a single massively parallel sequencing run.
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    Kim, J.; Bae, J. H.; Baym, M.; Zhang, D. Y. Metastable Hybridization-Based DNA Information Storage to Allow Rapid and Permanent Erasure. Nat. Commun. 2020, 11, 5008,  DOI: 10.1038/s41467-020-18842-6
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    Metastable hybridization-based DNA information storage to allow rapid and permanent erasure
    Kim, Jangwon; Bae, Jin H.; Baym, Michael; Zhang, David Yu
    Nature Communications (2020), 11 (1), 5008CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The potential of DNA as an information storage medium is rapidly growing due to advances in DNA synthesis and sequencing. However, the chem. stability of DNA challenges the complete erasure of information encoded in DNA sequences. Here, we encode information in a DNA information soln., a mixt. of true message- and false message-encoded oligonucleotides, and enables rapid and permanent erasure of information. True messages are differentiated by their hybridization to a "truth marker" oligonucleotide, and only true messages can be read; binding of the truth marker can be effectively randomized even with a brief exposure to the elevated temp. We show 8 sep. bitmap images can be stably encoded and read after storage at 25°C for 65 days with an av. of over 99% correct information recall, which extrapolates to a half-life of over 15 years at 25°C. Heating to 95°C for 5 min, however, permanently erases the message.
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    Tabatabaei Yazdi, S. M. H.; Yuan, Y.; Ma, J.; Zhao, H.; Milenkovic, O. A Rewritable, Random-Access DNA-Based Storage System. Sci. Rep 2015, 5, 1– 10,  DOI: 10.1038/srep14138
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    Mayer, C.; McInroy, G. R.; Murat, P.; van Delft, P.; Balasubramanian, S. An Epigenetics-Inspired DNA-Based Data Storage System. Angew. Chem. 2016, 128 (37), 11310– 11314,  DOI: 10.1002/ange.201605531
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    Zhang, Y.; Ren, Y.; Liu, Y.; Wang, F.; Zhang, H.; Liu, K. Preservation and Encryption in DNA Digital Data Storage. ChemPlusChem. 2022, 87 (9), e202200183,  DOI: 10.1002/cplu.202200183
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    Preservation and Encryption in DNA Digital Data Storage
    Zhang, Yi; Ren, Yubin; Liu, Yangyi; Wang, Fan; Zhang, Hongjie; Liu, Kai
    ChemPlusChem (2022), 87 (9), e202200183CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The exponential growth of the total amt. of global data presents a huge challenge to mainstream storage media. The emergence of mol. digital storage inspires the development of the new-generation higher-d. digital data storage. In particular, DNA with high storage d., reproducibility, and long recoverable lifetime behaves the ideal representative of mol. digital storage media. With the development of DNA synthesis and sequencing technologies and the redn. of cost, DNA digital storage has attracted more and more attention and achieved significant breakthroughs. Herein, this Review briefly describes the workflow of DNA storage, and highlights the storage step of DNA digital data storage. Then, according to different information storage forms, the current DNA information encryption methods are emphatically expounded. Finally, the brief perspectives on the current challenges and optimizing proposals in DNA information preservation and encryption are presented.
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    Coming of age: ten years of next-generation sequencing technologies
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    A review. Since the completion of the human genome project in 2003, extraordinary progress has been made in genome sequencing technologies, which has led to a decreased cost per megabase and an increase in the no. and diversity of sequenced genomes. An astonishing complexity of genome architecture has been revealed, bringing these sequencing technologies to even greater advancements. Some approaches maximize the no. of bases sequenced in the least amt. of time, generating a wealth of data that can be used to understand increasingly complex phenotypes. Alternatively, other approaches now aim to sequence longer contiguous pieces of DNA, which are essential for resolving structurally complex regions. These and other strategies are providing researchers and clinicians a variety of tools to probe genomes in greater depth, leading to an enhanced understanding of how genome sequence variants underlie phenotype and disease.
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    Lopez, R.; Chen, Y. J.; Dumas Ang, S.; Yekhanin, S.; Makarychev, K.; Racz, M. Z.; Seelig, G.; Strauss, K.; Ceze, L. DNA Assembly for Nanopore Data Storage Readout. Nat. Commun. 2019, 10 (1), 1– 9,  DOI: 10.1038/s41467-019-10978-4
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    Decoupling of mechanical properties and ionic conductivity in supramolecular lithium ion conductors
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    Nature Communications (2019), 10 (1), 1-11CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The emergence of wearable electronics puts batteries closer to the human skin, exacerbating the need for battery materials that are robust, highly ionically conductive, and stretchable. Herein, we introduce a supramol. design as an effective strategy to overcome the canonical tradeoff between mech. robustness and ionic cond. in polymer electrolytes. The supramol. lithium ion conductor utilizes orthogonally functional H-bonding domains and ion-conducting domains to create a polymer electrolyte with unprecedented toughness (29.3 MJ m-3) and high ionic cond. (1.2 × 10-4 S cm-1 at 25°C). Implementation of the supramol. ion conductor as a binder material allows for the creation of stretchable lithium-ion battery electrodes with strain capability of over 900% via a conventional slurry process. The supramol. nature of these battery components enables intimate bonding at the electrode-electrolyte interface. Combination of these stretchable components leads to a stretchable battery with a capacity of 1.1 mAh cm-2 that functions even when stretched to 70% strain. The method reported here of decoupling ionic cond. from mech. properties opens a promising route to create high-toughness ion transport materials for energy storage applications.
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    Wang, Y.; Zhang, S.; Jia, W.; Fan, P.; Wang, L.; Li, X.; Chen, J.; Cao, Z.; Du, X.; Liu, Y.; Wang, K.; Hu, C.; Zhang, J.; Hu, J.; Zhang, P.; Chen, H.-Y.; Huang, S. Identification of Nucleoside Monophosphates and Their Epigenetic Modifications Using an Engineered Nanopore. Nat. Nanotechnol 2022, 17, 976,  DOI: 10.1038/s41565-022-01169-2
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    Nature Nanotechnology (2022), 17 (9), 976-983CODEN: NNAABX; ISSN:1748-3387. (Nature Portfolio)
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    A long-held goal in sequencing has been to use a voltage-biased nanoscale pore in a membrane to measure the passage of a linear, single-stranded (ss) DNA or RNA mol. through that pore. With the development of enzyme-based methods that ratchet polynucleotides through the nanopore, nucleobase-by-nucleobase, measurements of changes in the current through the pore can now be decoded into a DNA sequence using an algorithm. In this Historical Perspective, we describe the key steps in nanopore strand-sequencing, from its earliest conceptualization more than 25 years ago to its recent commercialization and application.
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    Jensen, M. A.; Davis, R. W. Template-Independent Enzymatic Oligonucleotide Synthesis (TiEOS): Its History, Prospects, and Challenges. Biochemistry 2018, 57 (12), 1821– 1832,  DOI: 10.1021/acs.biochem.7b00937
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    Template-Independent Enzymatic Oligonucleotide Synthesis (TiEOS): Its History, Prospects, and Challenges
    Jensen, Michael A.; Davis, Ronald W.
    Biochemistry (2018), 57 (12), 1821-1832CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    A review. There is a growing demand for sustainable methods in research and development, where instead of hazardous chems., an aq. medium is chosen to carry out biol. reactions. In this Perspective we examine the history and current methodol. of using enzymes to generate artificial single-stranded DNA. By using traditional solid-phase phosphoramidite chem. as a metric, we also explore criteria for the method of Template-independent Enzymic Oligonucleotide Synthesis (TiEOS). As its key component, we delve into the biol. of one of the most enigmatic enzymes, Terminal deoxynucleotidyl Transferase (TdT). Found to exponentially increase antigen receptor diversity in the vertebrate immune system by adding nucleotides in a template-free manner, researchers have exploited this function as an alternative to the phosphoramidite synthesis method. Though TdT is currently the preferred enzyme for TiEOS, its random nucleotide incorporation presents a barrier in synthesis automation. Taking a closer look at the TiEOS cycle, particularly the coupling step, we find it is comprised of addns. > n+1 and deletions. By tapping into the phys. and biochem. properties of TdT, we strive to further elucidate its mercurial behavior, and offer ways to better optimize TiEOS for prodn.-grade oligonucleotide synthesis.
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    Bošković, F.; Ohmann, A.; Keyser, U. F.; Chen, K. DNA Structural Barcode Copying and Random Access. Small Struct 2021, 2 (5), 2000144,  DOI: 10.1002/sstr.202000144
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    DNA Structural Barcode Copying and Random Access
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    Small Structures (2021), 2 (5), 2000144CODEN: SSMTB2; ISSN:2688-4062. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Digitally encoded DNA (DNA) nanostructures built via DNA self-assembly have established applications in multiplexed biosensing and storing digital information. However, a key challenge is that DNA structures are not easily copied which is of vital importance for their large-scale prodn. and access to desired mols. by target-specific amplification. Herein, DNA structural barcodes are built and the copying and random access of the barcodes from a library of mols. is demonstrated using a modified polymerase chain reaction (PCR). The structural barcodes are assembled by annealing a single-stranded DNA scaffold with complementary short oligonucleotides contg. protrusions as digital bits at defined locations. DNA nicks in these structures are ligated to facilitate barcode copying using PCR. To randomly access a target from a library of barcodes, a non-complementary end in the DNA construct that serves as a barcode-specific primer-template is used. Readout of the DNA structural barcodes is performed with nanopore measurements. The study provides a roadmap for the convenient prodn. of large quantities of self-assembled DNA nanostructures. In addn., this strategy offers access to specific targets, a crucial capability for multiplexed single-mol. sensing, and DNA data storage.
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    Zhu, J.; Ermann, N.; Chen, K.; Keyser, U. F. Image Encoding Using Multi-Level DNA Barcodes with Nanopore Readout. Small 2021, 17 (28), 2100711,  DOI: 10.1002/smll.202100711
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    Image Encoding Using Multi-Level DNA Barcodes with Nanopore Readout
    Zhu, Jinbo; Ermann, Niklas; Chen, Kaikai; Keyser, Ulrich F.
    Small (2021), 17 (28), 2100711CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    DNA (DNA) nanostructure-based data encoding is an emerging information storage mode, offering rewritable, editable, and secure data storage. Herein, a DNA nanostructure-based storage method established on a solid-state nanopore sensing platform to save and encrypt a 2D grayscale image is proposed. DNA multi-way junctions of different sizes are attached to a double strand of DNA carriers, resulting in distinct levels of current blockades when passing through a glass nanopore with diams. around 14 nm. The resulting quaternary encoding doubles the capacity relative to a classical binary system. Through toehold-mediated strand displacement reactions, the DNA nanostructures can be precisely added to and removed from the DNA carrier. By encoding the image into 16 DNA carriers using the quaternary barcodes and reading them in one simultaneous measurement, the image is successfully saved, encrypted, and recovered. Avoiding any proteins or enzymic reactions, the authors thus realize a pure DNA storage system on a nanopore platform with increased capacity and programmability.
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    Pinheiro, A. v.; Han, D.; Shih, W. M.; Yan, H. Challenges and Opportunities for Structural DNA Nanotechnology. Nat. Nanotechnol 2011, 6 (12), 763– 772,  DOI: 10.1038/nnano.2011.187
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    Challenges and opportunities for structural DNA nanotechnology
    Pinheiro, Andre V.; Han, Dongran; Shih, William M.; Yan, Hao
    Nature Nanotechnology (2011), 6 (12), 763-772CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    A review. DNA mols. have been used to build a variety of nanoscale structures and devices over the past 30 years, and potential applications have begun to emerge. But the development of more advanced structures and applications will require a no. of issues to be addressed, the most significant of which are the high cost of DNA and the high error rate of self-assembly. Here we examine the tech. challenges in the field of structural DNA nanotechnol. and outline some of the promising applications that could be developed if these hurdles can be overcome. In particular, we highlight the potential use of DNA nanostructures in mol. and cellular biophysics, as biomimetic systems, in energy transfer and photonics, and in diagnostics and therapeutics for human health.
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    Agarwal, N. P.; Matthies, M.; Joffroy, B.; Schmidt, T. L. Structural Transformation of Wireframe DNA Origami via DNA Polymerase Assisted Gap-Filling. ACS Nano 2018, 12 (3), 2546– 2553,  DOI: 10.1021/acsnano.7b08345
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    Structural Transformation of Wireframe DNA Origami via DNA Polymerase Assisted Gap-Filling
    Agarwal, Nayan P.; Matthies, Michael; Joffroy, Bastian; Schmidt, Thorsten L.
    ACS Nano (2018), 12 (3), 2546-2553CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    The programmability of DNA enables constructing nanostructures with almost any arbitrary shape, which can be decorated with many functional materials. Moreover, dynamic structures can be realized such as mol. motors and walkers. The authors have explored the possibility to synthesize the complementary sequences to single-stranded gap regions in the DNA origami scaffold cost effectively by a DNA polymerase rather than by a DNA synthesizer. For this purpose, four different wireframe DNA origami structures were designed to have single-stranded gap regions. This reduced the no. of staple strands needed to det. the shape and size of the final structure after gap filling. For this, several DNA polymerases and single-stranded binding (SSB) proteins were tested, with T4 DNA polymerase being the best fit. The structures could be folded in as little as 6 min, and the subsequent optimized gap-filling reaction was completed in <3 min. The introduction of flexible gap regions results in fully collapsed or partially bent structures due to entropic spring effects. Finally, the authors demonstrated structural transformations of such deformed wireframe DNA origami structures with DNA polymerases including the expansion of collapsed structures and the straightening of curved tubes. The authors anticipate that this approach will become a powerful tool to build DNA wireframe structures more material-efficiently, and to quickly prototype and test new wireframe designs that can be expanded, rigidified, or mech. switched. Mech. force generation and structural transitions will enable applications in structural DNA nanotechnol., plasmonics, or single-mol. biophysics.
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    Sobczak, J. P. J.; Martin, T. G.; Gerling, T.; Dietz, H. Rapid Folding of DNA into Nanoscale Shapes at Constant Temperature. Science 2012, 338 (6113), 1458– 1461,  DOI: 10.1126/science.1229919
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    Rapid Folding of DNA into Nanoscale Shapes at Constant Temperature
    Sobczak, Jean-Philippe J.; Martin, Thomas G.; Gerling, Thomas; Dietz, Hendrik
    Science (Washington, DC, United States) (2012), 338 (6113), 1458-1461CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    At const. temp., hundreds of DNA strands can cooperatively fold a long template DNA strand within minutes into complex nanoscale objects. Folding occurred out of equil. along nucleation-driven pathways at temps. that could be influenced by the choice of sequences, strand lengths, and chain topol. Unfolding occurred in apparent equil. at higher temps. than those for folding. Folding at optimized const. temps. enabled the rapid prodn. of three-dimensional DNA objects with yields that approached 100%. The results point to similarities with protein folding in spite of chem. and structural differences. The possibility for rapid and high-yield assembly will enable DNA nanotechnol. for practical applications.
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    Rizzuto, F. J.; Platnich, C. M.; Luo, X.; Shen, Y.; Dore, M. D.; Lachance-Brais, C.; Guarné, A.; Cosa, G.; Sleiman, H. F. A Dissipative Pathway for the Structural Evolution of DNA Fibres. Nat. Chem. 2021, 13 (9), 843– 849,  DOI: 10.1038/s41557-021-00751-w
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    A dissipative pathway for the structural evolution of DNA fibres
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    Nature Chemistry (2021), 13 (9), 843-849CODEN: NCAHBB; ISSN:1755-4330. (Nature Portfolio)
    Biochem. networks interconnect, grow and evolve to express new properties as different chem. pathways are selected during a continuous cycle of energy consumption and transformation. In contrast, synthetic systems that push away from equil. usually return to the same self-assembled state, often generating waste that limits system recyclability and prevents the formation of adaptable networks. Here we show that annealing by slow proton dissipation selects for otherwise inaccessible morphologies of fibers built from DNA and cyanuric acid. Using single-mol. fluorescence microscopy, we observe that proton dissipation influences the growth mechanism of supramol. polymn., healing gaps within fibers and converting highly branched, interwoven networks into nanocable superstructures. Just as the growth kinetics of natural fibers det. their structural attributes to modulate function, our system of photoacid-enabled depolymn. and repolymn. selects for healed materials to yield organized, robust fibers. Our method provides a chem. route for error-checking, distinct from thermal annealing, that improves the morphologies and properties of supramol. materials using out-of-equil. systems.
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    Bornholt, J.; Lopez, R.; Carmean, D.; Ceze, L.; Seelig, G.; Strauss, K. A DNA-Based Archival Storage System. IEEE Micro 2017, 37, 98– 104,  DOI: 10.1109/MM.2017.70
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    Dey, S.; Fan, C.; Gothelf, K. v.; Li, J.; Lin, C.; Liu, L.; Liu, N.; Nijenhuis, M. A. D.; Saccà, B.; Simmel, F. C.; Yan, H.; Zhan, P. DNA Origami. Nature Reviews Methods Primers 2021, 1 (1), 13,  DOI: 10.1038/s43586-020-00009-8
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    DNA origami
    Dey, Swarup; Fan, Chunhai; Gothelf, Kurt V.; Li, Jiang; Lin, Chenxiang; Liu, Longfei; Liu, Na; Nijenhuis, Minke A. D.; Sacca, Barbara; Simmel, Friedrich C.; Yan, Hao; Zhan, Pengfei
    Nature Reviews Methods Primers (2021), 1 (1), 13CODEN: NRMPAT; ISSN:2662-8449. (Nature Portfolio)
    A review. Biol. materials are self-assembled with near-at. precision in living cells, whereas synthetic 3D structures generally lack such precision and controllability. Recently, DNA nanotechnol., esp. DNA origami technol., has been useful in the bottom-up fabrication of well-defined nanostructures ranging from tens of nanometers to sub-micrometres. In this Primer, we summarize the methodologies of DNA origami technol., including origami design, synthesis, functionalization and characterization. We highlight applications of origami structures in nanofabrication, nanophotonics and nanoelectronics, catalysis, computation, mol. machines, bioimaging, drug delivery and biophysics. We identify challenges for the field, including size limits, stability issues and the scale of prodn., and discuss their possible solns. We further provide an outlook on next-generation DNA origami techniques that will allow in vivo synthesis and multiscale manufg.
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    Jun, H.; Zhang, F.; Shepherd, T.; Ratanalert, S.; Qi, X.; Yan, H.; Bathe, M. Autonomously Designed Free-Form 2D DNA Origami. Sci. Adv. 2019, 5 (1), eaav0655,  DOI: 10.1126/sciadv.aav0655
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    Yao, G.; Zhang, F.; Wang, F.; Peng, T.; Liu, H.; Poppleton, E.; Šulc, P.; Jiang, S.; Liu, L.; Gong, C.; Jing, X.; Liu, X.; Wang, L.; Liu, Y.; Fan, C.; Yan, H. Meta-DNA Structures. Nat. Chem. 2020, 12 (11), 1067– 1075,  DOI: 10.1038/s41557-020-0539-8
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    Meta-DNA structures
    Yao, Guangbao; Zhang, Fei; Wang, Fei; Peng, Tianhuan; Liu, Hao; Poppleton, Erik; Sulc, Petr; Jiang, Shuoxing; Liu, Lan; Gong, Chen; Jing, Xinxin; Liu, Xiaoguo; Wang, Lihua; Liu, Yan; Fan, Chunhai; Yan, Hao
    Nature Chemistry (2020), 12 (11), 1067-1075CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    DNA origami has emerged as a highly programmable method to construct customized objects and functional devices in the 10-100 nm scale. Scaling up the size of the DNA origami would enable many potential applications, which include metamaterial construction and surface-based biophys. assays. A six-helix bundle DNA origami nanostructure in the submicrometre scale (meta-DNA) could be used as a magnified analog of single-stranded DNA, and two meta-DNAs that contain complementary 'meta-base pairs' can form double helixes with programmed handedness and helical pitches. By mimicking the mol. behaviors of DNA strands and their assembly strategies, the authors used meta-DNA building blocks to form diverse and complex structures on the micrometre scale. Using meta-DNA building blocks, the authors constructed a series of DNA architectures on a submicrometre-to-micrometre scale, which include meta-multi-arm junctions, three-dimensional (3D) polyhedrons, and various 2D/3D lattices. The authors also demonstrated a hierarchical strand-displacement reaction on meta-DNA to transfer the dynamic features of DNA into the meta-DNA. This meta-DNA self-assembly concept may transform the microscopic world of structural DNA nanotechnol.
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    Voigt, N. v.; Tørring, T.; Rotaru, A.; Jacobsen, M. F.; Ravnsbæk, J. B.; Subramani, R.; Mamdouh, W.; Kjems, J.; Mokhir, A.; Besenbacher, F.; Gothelf, K. V. Single-Molecule Chemical Reactions on DNA Origami. Nat. Nanotechnol 2010, 5 (3), 200– 203,  DOI: 10.1038/nnano.2010.5
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    Single-molecule chemical reactions on DNA origami
    Voigt, Niels V.; Torring, Thomas; Rotaru, Alexandru; Jacobsen, Mikkel F.; Ravnsbaek, Jens B.; Subramani, Ramesh; Mamdouh, Wael; Kjems, Jorgen; Mokhir, Andriy; Besenbacher, Flemming; Gothelf, Kurt Vesterager
    Nature Nanotechnology (2010), 5 (3), 200-203CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    DNA nanotechnol. and particularly DNA origami, in which long, single-stranded DNA mols. are folded into predetd. shapes, can be used to form complex self-assembled nanostructures. Although DNA itself has limited chem., optical or electronic functionality, DNA nanostructures can serve as templates for building materials with new functional properties. Relatively large nanocomponents such as nanoparticles and biomols. can also be integrated into DNA nanostructures and imaged. Here, we show that chem. reactions with single mols. can be performed and imaged at a local position on a DNA origami scaffold by at. force microscopy. The high yields and chemoselectivities of successive cleavage and bond-forming reactions obsd. in these expts. demonstrate the feasibility of post-assembly chem. modification of DNA nanostructures and their potential use as locally addressable solid supports.
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    Pal, S.; Deng, Z.; Ding, B.; Yan, H.; Liu, Y. DNA-Origami-Directed Self-Assembly of Discrete Silver-Nanoparticle Architectures. Angew. Chem. 2010, 122 (15), 2760– 2764,  DOI: 10.1002/ange.201000330
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    Halvorsen, K.; Wong, W. P. Binary DNA Nanostructures for Data Encryption. PLoS One 2012, 7 (9), e44212,  DOI: 10.1371/journal.pone.0044212
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    Binary DNA nanostructures for data encryption
    Halvorsen, Ken; Wong, Wesley P.
    PLoS One (2012), 7 (9), e44212CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    We present a simple and secure system for encrypting and decrypting information using DNA self-assembly. Binary data is encoded in the geometry of DNA nanostructures with two distinct conformations. Removing or leaving out a single component reduces these structures to an encrypted soln. of ssDNA, whereas adding back this missing "decryption key" causes the spontaneous formation of the message through self-assembly, enabling rapid read out via gel electrophoresis. Applications include authentication, secure messaging and barcoding.
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    Chandrasekaran, A. R.; Levchenko, O.; Patel, D. S.; Macisaac, M.; Halvorsen, K. Addressable Configurations of DNA Nanostructures for Rewritable Memory. Nucleic Acids Res. 2017, 45 (19), 11459– 11465,  DOI: 10.1093/nar/gkx777
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    114
    Addressable configurations of DNA nanostructures for rewritable memory
    Chandrasekaran, Arun Richard; Levchenko, Oksana; Patel, Dhruv S.; MacIsaac, Molly; Halvorsen, Ken
    Nucleic Acids Research (2017), 45 (19), 11459-11465CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    DNA serves as nature's information storage mol., and has been the primary focus of engineered systems for biol. computing and data storage. Here we combine recent efforts in DNA self-assembly and toe-hold-mediated strand displacement to develop a rewritable multi-bit DNA memory system. The system operates by encoding information in distinct and reversible conformations of a DNA nanoswitch and decoding by gel electrophoresis. Our strategy is simple to implement, requiring only a single mixing step at room temp. for each operation and std. gel electrophoresis to read the data. We envision such systems could find use in covert product labeling and barcoding, as well as secure messaging and authentication when combined with previously developed encryption strategies. Ultimately, this type of memory has exciting potential in biomedical sciences as data storage can be coupled to sensing of biol. mols.
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    Shin, J. S.; Pierce, N. A. Rewritable Memory by Controllable Nanopatterning of DNA. Nano Lett. 2004, 4 (5), 905– 909,  DOI: 10.1021/nl049658r
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    115
    Rewritable Memory by Controllable Nanopatterning of DNA
    Shin, Jong-Shik; Pierce, Niles A.
    Nano Letters (2004), 4 (5), 905-909CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Fabricating a nanostructure capable of reversibly patterning mols. is a fundamental goal within nanotechnol., underlying diverse processes such as information storage, scaffold-assisted assembly, and mol. transport. Here, we describe a DNA scaffold supporting a one-dimensional array of independently and reversibly addressable sites at 7 nm spacing. As a proof-of-concept, we demonstrate robust functioning of the device as rewritable memory. The bit state of each address is controlled by specific DNA strands with external readout provided by fluorescence measurements.
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    Zhang, Y.; Li, F.; Li, M.; Mao, X.; Jing, X.; Liu, X.; Li, Q.; Li, J.; Wang, L.; Fan, C.; Zuo, X. Encoding Carbon Nanotubes with Tubular Nucleic Acids for Information Storage. J. Am. Chem. Soc. 2019, 141 (44), 17861– 17866,  DOI: 10.1021/jacs.9b09116
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    Encoding Carbon Nanotubes with Tubular Nucleic Acids for Information Storage
    Zhang, Yueyue; Li, Fan; Li, Min; Mao, Xiuhai; Jing, Xinxin; Liu, Xiaoguo; Li, Qian; Li, Jiang; Wang, Lihua; Fan, Chunhai; Zuo, Xiaolei
    Journal of the American Chemical Society (2019), 141 (44), 17861-17866CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    DNA has been evolved to be a type of unparalleled materials for storing and transmitting genetic information. Much recent attention has been drawn to translate the natural specificity of DNA hybridization reactions for information storage in vitro. In this work, the authors developed a new type of tubular nucleic acids (TNAs) by condensing DNA chains on the surface of one-dimensional carbon nanotubes (CNTs). The authors find that DNA interacts with CNTs in a sequence-specific manner, resulting in different conformations including helix, i-motif and G-quadruplex. Atomic force microscopic (AFM) imaging revealed that TNAs exhibit distinct patterns with characteristic height and distance that can be exploited for two-dimensional encoding on CNTs. The authors further demonstrate the use of TNA-CNT for information storage with visual output. This noncanonical, DNA hybridization-free strategy provides a new route to DNA-based data storage.
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    Pan, V.; Wang, W.; Heaven, I.; Bai, T.; Cheng, Y.; Chen, C.; Ke, Y.; Wei, B. Monochromatic Fluorescent Barcodes Hierarchically Assembled from Modular DNA Origami Nanorods. ACS Nano 2021, 15 (10), 15892– 15901,  DOI: 10.1021/acsnano.1c03796
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    117
    Monochromatic Fluorescent Barcodes Hierarchically Assembled from Modular DNA Origami Nanorods
    Pan, Victor; Wang, Wen; Heaven, Ian; Bai, Tanxi; Cheng, Yongxin; Chen, Chunlai; Ke, Yonggang; Wei, Bryan
    ACS Nano (2021), 15 (10), 15892-15901CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    With the rapid advancement of fluorescence microscopy, there is a growing interest in the multiplexed detection and identification of various bioanalytes (e.g., nucleic acids and proteins) for efficient sample processing and anal. We introduce in this work a simple and robust method to provide combinations for micrometer-scale fluorescent DNA barcodes of hierarchically assembled DNA origami superstructures for multiplexed mol. probing. In addn. to optically resolvable dots, we placed fluorescent loci on adjacent origami within the diffraction limit of each other, rendering them as unresolvable bars of measurable lengths. We created a basic set of barcodes and trained a machine learning algorithm to process and identify individual barcodes from raw images with high accuracy. Moreover, we demonstrated that the no. of combinations can be increased exponentially by generating longer barcodes, by controlling the no. of incorporated fluorophores to create multiple levels of fluorescence intensity, and by employing super-resoln. imaging. To showcase the readiness of the barcodes for applications, we used our barcodes to capture and identify target nucleic acid sequences and for simultaneous multiplexed characterization of binding kinetics of several orthogonal complementary nucleic acids.
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    Takinoue, M.; Suyama, A. Hairpin-DNA Memory Using Molecular Addressing. Small 2006, 2 (11), 1244– 1247,  DOI: 10.1002/smll.200600237
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    Hairpin-DNA memory using molecular addressing
    Takinoue, Masahiro; Suyama, Akira
    Small (2006), 2 (11), 1244-1247CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A memorable loopy address: A simple mol. memory, named the "hairpin-DNA memory", has been developed (see schematic). The memory employs the temp.-controlled conformational transition of hairpin-DNA strands in memory writing and erasing and allows parallel addressing of a very large memory space without phys. wiring. Expts. on repetitive memory writing and erasing demonstrated that the mol. addressing was highly selective and parallel.
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    Mottaghi, M. D.; Dwyer, C. Thousand-Fold Increase in Optical Storage Density by Polychromatic Address Multiplexing on Self-Assembled DNA Nanostructures. Adv. Mater. 2013, 25 (26), 3593– 3598,  DOI: 10.1002/adma.201301141
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    119
    Thousand-Fold Increase in Optical Storage Density by Polychromatic Address Multiplexing on Self-Assembled DNA Nanostructures
    Mottaghi, Mohammad D.; Dwyer, Chris
    Advanced Materials (Weinheim, Germany) (2013), 25 (26), 3593-3598CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors demonstrated a novel information retrieval technique called polychromatic address multiplexing (PAM) which, among its various applications, has the potential to enable a several-thousand-fold increase in the areal storage d. of optical disks beyond the diffraction limit. PAM exploits acceptor satn. in precisely-assembled nanoscale FRET-based structures to induce a fluorescence increase which is exclusively caused by the addressed structures while other structures remain inactive. Using com. available dyes, the authors synthesized two kinds of storage elements to exptl. demonstrate, as a proof-of-concept, storage cell capacities of two, three, and four bits. The authors also simulated 6-color storage-elements based on PAM-optimized synthetic dyes and the channel capacities were shown to be at least six bits. The exponential growth of the address space enabled by PAM makes it an efficient technique for many data-multiplexing applications including, but not limited to, optical storage media.
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    Lin, C.; Jungmann, R.; Leifer, A. M.; Li, C.; Levner, D.; Church, G. M.; Shih, W. M.; Yin, P. Submicrometre Geometrically Encoded Fluorescent Barcodes Self-Assembled from DNA. Nat. Chem. 2012, 4 (10), 832– 839,  DOI: 10.1038/nchem.1451
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    Submicrometre geometrically encoded fluorescent barcodes self-assembled from DNA
    Lin, Chenxiang; Jungmann, Ralf; Leifer, Andrew M.; Li, Chao; Levner, Daniel; Church, George M.; Shih, William M.; Yin, Peng
    Nature Chemistry (2012), 4 (10), 832-839CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The identification and differentiation of a large no. of distinct mol. species with high temporal and spatial resoln. is a major challenge in biomedical science. Fluorescence microscopy is a powerful tool, but its multiplexing ability is limited by the no. of spectrally distinguishable fluorophores. Here, the authors used (deoxy)RNA (DNA)-origami technol. to construct submicrometer nanorods that act as fluorescent barcodes. Spatial control over the positioning of fluorophores on the surface of a stiff DNA nanorod can produce 216 distinct barcodes that can be decoded unambiguously using epifluorescence or total internal reflection fluorescence microscopy. Barcodes with higher spatial information d. were demonstrated via the construction of super-resoln. barcodes with features spaced by ∼40 nm. One species of the barcodes was used to tag yeast surface receptors, which suggests their potential applications as in situ imaging probes for diverse biomol. and cellular entities in their native environments.
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    Choudhary, A.; Maffeo, C.; Aksimentiev, A. Multi-Resolution Simulation of DNA Transport through Large Synthetic Nanostructures. Phys. Chem. Chem. Phys. 2022, 24 (5), 2706– 2716,  DOI: 10.1039/D1CP04589J
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    121
    Multi-resolution simulation of DNA transport through large synthetic nanostructures
    Choudhary, Adnan; Maffeo, Christopher; Aksimentiev, Aleksei
    Physical Chemistry Chemical Physics (2022), 24 (5), 2706-2716CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    Modeling and simulation has become an invaluable partner in development of nanopore sensing systems. The key advantage of the nanopore sensing method - the ability to rapidly detect individual biomols. as a transient redn. of the ionic current flowing through the nanopore - is also its key deficiency, as the current signal itself rarely provides direct information about the chem. structure of the biomol. Complementing exptl. calibration of the nanopore sensor readout, coarse-grained and all-atom mol. dynamics simulations have been used extensively to characterize the nanopore translocation process and to connect the microscopic events taking place inside the nanopore to the exptl. measured ionic current blockades. Traditional coarse-grained simulations, however, lack the precision needed to predict ionic current blockades with at. resoln. whereas traditional all-atom simulations are limited by the length and time scales amenable to the method. Here, we describe a multi-resoln. framework for modeling elec. field-driven passage of DNA mols. and nanostructures through to-scale models of synthetic nanopore systems. We illustrate the method by simulating translocation of double-stranded DNA through a solid-state nanopore and a micron-scale slit, capture and translocation of single-stranded DNA in a double nanopore system, and modeling ionic current readout from a DNA origami nanostructure passage through a nanocapillary. We expect our multi-resoln. simulation framework to aid development of the nanopore field by providing accurate, to-scale modeling capability to research labs. that do not have access to leadership supercomputer facilities.
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    Schnitzbauer, J.; Strauss, M. T.; Schlichthaerle, T.; Schueder, F.; Jungmann, R. Super-Resolution Microscopy with DNA-PAINT. Nat. Protoc 2017, 12 (6), 1198– 1228,  DOI: 10.1038/nprot.2017.024
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    Super-resolution microscopy with DNA-PAINT
    Schnitzbauer, Joerg; Strauss, Maximilian T.; Schlichthaerle, Thomas; Schueder, Florian; Jungmann, Ralf
    Nature Protocols (2017), 12 (6), 1198-1228CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    Super-resoln. techniques have begun to transform biol. and biomedical research by allowing researchers to observe structures well below the classic diffraction limit of light. DNA points accumulation for imaging in nanoscale topog. (DNA-PAINT) offers an easy-to-implement approach to localization-based super-resoln. microscopy, owing to the use of DNA probes. In DNA-PAINT, transient binding of short dye-labeled ('imager') oligonucleotides to their complementary target ('docking') strands creates the necessary 'blinking' to enable stochastic super-resoln. microscopy. Using the programmability and specificity of DNA mols. as imaging and labeling probes allows researchers to decouple blinking from dye photophysics, alleviating limitations of current super-resoln. techniques, making them compatible with virtually any single-mol.-compatible dye. Recent developments in DNA-PAINT have enabled spectrally unlimited multiplexing, precise mol. counting and ultra-high, mol.-scale (sub-5-nm) spatial resoln., reaching ∼1-nm localization precision. DNA-PAINT can be applied to a multitude of in vitro and cellular applications by linking docking strands to antibodies. Here, we present a protocol for the key aspects of the DNA-PAINT framework for both novice and expert users. This protocol describes the creation of DNA origami test samples, in situ sample prepn., multiplexed data acquisition, data simulation, super-resoln. image reconstruction and post-processing such as drift correction, mol. counting (qPAINT) and particle averaging. Moreover, we provide an integrated software package, named Picasso, for the computational steps involved. The protocol is designed to be modular, so that individual components can be chosen and implemented per requirements of a specific application. The procedure can be completed in 1-2 d.
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    Wei, B.; Dai, M.; Yin, P. Complex Shapes Self-Assembled from Single-Stranded DNA Tiles. Nature 2012, 485 (7400), 623– 626,  DOI: 10.1038/nature11075
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    Complex shapes self-assembled from single-stranded DNA tiles
    Wei, Bryan; Dai, Mingjie; Yin, Peng
    Nature (London, United Kingdom) (2012), 485 (7400), 623-626CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Programmed self-assembly of strands of nucleic acid has proved highly effective for creating a wide range of structures with desired shapes. A particularly successful implementation is DNA origami, in which a long scaffold strand is folded by hundreds of short auxiliary strands into a complex shape. Modular strategies are in principle simpler and more versatile and have been used to assemble DNA or RNA tiles into periodic and algorithmic two-dimensional lattices, extended ribbons and tubes, three-dimensional crystals, polyhedra and simple finite two-dimensional shapes. But creating finite yet complex shapes from a large no. of uniquely addressable tiles remains challenging. Here we solve this problem with the simplest tile form, a single-stranded tile (SST) that consists of a 42-base strand of DNA composed entirely of concatenated sticky ends and that binds to four local neighbors during self-assembly. Although ribbons and tubes with controlled circumferences have been created using the SST approach, we extend it to assemble complex two-dimensional shapes and tubes from hundreds (in some cases more than one thousand) distinct tiles. Our main design feature is a self-assembled rectangle that serves as a mol. canvas, with each of its constituent SST strands-folded into a 3 nm-by-7 nm tile and attached to four neighboring tiles-acting as a pixel. A desired shape, drawn on the canvas, is then produced by one-pot annealing of all those strands that correspond to pixels covered by the target shape; the remaining strands are excluded. We implement the strategy with a master strand collection that corresponds to a 310-pixel canvas, and then use appropriate strand subsets to construct 107 distinct and complex two-dimensional shapes, thereby establishing SST assembly as a simple, modular and robust framework for constructing nanostructures with prescribed shapes from short synthetic DNA strands.
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    Tikhomirov, G.; Petersen, P.; Qian, L. Fractal Assembly of Micrometre-Scale DNA Origami Arrays with Arbitrary Patterns. Nature 2017, 552 (7683), 67– 71,  DOI: 10.1038/nature24655
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    Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns
    Tikhomirov, Grigory; Petersen, Philip; Qian, Lulu
    Nature (London, United Kingdom) (2017), 552 (7683), 67-71CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Self-assembled DNA nanostructures enable nanometer-precise patterning that can be used to create programmable mol. machines and arrays of functional materials. DNA origami is particularly versatile in this context because each DNA strand in the origami nanostructure occupies a unique position and can serve as a uniquely addressable pixel. However, the scale of such structures has been limited to about 0.05 square micrometres, hindering applications that demand a larger layout and integration with more conventional patterning methods. Hierarchical multistage assembly of simple sets of tiles can in principle overcome this limitation, but so far has not been sufficiently robust to enable successful implementation of larger structures using DNA origami tiles. Here we show that by using simple local assembly rules that are modified and applied recursively throughout a hierarchical, multistage assembly process, a small and const. set of unique DNA strands can be used to create DNA origami arrays of increasing size and with arbitrary patterns. We illustrate this method, which we term 'fractal assembly', by producing DNA origami arrays with sizes of up to 0.5 square micrometres and with up to 8,704 pixels, allowing us to render images such as the Mona Lisa and a rooster. We find that self-assembly of the tiles into arrays is unaffected by changes in surface patterns on the tiles, and that the yield of the fractal assembly process corresponds to about 0.95m - 1 for arrays contg. m tiles. When used in conjunction with a software tool that we developed that converts an arbitrary pattern into DNA sequences and exptl. protocols, our assembly method is readily accessible and will facilitate the construction of sophisticated materials and devices with sizes similar to that of a bacterium using DNA nanostructures.
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    Rothemund, P. W. K. Folding DNA to Create Nanoscale Shapes and Patterns. Nature 2006, 440 (7082), 297– 302,  DOI: 10.1038/nature04586
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    Folding DNA to create nanoscale shapes and patterns
    Rothemund, Paul W. K.
    Nature (London, United Kingdom) (2006), 440 (7082), 297-302CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    'Bottom-up fabrication', which exploits the intrinsic properties of atoms and mols. to direct their self-organization, is widely used to make relatively simple nanostructures. A key goal for this approach is to create nanostructures of high complexity, matching that routinely achieved by 'top-down' methods. The self-assembly of DNA mols. provides an attractive route towards this goal. Here the author describe a simple method for folding long, single-stranded DNA mols. into arbitrary two-dimensional shapes. The design for a desired shape is made by raster-filling the shape with a 7-kilobase single-stranded scaffold and by choosing over 200 short oligonucleotide 'staple strands' to hold the scaffold in place. Once synthesized and mixed, the staple and scaffold strands self-assemble in a single step. The resulting DNA structures are roughly 100 nm in diam. and approx. desired shapes such as squares, disks and five-pointed stars with a spatial resoln. of 6 nm. Because each oligonucleotide can serve as a 6-nm pixel, the structures can be programmed to bear complex patterns such as words and images on their surfaces. Finally, individual DNA structures can be programmed to form larger assemblies, including extended periodic lattices and a hexamer of triangles (which constitutes a 30-megadalton mol. complex).
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    Platnich, C. M.; Rizzuto, F. J.; Cosa, G.; Sleiman, H. F. Single-Molecule Methods in Structural DNA Nanotechnology. Chem. Soc. Rev. 2020, 49 (13), 4220– 4233,  DOI: 10.1039/C9CS00776H
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    Single-molecule methods in structural DNA nanotechnology
    Platnich, Casey M.; Rizzuto, Felix J.; Cosa, Gonzalo; Sleiman, Hanadi F.
    Chemical Society Reviews (2020), 49 (13), 4220-4233CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Single mols. can now be visualised with unprecedented precision. As the resoln. of single-mol. expts. improves, so too does the breadth, quantity and quality of information that can be extd. using these methodologies. In the field of DNA nanotechnol., we use programmable interactions between nucleic acids to generate complex, multidimensional structures. We can use single-mol. techniques - ranging from electron and fluorescence microscopies to elec. and force spectroscopies - to report on the structure, morphol., robustness, sample heterogeneity and other properties of these DNA nanoconstructs. In this Tutorial Review, we will detail how complementarity between static and dynamic single-mol. techniques can provide a unified image of DNA nanoarchitectures. The single-mol. methods that we discuss provide unprecedented insight into chem. and structural behavior, yielding not just an av. outcome but reporting on the distribution of values, ultimately showing how bulk properties arise from the collective behavior of individual structures. As the fields of both DNA nanotechnol. and single-mol. characterization intertwine, a feedback loop is generated between disciplines, providing new opportunities for the development and operation of DNA-based materials as sensors, delivery vehicles, machinery and structural scaffolds.
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    Zhang, Y.; Wang, F.; Chao, J.; Xie, M.; Liu, H.; Pan, M.; Kopperger, E.; Liu, X.; Li, Q.; Shi, J.; Wang, L.; Hu, J.; Wang, L.; Simmel, F. C.; Fan, C. DNA Origami Cryptography for Secure Communication. Nat. Commun. 2019, 10 (1), 5469,  DOI: 10.1038/s41467-019-13517-3
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    DNA origami cryptography for secure communication
    Zhang Yinan; Wang Fei; Liu Xiaoguo; Li Qian; Fan Chunhai; Zhang Yinan; Xie Mo; Pan Muchen; Shi Jiye; Wang Lihua; Hu Jun; Chao Jie; Wang Lianhui; Liu Huajie; Kopperger Enzo; Simmel Friedrich C; Wang Lihua; Hu Jun
    Nature communications (2019), 10 (1), 5469 ISSN:.
    Biomolecular cryptography exploiting specific biomolecular interactions for data encryption represents a unique approach for information security. However, constructing protocols based on biomolecular reactions to guarantee confidentiality, integrity and availability (CIA) of information remains a challenge. Here we develop DNA origami cryptography (DOC) that exploits folding of a M13 viral scaffold into nanometer-scale self-assembled braille-like patterns for secure communication, which can create a key with a size of over 700 bits. The intrinsic nanoscale addressability of DNA origami additionally allows for protein binding-based steganography, which further protects message confidentiality in DOC. The integrity of a transmitted message can be ensured by establishing specific linkages between several DNA origamis carrying parts of the message. The versatility of DOC is further demonstrated by transmitting various data formats including text, musical notes and images, supporting its great potential for meeting the rapidly increasing CIA demands of next-generation cryptography.
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    Numajiri, K.; Kimura, M.; Kuzuya, A.; Komiyama, M. Stepwise and Reversible Nanopatterning of Proteins on a DNA Origami Scaffold. Chem. Commun. 2010, 46 (28), 5127– 5129,  DOI: 10.1039/c0cc00044b
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    Stepwise and reversible nanopatterning of proteins on a DNA origami scaffold
    Numajiri, Kentaro; Kimura, Mayumi; Kuzuya, Akinori; Komiyama, Makoto
    Chemical Communications (Cambridge, United Kingdom) (2010), 46 (28), 5127-5129CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Stepwise introduction of multiple streptavidin tetramers into a nanoarray formed in a stick-like punched DNA origami as well as selective removal of predetd. tetramer from the array were successfully achieved by applying a programmed strand displacement technique to a DNA origami scaffold.
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  129. 129
    Wang, P.; Rahman, M. A.; Zhao, Z.; Weiss, K.; Zhang, C.; Chen, Z.; Hurwitz, S. J.; Chen, Z. G.; Shin, D. M.; Ke, Y. Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells. J. Am. Chem. Soc. 2018, 140 (7), 2478– 2484,  DOI: 10.1021/jacs.7b09024
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    129
    Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells
    Wang, Pengfei; Rahman, Mohammad Aminur; Zhao, Zhixiang; Weiss, Kristin; Zhang, Chao; Chen, Zhengjia; Hurwitz, Selwyn J.; Chen, Zhuo G.; Shin, Dong M.; Ke, Yonggang
    Journal of the American Chemical Society (2018), 140 (7), 2478-2484CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    DNA origami is a promising mol. delivery system for a variety of therapeutic applications including cancer therapy, given its capability to fabricate homogeneous nanostructures whose physicochem. properties (size, shape, surface chem.) can be precisely tailored. However, the correlation between DNA-origami design and internalization efficiency in different cancer cell lines remains elusive. The authors investigated the cellular uptake of four DNA-origami nanostructures (DONs) with programmed sizes and shapes in multiple human cancer cell lines. The cellular uptake efficiency of DONs was influenced by size, shape, and cell line. Scavenger receptors were responsible for the internalization of DONs into cancer cells. The authors obsd. distinct stages of the internalization process of a gold nanoparticle (AuNP)-tagged rod-shape DON, using high-resoln. TEM. This study provides detailed understanding of cellular uptake and intracellular trafficking of DONs in cancer cells, and offers new insights for future optimization of DON-based drug delivery systems for cancer treatment.
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  130. 130
    Bošković, F.; Keyser, U. F. Nanopore Microscope Identifies RNA Isoforms with Structural Colours. Nat. Chem. 2022. DOI: 10.1038/s41557-022-01037-5 .
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    Misiunas, K.; Ermann, N.; Keyser, U. F. QuipuNet: Convolutional Neural Network for Single-Molecule Nanopore Sensing. Nano Lett. 2018, 18 (6), 4040– 4045,  DOI: 10.1021/acs.nanolett.8b01709
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    131
    QuipuNet: Convolutional Neural Network for Single-Molecule Nanopore Sensing
    Misiunas, Karolis; Ermann, Niklas; Keyser, Ulrich F.
    Nano Letters (2018), 18 (6), 4040-4045CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Nanopore sensing is a versatile technique for the anal. of mols. on the single-mol. level. However, extg. information from data with established algorithms usually requires time-consuming checks by an experienced researcher due to inherent variability of solid-state nanopores. Here, we develop a convolutional neural network (CNN) for the fully automated extn. of information from the time-series signals obtained by nanopore sensors. In our demonstration, we use a previously published data set on multiplexed single-mol. protein sensing. The neural network learns to classify translocation events with greater accuracy than previously possible, while also increasing the no. of analyzable events by a factor of 5. Our results demonstrate that deep learning can achieve significant improvements in single mol. nanopore detection with potential applications in rapid diagnostics.
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  132. 132
    Cao, C.; Krapp, L. F.; Al Ouahabi, A.; König, N. F.; Cirauqui, N.; Radenovic, A.; Lutz, J. F.; Peraro, M. D. Aerolysin Nanopores Decode Digital Information Stored in Tailored Macromolecular Analytes. Sci. Adv. 2020, 6 (50), eabc2661,  DOI: 10.1126/sciadv.abc2661
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    Ng, C. C. A.; Tam, W. M.; Yin, H.; Wu, Q.; So, P. K.; Wong, M. Y. M.; Lau, F. C. M.; Yao, Z. P. Data Storage Using Peptide Sequences. Nat. Commun. 2021, 12 (1), 1– 10,  DOI: 10.1038/s41467-021-24496-9
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    Dahlhauser, S. D.; Moor, S. R.; Vera, M. S.; York, J. T.; Ngo, P.; Boley, A. J.; Coronado, J. N.; Simpson, Z. B.; Anslyn, E. v. Efficient Molecular Encoding in Multifunctional Self-Immolative Urethanes. Cell Rep. Phys. Sci. 2021, 2 (4), 100393,  DOI: 10.1016/j.xcrp.2021.100393
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    134
    Efficient molecular encoding in multifunctional self-immolative urethanes
    Dahlhauser, Samuel D.; Moor, Sarah R.; Vera, Marissa S.; York, Jordan T.; Ngo, Phuoc; Boley, Alexander J.; Coronado, Jaime N.; Simpson, Zack B.; Anslyn, Eric V.
    Cell Reports Physical Science (2021), 2 (4), 100393CODEN: CRPSF5; ISSN:2666-3864. (Elsevier Inc.)
    Mol. encoding in sequence-defined polymers shows promise as a new paradigm for data storage. Here, we report what is, to our knowledge, the first use of self-immolative oligourethanes for storing and reading encoded information. As a proof of principle, we describe how a text passage from Jane Austen's Mansfield Park was encoded in sequence-defined oligourethanes and reconstructed via self-immolative sequencing. We develop Mol. E-coder, a software tool that uses a Huffman encoding scheme to convert the character table to hexadecimal. The oligourethanes are then generated by a high-throughput parallel synthesis. Sequencing of the oligourethanes by self-immolation is done concurrently in a parallel fashion, and the liq. chromatog.-mass spectrometry (LC-MS) information decoded by our Mol.E-decoder software. The passage is capable of being reproduced wholly intact by a third-party, without any purifications or the use of tandem MS (MS/MS), despite multiple rounds of compression, encoding, and synthesis.
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  135. 135
    Brinkerhoff, H.; Kang, A. S. W.; Liu, J.; Aksimentiev, A.; Dekker, C. Multiple Rereads of Single Proteins at Single–Amino Acid Resolution Using Nanopores. Science 2021, 374, 1509,  DOI: 10.1126/science.abl4381
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    135
    Multiple rereads of single proteins at single-amino acid resolution using nanopores
    Brinkerhoff, Henry; Kang, Albert S. W.; Liu, Jingqian; Aksimentiev, Aleksei; Dekker, Cees
    Science (Washington, DC, United States) (2021), 374 (6574), 1509-1513CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
    A proteomics tool capable of identifying single proteins would be important for cell biol. research and applications. Here, we demonstrate a nanopore-based single-mol. peptide reader sensitive to single-amino acid substitutions within individual peptides. A DNA-peptide conjugate was pulled through the biol. nanopore MspA by the DNA helicase Hel308. Reading the ion current signal through the nanopore enabled discrimination of single-amino acid substitutions in single reads. Mol. dynamics simulations showed these signals to result from size exclusion and pore binding. We also demonstrate the capability to "rewind" peptide reads, obtaining numerous independent reads of the same mol., yielding an error rate of <10-6 in single amino acid variant identification. These proof-of-concept expts. constitute a promising basis for the development of a single-mol. protein fingerprinting and anal. technol.
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    Adleman, L. M. Molecular Computation of Solutions to Combinatorial Problems. Science 1994, 266 (5187), 1021– 1024,  DOI: 10.1126/science.7973651
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    Molecular computation of solutions to combinatorial problems
    Adleman, Leonard M.
    Science (Washington, D. C.) (1994), 266 (5187), 1021-4CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    The tools of mol. biol. were used to solve an instance of the directed Hamiltonian path problem. A small graph was encoded in mols. of DNA, and the "operations" of the computation were performed with std. protocols and enzymes. This expt. demonstrates the feasibility of carrying out computations at the mol. level.
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    Ogasawara, S.; Fujimoto, K. Solution of a SAT Problem on a Photochemical DNA Computer. Chem. Lett. 2005, 34 (3), 378– 379,  DOI: 10.1246/cl.2005.378
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    Solution of a SAT problem on a photochemical DNA computer
    Ogasawara, Shinzi; Fujimoto, Kenzo
    Chemistry Letters (2005), 34 (3), 378-379CODEN: CMLTAG; ISSN:0366-7022. (Chemical Society of Japan)
    The photochem. DNA computing via 5-carboxyvinyl-deoxyuridine (cvU) in anchor oligodeoxynucleotides (ODNs) to tether the multiple "DNA words" was demonstrated. A new MARK and UNMARK operation based on the cvU mediated reversible DNA photoligation has been developed for multiple-words DNA computing. The utility of this operation for DNA computing was demonstrated by solving a satisfiability problem (SAT problem) in which information was encoded in three tandem words.
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    Lipton, R. J. DNA Solution of Hard Computational Problems. Science 1995, 268 (5210), 542– 545,  DOI: 10.1126/science.7725098
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    DNA solution of hard computational problems
    Lipton, Richard J.
    Science (Washington, D. C.) (1995), 268 (5210), 542-5CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    DNA expts. are proposed to solve the famous SAT problem of computer science. This is a special case of a more general method that can solve NP-complete problems. The advantage of these results is the huge parallelism inherent in DNA-based computing. It has the potential to yield vast speedups over conventional electronic-based computers for such search problems.
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    Su, H.; Xu, J.; Wang, Q.; Wang, F.; Zhou, X. High-Efficiency and Integrable DNA Arithmetic and Logic System Based on Strand Displacement Synthesis. Nat. Commun. 2019, 10 (1), 1– 8,  DOI: 10.1038/s41467-019-13310-2
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    Structural basis for DNA unwinding at forked dsDNA by two coordinating Pif1 helicases
    Su, Nannan; Byrd, Alicia K.; Bharath, Sakshibeedu R.; Yang, Olivia; Jia, Yu; Tang, Xuhua; Ha, Taekjip; Raney, Kevin D.; Song, Haiwei
    Nature Communications (2019), 10 (1), 1-11CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Pif1 plays multiple roles in maintaining genome stability and preferentially unwinds forked dsDNA, but the mechanism by which Pif1 unwinds forked dsDNA remains elusive. Here we report the structure of Bacteroides sp Pif1 (BaPif1) in complex with a sym. double forked dsDNA. Two interacting BaPif1 mols. are bound to each fork of the partially unwound dsDNA, and interact with the 5' arm and 3' ss/dsDNA resp. Each of the two BaPif1 mols. is an active helicase and their interaction may regulate their helicase activities. The binding of BaPif1 to the 5' arm causes a sharp bend in the 5' ss/dsDNA junction, consequently breaking the first base-pair. BaPif1 bound to the 3' ss/dsDNA junction impacts duplex unwinding by stabilizing the unpaired first base-pair and engaging the second base-pair poised for breaking. Our results provide an unprecedented insight into how two BaPif1 coordinate with each other to unwind the forked dsDNA.
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    Liu, H.; Wang, J.; Song, S.; Fan, C.; Gothelf, K. v. A DNA-Based System for Selecting and Displaying the Combined Result of Two Input Variables. Nat. Commun. 2015, 6, 1– 7,  DOI: 10.1038/ncomms10089
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    Winfree, E.; Liu, F.; Wenzler, L. A.; Seeman, N. C. Design and Self-Assembly of Two-Dimensional DNA Crystals. Nature 1998, 394 (6693), 539– 544,  DOI: 10.1038/28998
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    Design and self-assembly of two-dimensional DNA crystals
    Winfree, Erik; Liu, Furong; Wenzler, Lisa A.; Seeman, Nadrian C.
    Nature (London) (1998), 394 (6693), 539-544CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
    Mol. self-assembly presents a bottom-up approach to the fabrication of objects specified with nanometer precision. DNA mol. structures and intermol. interactions are particularly amenable to the design and synthesis of complex mol. objects. We report the design and observation of two-dimensional cryst. forms of DNA that self-assemble from synthetic DNA double-crossover mols. Intermol. interactions between the structural units are programmed by the design of sticky ends that assoc. according to Watson-Crick complementarity, enabling us to create specific periodic patterns on the nanometer scale. The patterned crystals have been visualized by at. force microscopy.
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  142. 142
    Mao, C.; LaBean, T. H.; Reif, J. H.; Seeman, N. C. Logical Computation Using Algorithmic Self-Assembly of DNA Triple-Crossover Molecules. Nature 2000, 407 (6803), 493– 496,  DOI: 10.1038/35035038
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    Logical computation using algorithmic self-assembly of DNA triple-crossover molecules
    Mao, Chengde; LaBean, Thomas H.; Reif, John H.; Seeman, Nadrian C.
    Nature (London) (2000), 407 (6803), 493-496CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Recent work has demonstrated the self-assembly of designed periodic two-dimensional arrays composed of DNA tiles, in which the intermol. contacts are directed by 'sticky' ends. In a math. context, aperiodic mosaics may be formed by the self-assembly of 'Wang' tiles, a process that emulates the operation of a Turing machine. Macroscopic self-assembly has been used to perform computations; there is also a logical equivalence between DNA sticky ends and Wang tile edges. This suggests that the self-assembly of DNA-based tiles could be used to perform DNA-based computation. Algorithmic aperiodic self-assembly requires greater fidelity than periodic self-assembly, because correct tiles must compete with partially correct tiles. Here we report a one-dimensional algorithmic self-assembly of DNA triple-crossover mols. that can be used to execute four steps of a logical (cumulative XOR) operation on a string of binary bits.
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  143. 143
    Yin, P.; Hariadi, R. F.; Sahu, S.; Choi, H. M. T.; Sung, H. P.; LaBean, T. H.; Reif, J. H. Programming DNA Tube Circumferences. Science 2008, 321 (5890), 824– 826,  DOI: 10.1126/science.1157312
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    143
    Programming DNA Tube Circumferences
    Yin, Peng; Hariadi, Rizal F.; Sahu, Sudheer; Choi, Harry M. T.; Park, Sung Ha; LaBean, Thomas H.; Reif, John H.
    Science (Washington, DC, United States) (2008), 321 (5890), 824-826CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Synthesizing mol. tubes with monodisperse, programmable circumferences is an important goal shared by nanotechnol., materials science, and supermol. chem. We program mol. tube circumferences by specifying the complementarity relationships between modular domains in a 42-base single-stranded DNA motif. Single-step annealing results in the self-assembly of long tubes displaying monodisperse circumferences of 4, 5, 6, 7, 8, 10, or 20 DNA helixes.
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  144. 144
    Woods, D.; Doty, D.; Myhrvold, C.; Hui, J.; Zhou, F.; Yin, P.; Winfree, E. Diverse and Robust Molecular Algorithms Using Reprogrammable DNA Self-Assembly. Nature 2019, 567 (7748), 366– 372,  DOI: 10.1038/s41586-019-1014-9
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    144
    Diverse and robust molecular algorithms using reprogrammable DNA self-assembly
    Woods, Damien; Doty, David; Myhrvold, Cameron; Hui, Joy; Zhou, Felix; Yin, Peng; Winfree, Erik
    Nature (London, United Kingdom) (2019), 567 (7748), 366-372CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Mol. biol. provides an inspiring proof-of-principle that chem. systems can store and process information to direct mol. activities such as the fabrication of complex structures from mol. components. To develop information-based chem. as a technol. for programming matter to function in ways not seen in biol. systems, it is necessary to understand how mol. interactions can encode and execute algorithms. The self-assembly of relatively simple units into complex products1 is particularly well suited for such investigations. Theory that combines math. tiling and statistical-mech. models of mol. crystn. has shown that algorithmic behavior can be embedded within mol. self-assembly processes2,3, and this has been exptl. demonstrated using DNA nanotechnol.4 with up to 22 tile types5-11. However, many information technologies exhibit a complexity threshold-such as the min. transistor count needed for a general-purpose computer-beyond which the power of a reprogrammable system increases qual., and it has been unclear whether the biophysics of DNA self-assembly allows that threshold to be exceeded. Here we report the design and exptl. validation of a DNA tile set that contains 355 single-stranded tiles and can, through simple tile selection, be reprogrammed to implement a wide variety of 6-bit algorithms. We use this set to construct 21 circuits that execute algorithms including copying, sorting, recognizing palindromes and multiples of 3, random walking, obtaining an unbiased choice from a biased random source, electing a leader, simulating cellular automata, generating deterministic and randomized patterns, and counting to 63, with an overall per-tile error rate of less than 1 in 3,000. These findings suggest that mol. self-assembly could be a reliable algorithmic component within programmable chem. systems. The development of mol. machines that are reprogrammable-at a high level of abstraction and thus without requiring knowledge of the underlying physics-will establish a creative space in which mol. programmers can flourish.
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  145. 145
    Rothemund, P. W. K.; Papadakis, N.; Winfree, E. Algorithmic Self-Assembly of DNA Sierpinski Triangles. PLoS Biol. 2004, 2 (12), e424,  DOI: 10.1371/journal.pbio.0020424
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    145
    Algorithmic self-assembly of DNA Sierpinski triangles
    Rothemund Paul W K; Papadakis Nick; Winfree Erik
    PLoS biology (2004), 2 (12), e424 ISSN:.
    Algorithms and information, fundamental to technological and biological organization, are also an essential aspect of many elementary physical phenomena, such as molecular self-assembly. Here we report the molecular realization, using two-dimensional self-assembly of DNA tiles, of a cellular automaton whose update rule computes the binary function XOR and thus fabricates a fractal pattern--a Sierpinski triangle--as it grows. To achieve this, abstract tiles were translated into DNA tiles based on double-crossover motifs. Serving as input for the computation, long single-stranded DNA molecules were used to nucleate growth of tiles into algorithmic crystals. For both of two independent molecular realizations, atomic force microscopy revealed recognizable Sierpinski triangles containing 100-200 correct tiles. Error rates during assembly appear to range from 1% to 10%. Although imperfect, the growth of Sierpinski triangles demonstrates all the necessary mechanisms for the molecular implementation of arbitrary cellular automata. This shows that engineered DNA self-assembly can be treated as a Turing-universal biomolecular system, capable of implementing any desired algorithm for computation or construction tasks.
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  146. 146
    Church, G. M.; Gao, Y.; Kosuri, S. Next-Generation Digital Information Storage in DNA. Science 2012, 337 (6102), 1628– 1628,  DOI: 10.1126/science.1226355
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    146
    Next-Generation Digital Information Storage in DNA
    Church, George M.; Gao, Yuan; Kosuri, Sriram
    Science (Washington, DC, United States) (2012), 337 (6102), 1628CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Digital information is accumulating at an astounding rate, straining our ability to store and archive it. DNA is among the most dense and stable information media known. The development of new technologies in both DNA synthesis and sequencing make DNA an increasingly feasible digital storage medium. We developed a strategy to encode arbitrary digital information in DNA, wrote a 5.27-megabit book using DNA microchips, and read the book by using next-generation DNA sequencing.
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  147. 147
    Hoshika, S.; Leal, N. A.; Kim, M.-J.; Kim, M.-S.; Karalkar, N. B.; Kim, H.-J.; Bates, A. M.; Watkins, N. E.; SantaLucia, H. A.; Meyer, A. J.; DasGupta, S.; Piccirilli, J. A.; Ellington, A. D.; SantaLucia, J.; Georgiadis, M. M.; Benner, S. A. Hachimoji DNA and RNA: A Genetic System with Eight Building Blocks. Science 2019, 363 (6429), 884– 887,  DOI: 10.1126/science.aat0971
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    147
    Hachimoji DNA and RNA: A genetic system with eight building blocks
    Hoshika, Shuichi; Leal, Nicole A.; Kim, Myong-Jung; Kim, Myong-Sang; Karalkar, Nilesh B.; Kim, Hyo-Joong; Bates, Alison M.; Watkins, Norman E., Jr.; SantaLucia, Holly A.; Meyer, Adam J.; DasGupta, Saurja; Piccirilli, Joseph A.; Ellington, Andrew D.; SantaLucia, John, Jr.; Georgiadis, Millie M.; Benner, Steven A.
    Science (Washington, DC, United States) (2019), 363 (6429), 884-887CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    We report DNA- and RNA-like systems built from eight nucleotide "letters" (hence the name "hachimoji") that form four orthogonal pairs. These synthetic systems meet the structural requirements needed to support Darwinian evolution, including a polyelectrolyte backbone, predictable thermodn. stability, and stereoregular building blocks that fit a Schroedinger aperiodic crystal. Measured thermodn. parameters predict the stability of hachimoji duplexes, allowing hachimoji DNA to increase the information d. of natural terran DNA. Three crystal structures show that the synthetic building blocks do not perturb the aperiodic crystal seen in the DNA double helix. Hachimoji DNA was then transcribed to give hachimoji RNA in the form of a functioning fluorescent hachimoji aptamer. These results expand the scope of mol. structures that might support life, including life throughout the cosmos.
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  148. 148
    Avakyan, N.; Greschner, A. A.; Aldaye, F.; Serpell, C. J.; Toader, V.; Petitjean, A.; Sleiman, H. F. Reprogramming the Assembly of Unmodified DNA with a Small Molecule. Nat. Chem. 2016, 8 (4), 368– 376,  DOI: 10.1038/nchem.2451
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    148
    Reprogramming the assembly of unmodified DNA with a small molecule
    Avakyan, Nicole; Greschner, Andrea A.; Aldaye, Faisal; Serpell, Christopher J.; Toader, Violeta; Petitjean, Anne; Sleiman, Hanadi F.
    Nature Chemistry (2016), 8 (4), 368-376CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The ability of DNA to store and encode information arises from base pairing of the four-letter nucleobase code to form a double helix. Expanding this DNA 'alphabet' by synthetic incorporation of new bases can introduce new functionalities and enable the formation of novel nucleic acid structures. However, reprogramming the self-assembly of existing nucleobases presents an alternative route to expand the structural space and functionality of nucleic acids. Here we report the discovery that a small mol., cyanuric acid, with three thymine-like faces, reprogrammes the assembly of unmodified poly(adenine) (poly(A)) into stable, long and abundant fibers with a unique internal structure. Poly(A) DNA, RNA and peptide nucleic acid (PNA) all form these assemblies. Our studies are consistent with the assocn. of adenine and cyanuric acid units into a hexameric rosette, which brings together poly(A) triplexes with a subsequent cooperative polymn. Fundamentally, this study shows that small hydrogen-bonding mols. can be used to induce the assembly of nucleic acids in water, which leads to new structures from inexpensive and readily available materials.
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This article is cited by 7 publications.

  1. Ruru Gao, Xiu-Shen Wei, Zelin Chen, Aming Xie, Wei Dong. Leveraging DNA-Based Nanostructures for Advanced Error Detection and Correction in Data Communication. ACS Nano 2023, 17 (18) , 18055-18061. https://doi.org/10.1021/acsnano.3c04777
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  • Abstract

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    Figure 1

    Figure 1. General strategy for DNA data storage, wherein the data is stored directly in the sequence of the oligonucleotides. The six main steps─encoding, writing, storage, access, reading, and decoding─are depicted.

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    Figure 2

    Figure 2. Comparison of the main differences between sequence-based (A,B) and structure-based DNA data storage (C,D), as has been presented in the literature to date. (A,B) Sequence-based storage relies on the de novo synthesis of DNA strands and the subsequent sequencing of these entities is performed using next-generation methods. Image adapted with permission from ref (12). Copyright 2019 Springer Nature. (C) By contrast, structure-based methods utilize self-assembly, which means that the information is encoded into their three-dimensional shape. Images adapted with permission: ref (21), copyright 2016 Springer Nature; ref (22), under a Creative Commons Attribution 4.0 License (CC BY), copyright 2021 Springer Nature. (D) These shapes can then be read off using single-molecule methods, including fluorescence, atomic force microscopy, and nanopore techniques. Image adapted from ref (23). Copyright 2019 American Chemical Society.

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    Figure 3

    Figure 3. An overview of chemical and enzymatic strategies to synthesize custom DNA sequences. (A) Phosphoramidite synthesis─the most widely used chemical strategy for the synthesis of DNA─involves the sequential addition of nucleotides to a growing chain anchored on a solid support. Protecting groups are employed to ensure that no more than one nucleotide is added at each step and are then subsequently removed via chemical deblocking. (B) Deblocking can also be performed by electrochemistry. Reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY-NC) from ref (31). Copyright 2021 AAAS. (C) Enzymatic methods relying on T4rnl ligase or TdT can also be used to specifically add bases to a growing oligonucleotide in aqueous environments, which eliminates the need for organic solvents. Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (32). Copyright 2021 Elsevier B.V.

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    Figure 4

    Figure 4. Overview of random access strategies to select a subpool of sequences, usually a file, from a large pool. PCR-based addressing methods leverage the high specificity of primers and the exponential amplification of PCR to enrich target sequences by using either a single or multiple PCR runs. Methods using physical separation as a tool to select sequences also rely on the high specificity of short primers or barcode sequences, but remove the desired sequences using magnetic bead extraction or fluorescence-activated sorting. Images adapted from ref (71) and reproduced with permission from ref (75). Copyright 2019 American Chemical Society and copyright 2021 Springer Nature, respectively.

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    Figure 5

    Figure 5. Overview of next-generation sequencing technologies presently used in DNA data storage. (A) Illumina sequencing generates clusters of identical single-stranded oligonucleotides. As the complement is synthesized using spectrally distinct, fluorescently tagged nucleotides, the identity of each base along the strand can be determined through the color of emission. (B) Oxford Nanopore measurements do not require fluorescent dye molecules. As the oligonucleotide passes through the protein pore, the three-dimensional shape of each base will modulate the ionic current, which results in a current–time trace that corresponds to the specific sequence. Images adapted with permission from ref (85). Copyright 2016 Springer Nature.

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    Figure 6

    Figure 6. Inner–Outer Code. Encoding. The original information is first encoded with an outer code that introduces redundancy and protects against the loss of sequences. In Grass et al. (4) the original information was first grouped into blocks of multiple sequences (light blue). Then, each row was encoded with a Reed–Solomon code that adds redundancy (yellow). The columns correspond to single DNA sequences. These are labeled with a unique index (purple). Each column is then encoded with an inner code that adds logical redundancy on the level of each sequence (green). In general, the inner and outer codes need not add the redundancy separate from the original data, but instead return a modified longer word. Decoding. The original information from the set of noisy sequences (errors marked in red) is retrieved by first decoding the inner code. This removes most errors within the sequences. For large error rates dominated by insertions and deletions, this step may be preceded by a clustering and alignment step that generates sequences with fewer errors from multiple noisy copies. The sequences are ordered by their index. The ordered sequences are then decoded by the outer code. Here, lost sequences correspond to erasures and erroneous sequences to substitutions. These are corrected by the outer code.

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    Figure 7

    Figure 7. (A) Cost trend of hard disk drives (HDD), NAND flash-based storage devices, linear tape-open tape cartridges (LTO tape), and optical Blu-ray (BD-RE). Image has been reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (99). Copyright 2018 AIP Publishing LLC. (B) Cost comparison between DNA synthesis for data storage and LTO tape storage. (C–E) Comparison of different DNA synthesis platforms and their characteristic traits. (C) Printing technology is primarily used by Twist and Agilent. (D) Electrochemical synthesis is employed by Custom Array. (E) Antkowiak et al. used light-directed synthesis. (C–E) Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (42). Copyright 2020 Springer Nature.

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    Figure 8

    Figure 8. DNA nanostructures are data storage architectures. (A) DNA origami leverages the specific base-pairing motifs of DNA to create arbitrary structures. When a long scaffold strand (several thousand nucleotides in length) is combined with hundreds of short “staple” strands, complementary regions on the different strands will hybridize, thereby folding the scaffold into a desired conformation. These structures can then be examined using (B) atomic force microscopy or (C) electron microscopy, for example. (D) Data can be written onto DNA origami sheets through the site-specific addition of proteins; the data may be read using AFM. (E) Nanoparticles can also be controllably positioned on DNA origami with nanometer-scale resolution, which enables data writing with cryo-EM readout. (A) Image reproduced with permission from ref (108). Copyright Springer Nature 2021. (B) Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (109). Copyright 2019 AAAS. (C) Image reproduced with permission from ref (110). Copyright 2020 Springer Nature. (D) Image reproduced with permission from ref (111). Copyright 2010 Springer Nature. (E) Image reproduced with permission from ref (112). Copyright 2010 Wiley-VCH.

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    Figure 9

    Figure 9. Examples of DNA nanostructures for digital information storage. (A) The folding of DNA origami into loop structures upon binding of a biomolecule target generates a shift in the assembly’s electrophoretic mobility. Image adapted with permission under a Creative Commons Attribution 4.0 license (CC BY) from ref (114). Copyright 2017 Oxford University Press. (B) The association of different DNA sequences to carbon nanotubes produces an array of morphologies and, therefore, can be used to produce barcodes. Image adapted from ref (116). Copyright 2019 American Chemical Society. (C). Data strings based on regions of varying fluorescence intensities along a DNA nanotube can be read out using single-molecule fluorescence microscopy. Image adapted from ref (117). Copyright 2021 American Chemical Society.

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    Figure 10

    Figure 10. DNA data storage structures relying on nanopore readout. (A) An encrypted “DNA hard drive,” wherein readout may only occur once the correct molecular “keywords” have been added. Streptavidin molecules (gray circle in inset) partially block the nanopore as they translocate, which causes a momentary decrease in the current. Image reproduced from ref (25). Copyright 2020 American Chemical Society. (B) Multilevel barcoding is achievable by exploiting DNA junctions with different sizes, which create current drops of variable magnitude. Image reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (102). Copyright 2021 Wiley-VCH. (C) A DNA barcode with “structural colors” can also be formed by closely packing structural units, which therefore read as one protrusion. These units may be based on either monovalent streptavidin or a DNA cuboid. (D) Nanopore microscope can be used to detect up to 10 structural colors within the same DNA data string. The correct identification of the “color” was verified using fluorescence microscopy, wherein fluorescently labeled (5′-fluorescein) structural units were used. (C,D) Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (130). Copyright 2022 Springer Nature.

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    Figure 11

    Figure 11. Tile-based computations and algorithmic self-assembly. (A) Self-assembly by SSTs. From a seed, tiles attach to the frontier of a growing SST lattice according to interaction rules determined by their exposed recognition sequences. (B) An iterated Boolean circuit mimicking the function of a computation to determine whether or not a binary number is a multiple of 310. A long enough lattice will settle into one or another fixed pattern corresponding to the calculation result. (C) The result of four “multiple of 3” tilings. The numbers at the left mark the experiment number. The tilings correctly determine which input numbers have a factor of 3. (A–C) Images adapted with permission from ref (144). Copyright 2019 Springer Nature. (D) A Sierpinski triangle created by a cumulative XOR computation performed by DNA tiles. Sierpinski’s triangle is a fractal pattern, and the self-assembly rule that creates it is Turing complete. Images reproduced with permission under a Creative Commons Attribution 4.0 License (CC BY) from ref (145). Copyright 2004 PLoS Biology.

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      Data Storage Based on DNA
      Hao, Yaya; Li, Qian; Fan, Chunhai; Wang, Fei
      Small Structures (2021), 2 (2), 2000046CODEN: SSMTB2; ISSN:2688-4062. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Recent years have witnessed the exponential growth of information, calling for the development of new storage media. The DNA provides an attractive alternative for data storage due to its high phys. d., reproducibility, and excellent durability that have been tested by nature. Rapid progress has been made during the past decade by exploiting artificially designed DNA materials for data storage. Herein, recent advances of DNA-based encoding, writing, storage, retrieving, reading, and decoding for data storage are summarized. In addn. to encoding with nucleic acid sequences, different forms of data storage strategies using DNA nanostructures are also highlighted. Also, in vivo DNA data storage, esp. with the use of clustered regularly interspaced short palindromic repeat-Cas systems, is discussed. The challenges and opportunities for the development and application of DNA-based data storage are presented.
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    9. 9
      Goldman, N.; Bertone, P.; Chen, S.; Dessimoz, C.; Leproust, E. M.; Sipos, B.; Birney, E. Towards Practical, High-Capacity, Low-Maintenance Information Storage in Synthesized DNA. Nature 2013, 494 (7435), 77– 80,  DOI: 10.1038/nature11875
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      9
      Towards practical, high-capacity, low-maintenance information storage in synthesized DNA
      Goldman, Nick; Bertone, Paul; Chen, Siyuan; Dessimoz, Christophe; LeProust, Emily M.; Sipos, Botond; Birney, Ewan
      Nature (London, United Kingdom) (2013), 494 (7435), 77-80CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Digital prodn., transmission and storage have revolutionized how we access and use information but have also made archiving an increasingly complex task that requires active, continuing maintenance of digital media. This challenge has focused some interest on DNA as an attractive target for information storage because of its capacity for high-d. information encoding, longevity under easily achieved conditions and proven track record as an information bearer. Previous DNA-based information storage approaches have encoded only trivial amts. of information or were not amenable to scaling-up, and used no robust error-correction and lacked examn. of their cost-efficiency for large-scale information archival. Here we describe a scalable method that can reliably store more information than has been handled before. We encoded computer files totalling 739 kilobytes of hard-disk storage and with an estd. Shannon information of 5.2 × 106 bits into a DNA code, synthesized this DNA, sequenced it and reconstructed the original files with 100% accuracy. Theor. anal. indicates that our DNA-based storage scheme could be scaled far beyond current global information vols. and offers a realistic technol. for large-scale, long-term and infrequently accessed digital archiving. In fact, current trends in technol. advances are reducing DNA synthesis costs at a pace that should make our scheme cost-effective for sub-50-yr archiving within a decade.
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    10. 10
      Meiser, L. C.; Nguyen, B. H.; Chen, Y. J.; Nivala, J.; Strauss, K.; Ceze, L.; Grass, R. N. Synthetic DNA Applications in Information Technology. Nat. Commun. 2022, 13 (1), 1– 13,  DOI: 10.1038/s41467-021-27846-9
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      There is no corresponding record for this reference.
    11. 11
      Meiser, L. C.; Antkowiak, P. L.; Koch, J.; Chen, W. D.; Kohll, A. X.; Stark, W. J.; Heckel, R.; Grass, R. N. Reading and Writing Digital Data in DNA. Nat. Protoc 2020, 15 (1), 86– 101,  DOI: 10.1038/s41596-019-0244-5
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      11
      Reading and writing digital data in DNA
      Meiser, Linda C.; Antkowiak, Philipp L.; Koch, Julian; Chen, Weida D.; Kohll, A. Xavier; Stark, Wendelin J.; Heckel, Reinhard; Grass, Robert N.
      Nature Protocols (2020), 15 (1), 86-101CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
      In this work, we provide instructions for archiving digital information in the form of DNA and for subsequently retrieving it from the DNA. In principle, information can be represented in DNA by simply mapping the digital information to DNA and synthesizing it. However, imperfections in synthesis, sequencing, storage and handling of the DNA induce errors within the mols., making error-free information storage challenging. Along with the protocol, we provide computer code that automatically encodes digital information to DNA sequences and decodes the information back from DNA to a digital file. The required software is provided on a Github repository. The protocol relies on com. DNA synthesis and DNA sequencing via Illumina dye sequencing, and requires 1-2 h of prepn. time, 1/2 d for sequencing prepn. and 2-4 h for data anal. This protocol focuses on storage scales of ~ 100 kB to 15 MB, offering an ideal starting point for small expts. It can be augmented to enable higher data vols. and random access to the data and also allows for future sequencing and synthesis technologies, by changing the parameters of the encoder/decoder to account for the corresponding error rates.
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    12. 12
      Ceze, L.; Nivala, J.; Strauss, K. Molecular Digital Data Storage Using DNA. Nat. Rev. Genet 2019, 20 (8), 456– 466,  DOI: 10.1038/s41576-019-0125-3
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      12
      Molecular digital data storage using DNA
      Ceze, Luis; Nivala, Jeff; Strauss, Karin
      Nature Reviews Genetics (2019), 20 (8), 456-466CODEN: NRGAAM; ISSN:1471-0056. (Nature Research)
      A review. Mol. data storage is an attractive alternative for dense and durable information storage, which is sorely needed to deal with the growing gap between information prodn. and the ability to store data. DNA is a clear example of effective archival data storage in mol. form. In this Review, we provide an overview of the process, the state of the art in this area and challenges for mainstream adoption. We also survey the field of in vivo mol. memory systems that record and store information within the DNA of living cells, which, together with in vitro DNA data storage, lie at the growing intersection of computer systems and biotechnol.
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      Song, X.; Reif, J. Nucleic Acid Databases and Molecular-Scale Computing. ACS Nano 2019, 13 (6), 6256– 6268,  DOI: 10.1021/acsnano.9b02562
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      13
      Nucleic Acid Databases and Molecular-Scale Computing
      Song, Xin; Reif, John
      ACS Nano (2019), 13 (6), 6256-6268CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A review. DNA outperforms most conventional storage media in terms of information retention time, phys. d., and volumetric coding capacity. Advances in synthesis and sequencing technologies have enabled implementations of large synthetic DNA databases with impressive storage capacity and reliable data recovery. Several robust DNA storage architectures featuring random access, error correction, and content rewritability have been constructed with the potential for scalability and cost redn. We survey these recent achievements and discuss alternative routes for overcoming the hurdles of engineering practical DNA storage systems. We also review recent exciting work on in vivo DNA memory including intracellular recorders constructed by programmable genome editing tools. Besides information storage, DNA could serve as a versatile mol. computing substrate. We highlight several state-of-the-art DNA computing techniques such as strand displacement, localized hybridization chain reactions, and enzymic reaction networks. We summarize how these simple primitives have facilitated rational designs and implementations of in vitro DNA reaction networks that emulate digital/analog circuits, artificial neural networks, or nonlinear dynamic systems. We envision these modular primitives could be strategically adapted for sophisticated database operations and massively parallel computations on DNA databases. We also highlight in vivo DNA computing modules such as CRISPR logic gates for building scalable genetic circuits in living cells. To conclude, we discuss various implications and challenges of DNA-based storage and computing, and we particularly encourage innovative work on bridging these two areas of research to further explore mol. parallelism and near-data processing. Such integrated mol. systems could lead to far-reaching applications in biocomputing, security, and medicine.
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    14. 14
      Erlich, Y.; Zielinski, D. DNA Fountain Enables a Robust and Efficient Storage Architecture. Science 2017, 355 (6328), 950– 954,  DOI: 10.1126/science.aaj2038
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      14
      DNA Fountain enables a robust and efficient storage architecture
      Erlich, Yaniv; Zielinski, Dina
      Science (Washington, DC, United States) (2017), 355 (6328), 950-954CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      DNA is an attractive medium to store digital information. Here the authors report a storage strategy, called DNA Fountain, that is highly robust and approaches the information capacity per nucleotide. Using the approach, the authors stored a full computer operating system, movie, and other files with a total of 2.14 × 106 bytes in DNA oligonucleotides and perfectly retrieved the information from a sequencing coverage equiv. to a single tile of Illumina sequencing. The authors also tested a process that can allow 2.18 × 1015 retrievals using the original DNA sample and were able to perfectly decode the data. Finally, the authors explored the limit of the architecture in terms of bytes per mol. and obtained a perfect retrieval from a d. of 215 petabytes per g of DNA, orders of magnitude higher than previous reports.
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    15. 15
      Caruthers, M. H. A Brief Review of DNA and RNA Chemical Synthesis. Biochem. Soc. Trans. 2011, 39 (2), 575– 580,  DOI: 10.1042/BST0390575
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      15
      A brief review of DNA and RNA chemical synthesis
      Caruthers, Marvin H.
      Biochemical Society Transactions (2011), 39 (2), 575-580CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)
      A review. Current methodologies used to synthesize DNA and RNA are reviewed. These focus on using controlled pore glass and microarrays on glass slides.
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    16. 16
      Lee, H. H.; Kalhor, R.; Goela, N.; Bolot, J.; Church, G. M. Terminator-Free Template-Independent Enzymatic DNA Synthesis for Digital Information Storage. Nat. Commun. 2019, 10, 2383,  DOI: 10.1038/s41467-019-10258-1
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      16
      Terminator-free template-independent enzymatic DNA synthesis for digital information storage
      Lee Henry H; Kalhor Reza; Church George M; Lee Henry H; Kalhor Reza; Church George M; Goela Naveen; Bolot Jean
      Nature communications (2019), 10 (1), 2383 ISSN:.
      DNA is an emerging medium for digital data and its adoption can be accelerated by synthesis processes specialized for storage applications. Here, we describe a de novo enzymatic synthesis strategy designed for data storage which harnesses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT) in kinetically controlled conditions. Information is stored in transitions between non-identical nucleotides of DNA strands. To produce strands representing user-defined content, nucleotide substrates are added iteratively, yielding short homopolymeric extensions whose lengths are controlled by apyrase-mediated substrate degradation. With this scheme, we synthesize DNA strands carrying 144 bits, including addressing, and demonstrate retrieval with streaming nanopore sequencing. We further devise a digital codec to reduce requirements for synthesis accuracy and sequencing coverage, and experimentally show robust data retrieval from imperfectly synthesized strands. This work provides distributive enzymatic synthesis and information-theoretic approaches to advance digital information storage in DNA.
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    17. 17
      Lee, H.; Wiegand, D. J.; Griswold, K.; Punthambaker, S.; Chun, H.; Kohman, R. E.; Church, G. M. Photon-Directed Multiplexed Enzymatic DNA Synthesis for Molecular Digital Data Storage. Nat. Commun. 2020, 11, 5246,  DOI: 10.1038/s41467-020-18681-5
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      17
      Photon-directed multiplexed enzymatic DNA synthesis for molecular digital data storage
      Lee, Howon; Wiegand, Daniel J.; Griswold, Kettner; Punthambaker, Sukanya; Chun, Honggu; Kohman, Richie E.; Church, George M.
      Nature Communications (2020), 11 (1), 5246CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: New storage technologies are needed to keep up with the global demands of data generation. DNA is an ideal storage medium due to its stability, information d. and ease-of-readout with advanced sequencing techniques. However, progress in writing DNA is stifled by the continued reliance on chem. synthesis methods. The enzymic synthesis of DNA is a promising alternative, but thus far has not been well demonstrated in a parallelized manner. Here, we report a multiplexed enzymic DNA synthesis method using maskless photolithog. Rapid uncaging of Co2+ ions by patterned UV light activates Terminal deoxynucleotidyl Transferase (TdT) for spatially-selective synthesis on an array surface. Spontaneous quenching of reactions by the diffusion of excess caging mols. confines synthesis to light patterns and controls the extension length. We show that our multiplexed synthesis method can be used to store digital data by encoding 12 unique DNA oligonucleotide sequences with video game music, which is equiv. to 84 trits or 110 bits of data.
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    18. 18
      Kubista, M.; Andrade, J. M.; Bengtsson, M.; Forootan, A.; Jonák, J.; Lind, K.; Sindelka, R.; Sjöback, R.; Sjögreen, B.; Strömbom, L.; Ståhlberg, A.; Zoric, N. The Real-Time Polymerase Chain Reaction. Mol. Aspects Med. 2006, 27 (2–3), 95– 125,  DOI: 10.1016/j.mam.2005.12.007
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      18
      The real-time polymerase chain reaction
      Kubista, Mikael; Andrade, Jose Manuel; Bengtsson, Martin; Forootan, Amin; Jonak, Jiri; Lind, Kristina; Sindelka, Radek; Sjoeback, Robert; Sjoegreen, Bjoern; Stroembom, Linda; Stahlberg, Anders; Zoric, Neven
      Molecular Aspects of Medicine (2006), 27 (2-3), 95-125CODEN: MAMED5; ISSN:0098-2997. (Elsevier B.V.)
      A review. The scientific, medical, and diagnostic communities have been presented the most powerful tool for quant. nucleic acids anal.: real-time PCR [Bustin, S.A., 2004. A-Z of Quant. PCR. IUL Press, San Diego, CA]. This new technique is a refinement of the original Polymerase Chain Reaction (PCR) developed by Kary Mullis and coworkers in the mid-80s, for which Kary Mullis was awarded the 1993 Nobel prize in Chem. By PCR essentially any nucleic acid sequence present in a complex sample can be amplified in a cyclic process to generate a large no. of identical copies that can readily be analyzed. This made it possible, for example, to manipulate DNA for cloning purposes, genetic engineering, and sequencing. But as an anal. technique the original PCR method had some serious limitations. By first amplifying the DNA sequence and then analyzing the product, quantification was exceedingly difficult since the PCR gave rise to essentially the same amt. of product independently of the initial amt. of DNA template mols. that were present. This limitation was resolved in 1992 by the development of real-time PCR by Higuchi et al. In real-time PCR the amt. of product formed is monitored during the course of the reaction by monitoring the fluorescence of dyes or probes introduced into the reaction that is proportional to the amt. of product formed, and the no. of amplification cycles required to obtain a particular amt. of DNA mols. is registered. Assuming a certain amplification efficiency, which typically is close to a doubling of the no. of mols. per amplification cycle, it is possible to calc. the no. of DNA mols. of the amplified sequence that were initially present in the sample. With the highly efficient detection chemistries, sensitive instrumentation, and optimized assays that are available today the no. of DNA mols. of a particular sequence in a complex sample can be detd. with unprecedented accuracy and sensitivity sufficient to detect a single mol. Typical uses of real-time PCR include pathogen detection, gene expression anal., single nucleotide polymorphism (SNP) anal., anal. of chromosome aberrations, and most recently also protein detection by real-time immuno PCR.
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    19. 19
      Shendure, J.; Balasubramanian, S.; Church, G. M.; Gilbert, W.; Rogers, J.; Schloss, J. A.; Waterston, R. H. DNA Sequencing at 40: Past, Present and Future. Nature 2017, 550 (7676), 345,  DOI: 10.1038/nature24286
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      19
      DNA sequencing at 40: past, present and future
      Shendure, Jay; Balasubramanian, Shankar; Church, George M.; Gilbert, Walter; Rogers, Jane; Schloss, Jeffery A.; Waterston, Robert H.
      Nature (London, United Kingdom) (2017), 550 (7676), 345-353CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      This review commemorates the 40th anniversary of DNA sequencing, a period in which we have already witnessed multiple technol. revolutions and a growth in scale from a few kilobases to the first human genome, and now to millions of human and a myriad of other genomes. DNA sequencing has been extensively and creatively repurposed, including as a 'counter' for a vast range of mol. phenomena. We predict that in the long view of history, the impact of DNA sequencing will be on a par with that of the microscope.
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    20. 20
      Heckel, R.; Mikutis, G.; Grass, R. N. A Characterization of the DNA Data Storage Channel. Sci. Rep 2019, 9 (1), 1– 12,  DOI: 10.1038/s41598-019-45832-6
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      20
      The MyoRobot technology discloses a premature biomechanical decay of skeletal muscle fiber bundles derived from R349P desminopathy mice
      Haug, Michael; Meyer, Charlotte; Reischl, Barbara; Proelss, Gerhard; Vetter, Kristina; Iberl, Julian; Nuebler, Stefanie; Schuermann, Sebastian; Rupitsch, Stefan J.; Heckel, Michael; Poeschel, Thorsten; Winter, Lilli; Herrmann, Harald; Clemen, Christoph S.; Schroeder, Rolf; Friedrich, Oliver
      Scientific Reports (2019), 9 (1), 1-10CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Mutations in the Des gene coding for the muscle-specific intermediate filament protein desmin lead to myopathies and cardiomyopathies. We previously generated a R349P desmin knock-in mouse strain as a patient-mimicking model for the corresponding most frequent human desmin mutation R350P. Since nothing is known about the age-dependent changes in the biomechanics of affected muscles, we investigated the passive and active biomechanics of small fiber bundles from young (17-23 wks), adult (25-45 wks) and aged (>60 wks) heterozygous and homozygous R349P desmin knock-in mice in comparison to wild-type littermates. We used a novel automated biomechatronics platform, the MyoRobot, to perform coherent quant. recordings of passive (resting length-tension curves, visco-elasticity) and active (caffeine-induced force transients, pCa-force, 'slack-tests') parameters to det. age-dependent effects of the R349P desmin mutation in slow-twitch soleus and fast-twitch extensor digitorum longus small fiber bundles. We demonstrate that active force properties are not affected by this mutation while passive steady-state elasticity is vastly altered in R349P desmin fiber bundles compatible with a pre-aged phenotype exhibiting stiffer muscle prepns. Visco-elasticity on the other hand, was not altered. Our study represents the first systematic age-related characterization of small muscle fiber bundle prepn. biomechanics in conjunction with inherited desminopathy.
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      Bell, N. A. W.; Keyser, U. F. Digitally Encoded DNA Nanostructures for Multiplexed, Single-Molecule Protein Sensing with Nanopores. Nat. Nanotechnol 2016, 11 (7), 645– 651,  DOI: 10.1038/nnano.2016.50
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      Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores
      Bell, Nicholas A. W.; Keyser, Ulrich F.
      Nature Nanotechnology (2016), 11 (7), 645-651CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      The simultaneous detection of a large no. of different analytes is important in bionanotechnol. research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, highly multiplexed sensing of single mols. can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, the authors designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signaled by the presence or absence of multiple DNA dumbbell hairpins. A 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows the authors to simultaneously detect four different antibodies of the same isotype at nanomolar concn. levels.
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    22. 22
      Dickinson, G. D.; Mortuza, G. M.; Clay, W.; Piantanida, L.; Green, C. M.; Watson, C.; Hayden, E. J.; Andersen, T.; Kuang, W.; Graugnard, E.; Zadegan, R.; Hughes, W. L. An Alternative Approach to Nucleic Acid Memory. Nat. Commun. 2021, 12 (1), 2371,  DOI: 10.1038/s41467-021-22277-y
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      22
      An alternative approach to nucleic acid memory
      Dickinson, George D.; Mortuza, Golam Md; Clay, William; Piantanida, Luca; Green, Christopher M.; Watson, Chad; Hayden, Eric J.; Andersen, Tim; Kuang, Wan; Graugnard, Elton; Zadegan, Reza; Hughes, William L.
      Nature Communications (2021), 12 (1), 2371CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      DNA is a compelling alternative to non-volatile information storage technologies due to its information d., stability, and energy efficiency. Previous studies have used artificially synthesized DNA to store data and automated next-generation sequencing to read it back. Here, we report digital Nucleic Acid Memory (dNAM) for applications that require a limited amt. of data to have high information d., redundancy, and copy no. In dNAM, data is encoded by selecting combinations of single-stranded DNA with (1) or without (0) docking-site domains. When self-assembled with scaffold DNA, staple strands form DNA origami breadboards. Information encoded into the breadboards is read by monitoring the binding of fluorescent imager probes using DNA-PAINT super-resoln. microscopy. To enhance data retention, a multi-layer error correction scheme that combines fountain and bi-level parity codes is used. As a prototype, fifteen origami encoded with Data is in our DNA!\n are analyzed. Each origami encodes unique data-droplet, index, orientation, and error-correction information. The error-correction algorithms fully recover the message when individual docking sites, or entire origami, are missing. Unlike other approaches to DNA-based data storage, reading dNAM does not require sequencing. As such, it offers an addnl. path to explore the advantages and disadvantages of DNA as an emerging memory material.
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      Chen, K.; Kong, J.; Zhu, J.; Ermann, N.; Predki, P.; Keyser, U. F. Digital Data Storage Using DNA Nanostructures and Solid-State Nanopores. Nano Lett. 2019, 19 (2), 1210– 1215,  DOI: 10.1021/acs.nanolett.8b04715
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      23
      Digital Data Storage Using DNA Nanostructures and Solid-State Nanopores
      Chen, Kaikai; Kong, Jinglin; Zhu, Jinbo; Ermann, Niklas; Predki, Paul; Keyser, Ulrich F.
      Nano Letters (2019), 19 (2), 1210-1215CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Solid-state nanopores are powerful tools for reading the three-dimensional shape of mols., allowing for the translation of mol. structure information into elec. signals. Here, we show a high-resoln. integrated nanopore system for identifying DNA nanostructures that has the capability of distinguishing attached short DNA hairpins with only a stem length difference of 8 bp along a DNA double strand named the DNA carrier. Using our platform, we can read up to 112 DNA hairpins with a sepg. distance of 114 bp attached on a DNA carrier that carries digital information. Our encoding strategy allows for the creation of a library of mols. with a size of up to 5 × 1033 (2112) that is only built from a few hundred types of base mols. for data storage and has the potential to be extended by linking multiple DNA carriers. Our platform provides a nanopore- and DNA nanostructure-based data storage method with convenient access and the potential for miniature-scale integration.
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      Seeman, N. C.; Sleiman, H. F. DNA Nanotechnology. Nat. Rev. Mater. 2018, 3, 17068,  DOI: 10.1038/natrevmats.2017.68
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      DNA nanotechnology
      Seeman, Nadrian C.; Sleiman, Hanadi F.
      Nature Reviews Materials (2018), 3 (1), 17068CODEN: NRMADL; ISSN:2058-8437. (Nature Research)
      DNA is the mol. that stores and transmits genetic information in biol. systems. The field of DNA nanotechnol. takes this mol. out of its biol. context and uses its information to assemble structural motifs and then to connect them together. This field has had a remarkable impact on nanoscience and nanotechnol., and has been revolutionary in our ability to control mol. self-assembly. In this Review, we summarize the approaches used to assemble DNA nanostructures and examine their emerging applications in areas such as biophysics, diagnostics, nanoparticle and protein assembly, biomol. structure detn., drug delivery and synthetic biol. The introduction of orthogonal interactions into DNA nanostructures is discussed, and finally, a perspective on the future directions of this field is presented.
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      Chen, K.; Zhu, J.; Bošković, F.; Keyser, U. F. Nanopore-Based Dna Hard Drives for Rewritable and Secure Data Storage. Nano Lett. 2020, 20 (5), 3754– 3760,  DOI: 10.1021/acs.nanolett.0c00755
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      Nanopore-Based DNA Hard Drives for Rewritable and Secure Data Storage
      Chen, Kaikai; Zhu, Jinbo; Boskovic, Filip; Keyser, Ulrich F.
      Nano Letters (2020), 20 (5), 3754-3760CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Nanopores are powerful single-mol. tools for label-free sensing of nanoscale mols. including DNA that can be used for building designed nanostructures and performing computations. Here, DNA hard drives (DNA-HDs) are introduced based on DNA nanotechnol. and nanopore sensing as a rewritable mol. memory system, allowing for storing, operating, and reading data in the changeable three-dimensional structure of DNA. Writing and erasing data are significantly improved compared to previous mol. storage systems by employing controllable attachment and removal of mols. on a long double-stranded DNA. Data reading is achieved by detecting the single mols. at the millisecond time scale using nanopores. The DNA-HD also ensures secure data storage where the data can only be read after providing the correct phys. mol. keys. The approach allows for easy-writing and easy-reading, rewritable, and secure data storage toward a promising miniature scale integration for mol. data storage and computation.
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    26. 26
      Zhang, D. Y.; Seelig, G. Dynamic DNA Nanotechnology Using Strand-Displacement Reactions. Nat. Chem. 2011, 3 (2), 103– 113,  DOI: 10.1038/nchem.957
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      Dynamic DNA nanotechnology using strand-displacement reactions
      Zhang, David Yu; Seelig, Georg
      Nature Chemistry (2011), 3 (2), 103-113CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      A review. The specificity and predictability of Watson-Crick base pairing make DNA a powerful and versatile material for engineering at the nanoscale. This has enabled the construction of a diverse and rapidly growing set of DNA nanostructures and nanodevices through the programmed hybridization of complementary strands. Although it had initially focused on the self-assembly of static structures, DNA nanotechnol. is now also becoming increasingly attractive for engineering systems with interesting dynamic properties. Various devices, including circuits, catalytic amplifiers, autonomous mol. motors and reconfigurable nanostructures, have recently been rationally designed to use DNA strand-displacement reactions, in which two strands with partial or full complementarity hybridize, displacing in the process one or more pre-hybridized strands. This mechanism allows for the kinetic control of reaction pathways. Here, the authors review DNA strand-displacement-based devices, and look at how this relatively simple mechanism can lead to a surprising diversity of dynamic behavior.
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    27. 27
      Song, T.; Eshra, A.; Shah, S.; Bui, H.; Fu, D.; Yang, M.; Mokhtar, R.; Reif, J. Fast and Compact DNA Logic Circuits Based on Single-Stranded Gates Using Strand-Displacing Polymerase. Nat. Nanotechnol 2019, 14 (11), 1075– 1081,  DOI: 10.1038/s41565-019-0544-5
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      27
      Fast and compact DNA logic circuits based on single-stranded gates using strand-displacing polymerase
      Song, Tianqi; Eshra, Abeer; Shah, Shalin; Bui, Hieu; Fu, Daniel; Yang, Ming; Mokhtar, Reem; Reif, John
      Nature Nanotechnology (2019), 14 (11), 1075-1081CODEN: NNAABX; ISSN:1748-3387. (Nature Research)
      DNA is a reliable biomol. with which to build mol. computation systems. In particular, DNA logic circuits (diffusion-based) have shown good performance regarding scalability and correctness of computation. However, previous architectures of DNA logic circuits have two limitations. First, the speed of computation is slow, often requiring hours to compute a simple function. Second, the circuits are of high complexity regarding the no. of DNA strands. Here, the authors introduce an architecture of DNA logic circuits based on single-stranded logic gates using strand-displacing DNA polymerase. The logic gates consist of only single DNA strands, which largely reduces leakage reactions and signal restoration steps such that the circuits are improved in regard to both speed of computation and the no. of DNA strands needed. Large-scale logic circuits can be constructed from the gates by simple cascading strategies. In particular, the authors have demonstrated a fast and compact logic circuit that computes the square-root function of four-bit input nos.
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    28. 28
      Palluk, S.; Arlow, D. H.; de Rond, T.; Barthel, S.; Kang, J. S.; Bector, R.; Baghdassarian, H. M.; Truong, A. N.; Kim, P. W.; Singh, A. K.; Hillson, N. J.; Keasling, J. D. De Novo DNA Synthesis Using Polymerasenucleotide Conjugates. Nat. Biotechnol. 2018, 36 (7), 645– 650,  DOI: 10.1038/nbt.4173
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      28
      De novo DNA synthesis using polymerase-nucleotide conjugates
      Palluk, Sebastian; Arlow, Daniel H.; de Rond, Tristan; Barthel, Sebastian; Kang, Justine S.; Bector, Rathin; Baghdassarian, Hratch M.; Truong, Alisa N.; Kim, Peter W.; Singh, Anup K.; Hillson, Nathan J.; Keasling, Jay D.
      Nature Biotechnology (2018), 36 (7), 645-650CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
      Oligonucleotides are almost exclusively synthesized using the nucleoside phosphoramidite method, even though it is limited to the direct synthesis of ∼200 mers and produces hazardous waste. Here, we describe an oligonucleotide synthesis strategy that uses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT). Each TdT mol. is conjugated to a single deoxyribonucleoside triphosphate (dNTP) mol. that it can incorporate into a primer. After incorporation of the tethered dNTP, the 3' end of the primer remains covalently bound to TdT and is inaccessible to other TdT-dNTP mols. Cleaving the linkage between TdT and the incorporated nucleotide releases the primer and allows subsequent extension. We demonstrate that TdT-dNTP conjugates can quant. extend a primer by a single nucleotide in 10-20 s, and that the scheme can be iterated to write a defined sequence. This approach may form the basis of an enzymic oligonucleotide synthesizer.
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      Kosuri, S.; Church, G. M. Large-Scale de Novo DNA Synthesis: Technologies and Applications. Nat. Methods 2014, 11 (5), 499– 507,  DOI: 10.1038/nmeth.2918
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      29
      Large-scale de novo DNA synthesis: technologies and applications
      Kosuri, Sriram; Church, George M.
      Nature Methods (2014), 11 (5), 499-507CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      A review. For over 60 years, the synthetic prodn. of new DNA sequences has helped researchers understand and engineer biol. Here we summarize methods and caveats for the de novo synthesis of DNA, with particular emphasis on recent technologies that allow for large-scale and low-cost prodn. In addn., we discuss emerging applications enabled by large-scale de novo DNA constructs, as well as the challenges and opportunities that lie ahead.
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    30. 30
      LeProust, E. M.; Peck, B. J.; Spirin, K.; McCuen, H. B.; Moore, B.; Namsaraev, E.; Caruthers, M. H. Synthesis of High-Quality Libraries of Long (150mer) Oligonucleotides by a Novel Depurination Controlled Process. Nucleic Acids Res. 2010, 38 (8), 2522– 2540,  DOI: 10.1093/nar/gkq163
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      30
      Synthesis of high-quality libraries of long (150mer) oligonucleotides by a novel depurination controlled process
      LeProust Emily M; Peck Bill J; Spirin Konstantin; McCuen Heather Brummel; Moore Bridget; Namsaraev Eugeni; Caruthers Marvin H
      Nucleic acids research (2010), 38 (8), 2522-40 ISSN:.
      We have achieved the ability to synthesize thousands of unique, long oligonucleotides (150mers) in fmol amounts using parallel synthesis of DNA on microarrays. The sequence accuracy of the oligonucleotides in such large-scale syntheses has been limited by the yields and side reactions of the DNA synthesis process used. While there has been significant demand for libraries of long oligos (150mer and more), the yields in conventional DNA synthesis and the associated side reactions have previously limited the availability of oligonucleotide pools to lengths <100 nt. Using novel array based depurination assays, we show that the depurination side reaction is the limiting factor for the synthesis of libraries of long oligonucleotides on Agilent Technologies' SurePrint DNA microarray platform. We also demonstrate how depurination can be controlled and reduced by a novel detritylation process to enable the synthesis of high quality, long (150mer) oligonucleotide libraries and we report the characterization of synthesis efficiency for such libraries. Oligonucleotide libraries prepared with this method have changed the economics and availability of several existing applications (e.g. targeted resequencing, preparation of shRNA libraries, site-directed mutagenesis), and have the potential to enable even more novel applications (e.g. high-complexity synthetic biology).
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    31. 31
      Xu, C.; Ma, B.; Gao, Z.; Dong, X.; Zhao, C.; Liu, H. Electrochemical DNA Synthesis and Sequencing on a Single Electrode with Scalability for Integrated Data Storage. Sci. Adv. 2021, 7, abk0100,  DOI: 10.1126/sciadv.abk0100
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      Yoo, E.; Choe, D.; Shin, J.; Cho, S.; Cho, B. K. Mini Review: Enzyme-Based DNA Synthesis and Selective Retrieval for Data Storage. Comput. Struct Biotechnol J. 2021, 19, 2468– 2476,  DOI: 10.1016/j.csbj.2021.04.057
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      32
      Mini review: Enzyme-based DNA synthesis and selective retrieval for data storage
      Yoo, Eojin; Choe, Donghui; Shin, Jongoh; Cho, Suhyung; Cho, Byung-Kwan
      Computational and Structural Biotechnology Journal (2021), 19 (), 2468-2476CODEN: CSBJAC; ISSN:2001-0370. (Elsevier B.V.)
      A review. The market for using and storing digital data is growing, with DNA synthesis emerging as an efficient way to store massive amts. of data. Storing information in DNA mainly consists of two steps: data writing and reading. The writing step requires encoding data in DNA, building one nucleotide at a time as a form of single-stranded DNA (ssDNA). Once the data needs to be read, the target DNA is selectively retrieved and sequenced, which will also be in the form of an ssDNA. Recently, enzyme-based DNA synthesis is emerging as a new method to be a breakthrough on behalf of decades-old chem. synthesis. A few enzymic methods have been presented for data memory, including the use of terminal deoxynucleotidyl transferase. Besides, enzyme-based amplification or denaturation of the target strand into ssDNA provides selective access to the desired dataset. In this review, we summarize diverse enzymic methods for either synthesizing ssDNA or retrieving the data-contg. DNA.
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    33. 33
      Barthel, S.; Palluk, S.; Hillson, N. J.; Keasling, J. D.; Arlow, D. H. Enhancing Terminal Deoxynucleotidyl Transferase Activity on Substrates with 3′ Terminal Structures for Enzymatic De Novo DNA Synthesis. Genes (Basel) 2020, 11 (1), 102,  DOI: 10.3390/genes11010102
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      Pawloski, A. R.; McGall, G.; Kuimelis, R. G.; Barone, D.; Cuppoletti, A.; Ciccolella, P.; Spence, E.; Afroz, F.; Bury, P.; Chen, C.; Chen, C.; Pao, D.; Le, M.; McGee, B.; Harkins, E.; Savage, M.; Narasimhan, S.; Goldberg, M.; Rava, R.; Fodor, S. P. A. Photolithographic Synthesis of High-Density DNA Probe Arrays: Challenges and Opportunities. Journal of Vacuum Science & Technology B: Microelectronics and Nanometer Structures 2007, 25 (6), 2537,  DOI: 10.1116/1.2794325
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      Photolithographic synthesis of high-density DNA probe arrays: Challenges and opportunities
      Pawloski, Adam R.; McGall, Glenn; Kuimelis, Robert G.; Barone, Dale; Cuppoletti, Andrea; Ciccolella, Paul; Spence, Eric; Afroz, Farhana; Bury, Paul; Chen, Christy; Chen, Chuan; Pao, Dexter; Le, Mary; McGee, Becky; Harkins, Elizabeth; Savage, Michael; Narasimhan, Sim; Goldberg, Martin; Rava, Richard; Fodor, Stephen P. A.
      Journal of Vacuum Science & Technology, B: Microelectronics and Nanometer Structures--Processing, Measurement, and Phenomena (2007), 25 (6), 2537-2546CODEN: JVSTBM; ISSN:1071-1023. (American Institute of Physics)
      The continual need for increased manufg. capacity in the prodn. of GeneChip DNA probe arrays, and the expanding use of these arrays into new areas of application such as mol. medicine, has stimulated the development of new chemistries and prodn. methods with higher efficiency and resoln. For current prodn. methods based on contact photolithog., modifications in substrate materials and photoactivated synthesis reagents have provided significant improvements in array performance and information content (≥4 × 106 sequences/cm2). An alternative next-generation manufg. process is also in development, which utilizes photoacid generating polymer films, and automated projection lithog. systems. This process has the ability to fabricate arrays with 1 μ feature pitch and smaller, providing an unprecedented sequence d. of 108/cm2 and greater. (c) 2007 American Institute of Physics.
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    35. 35
      Nguyen, B. H.; Takahashi, C. N.; Gupta, G.; Smith, J. A.; Rouse, R.; Berndt, P.; Yekhanin, S.; Ward, D. P.; Ang, S. D.; Garvan, P.; Parker, H. Y.; Carlson, R.; Carmean, D.; Ceze, L.; Strauss, K. Scaling DNA Data Storage with Nanoscale Electrode Wells. Sci. Adv. 2021, 7 (48), 1– 7,  DOI: 10.1126/sciadv.abi6714
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      Zhang, Y.; Kong, L.; Wang, F.; Li, B.; Ma, C.; Chen, D.; Liu, K.; Fan, C.; Zhang, H. Information Stored in Nanoscale: Encoding Data in a Single DNA Strand with Base64. Nano Today 2020, 33, 100871,  DOI: 10.1016/j.nantod.2020.100871
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      Information stored in nanoscale: Encoding data in a single DNA strand with Base64
      Zhang, Yi; Kong, Linlin; Wang, Fei; Li, Bo; Ma, Chao; Chen, Dong; Liu, Kai; Fan, Chunhai; Zhang, Hongjie
      Nano Today (2020), 33 (), 100871CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
      DNA as a storage medium has enormous potential because of its high storage d., but the produced redundancy limits this potential. The introduction of less error corrections to fully increase the storage d. in DNA remains a major challenge. To address this, an optimized Base64 method is developed and accordingly we realized a high specific storage d. of 1.77 bits/nucleotide in a DNA single strand. In this strategy, by Base64 encoding, code reshaping and balancing, and data mapping, some random text information was encoded into a DNA sequence and the corresponding DNA mol. was synthesized. It was then inserted into a circular plasmid for long-term information storage. This is also particularly suitable for information replication at an exponential rate when it is transformed in a bacterium. The introduction of balance codes during the transcoding process effectively controlled the GC content and continuous base repeat, which is important to reduce the error rates in the encoded DNA synthesis and sequencing. Moreover, the circular plasmid platform enhanced the storage stability and sequencing accuracy. Therefore, our approach achieved a robust and high efficient storage and an accurate readout of digital data.
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    37. 37
      Newman, S.; Stephenson, A. P.; Willsey, M.; Nguyen, B. H.; Takahashi, C. N.; Strauss, K.; Ceze, L. High Density DNA Data Storage Library via Dehydration with Digital Microfluidic Retrieval. Nat. Commun. 2019, 10 (1), 1706,  DOI: 10.1038/s41467-019-09517-y
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      High density DNA data storage library via dehydration with digital microfluidic retrieval
      Newman, Sharon; Stephenson, Ashley P.; Willsey, Max; Nguyen, Bichlien H.; Takahashi, Christopher N.; Strauss, Karin; Ceze, Luis
      Nature Communications (2019), 10 (1), 1706CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      DNA promises to be a high d. data storage medium, but phys. storage poses a challenge. To store large amts. of data, pools must be phys. isolated so they can share the same addressing scheme. We propose the storage of dehydrated DNA spots on glass as an approach for scalable DNA data storage. The dried spots can then be retrieved by a water droplet using a digital microfluidic device. Here we show that this storage schema works with varying spot organization, spotted masses of DNA, and droplet retrieval dwell times. In all cases, the majority of the DNA was retrieved and successfully sequenced. We demonstrate that the spots can be densely arranged on a microfluidic device without significant contamination of the retrieval. We also demonstrate that 1 TB of data could be stored in a single spot of DNA and successfully retrieved using this method.
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      Erlich, Y. A Vision for Ubiquitous Sequencing. Genome Res. 2015, 25 (10), 1411– 1416,  DOI: 10.1101/gr.191692.115
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      A vision for ubiquitous sequencing
      Erlich, Yaniv
      Genome Research (2015), 25 (10), 1411-1416CODEN: GEREFS; ISSN:1088-9051. (Cold Spring Harbor Laboratory Press)
      A review. Genomics has recently celebrated reaching the $1000 genome milestone, making affordable DNA sequencing a reality. This goal of the sequencing revolution has been successfully completed. Looking forward, the next goal of the revolution can be ushered in by the advent of sequencing sensors -miniaturized sequencing devices that are manufd. for real time applications and deployed in large quantities at low costs. The first part of this manuscript envisions applications that will benefit from moving the sequencers to the samples in a range of domains. In the second part, the manuscript outlines the crit. barriers that need to be addressed in order to reach the goal of ubiquitous sequencing sensors.
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      Takahashi, C. N.; Nguyen, B. H.; Strauss, K.; Ceze, L. Demonstration of End-to-End Automation of DNA Data Storage. Sci. Rep 2019, 9 (1), 1– 6,  DOI: 10.1038/s41598-019-41228-8
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      Eurotium Cristatum Fermented Okara as a Potential Food Ingredient to Combat Diabetes
      Chan, Li Yan; Takahashi, Masaki; Lim, Pei Jean; Aoyama, Shinya; Makino, Saneyuki; Ferdinandus, Ferdinandus; Ng, Shi Ya Clara; Arai, Satoshi; Fujita, Hideaki; Tan, Hong Chang; Shibata, Shigenobu; Lee, Chi-Lik Ken
      Scientific Reports (2019), 9 (1), 1-9CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Type 2 diabetes mellitus (T2DM) is a chronic disease, and dietary modification is a crucial part of disease management. Okara is a sustainable source of fiber-rich food. Most of the valorization research on okara focused more on the phys. attributes instead of the possible health attributes. The fermn. of okara using microbes originated from food source, such as tea, sake, sufu and yoghurt, were explored here. The aim of this study is to investigate fermented okara as a functional food ingredient to reduce blood glucose levels. Fermented and non-fermented okara exts. were analyzed using the metabolomic approach with UHPLC-QTof-MSE. Statistical anal. demonstrated that the anthraquinones, emodin and physcion, served as potential markers and differentiated Eurotium cristatum fermented okara (ECO) over other choices of microbes. The in-vitro αglucosidase activity assays and in-vivo mice studies showed that ECO can reduce postprandial blood glucose levels. A 20% ECO loading crispy snack prototype revealed a good nutrition compn. and could serve as a fundamental formulation for future antidiabetes recipe development, strengthening the hypothesis that ECO can be used as a novel food ingredient for diabetic management.
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    40. 40
      Choi, H.; Choi, Y.; Choi, J.; Lee, A. C.; Yeom, H.; Hyun, J.; Ryu, T.; Kwon, S. Purification of Multiplex Oligonucleotide Libraries by Synthesis and Selection. Nat. Biotechnol. 2022, 40 (1), 47– 53,  DOI: 10.1038/s41587-021-00988-3
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      40
      Purification of multiplex oligonucleotide libraries by synthesis and selection
      Choi, Hansol; Choi, Yeongjae; Choi, Jaewon; Lee, Amos Chungwon; Yeom, Huiran; Hyun, Jinwoo; Ryu, Taehoon; Kwon, Sunghoon
      Nature Biotechnology (2022), 40 (1), 47-53CODEN: NABIF9; ISSN:1087-0156. (Nature Portfolio)
      Complex oligonucleotide (oligo) libraries are essential materials for diverse applications in synthetic biol., pharmaceutical prodn., nanotechnol. and DNA-based data storage. However, the error rates in synthesizing complex oligo libraries can be substantial, leading to increment in cost and labor for the applications. As most synthesis errors arise from faulty insertions and deletions, we developed a length-based method with single-base resoln. for purifn. of complex libraries contg. oligos of identical or different lengths. Our method-purifn. of multiplex oligonucleotide libraries by synthesis and selection-can be performed either step-by-step manually or using a next-generation sequencer. When applied to a digital data-encoded library contg. oligos of identical length, the method increased the purity of full-length oligos from 83% to 97%. We also show that libraries encoding the complementarity-detg. region H3 with three different lengths (with an empirically achieved diversity >106) can be simultaneously purified in one pot, increasing the in-frame oligo fraction from 49.6% to 83.5%.
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      Wang, Y.; Wang, M.; Wang, J.; Liu, J. An Adaptive Data Redundancy Strategy in Cloud Storage. In 2019 IEEE 2nd International Conference on Electronic Information and Communication Technology (ICEICT); IEEE, 2019; pp 40– 45.
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      Antkowiak, P. L.; Lietard, J.; Darestani, M. Z.; Somoza, M. M.; Stark, W. J.; Heckel, R.; Grass, R. N. Low Cost DNA Data Storage Using Photolithographic Synthesis and Advanced Information Reconstruction and Error Correction. Nat. Commun. 2020, 11, 5345,  DOI: 10.1038/s41467-020-19148-3
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      Low cost DNA data storage using photolithographic synthesis and advanced information reconstruction and error correction
      Antkowiak, Philipp L.; Lietard, Jory; Darestani, Mohammad Zalbagi; Somoza, Mark M.; Stark, Wendelin J.; Heckel, Reinhard; Grass, Robert N.
      Nature Communications (2020), 11 (1), 5345CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Due to its longevity and enormous information d., DNA is an attractive medium for archival storage. The current hamstring of DNA data storage systems-both in cost and speed-is synthesis. The key idea for breaking this bottleneck pursued in this work is to move beyond the low-error and expensive synthesis employed almost exclusively in today's systems, towards cheaper, potentially faster, but high-error synthesis technologies. Here, we demonstrate a DNA storage system that relies on massively parallel light-directed synthesis, which is considerably cheaper than conventional solid-phase synthesis. However, this technol. has a high sequence error rate when optimized for speed. We demonstrate that even in this high-error regime, reliable storage of information is possible, by developing a pipeline of algorithms for encoding and reconstruction of the information. In our expts., we store a file contg. sheet music of Mozart, and show perfect data recovery from low synthesis fidelity DNA.
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      Nguyen, T. T.; Cai, K.; Schouhamer Immink, K. A.; Kiah, H. M. Capacity-Approaching Constrained Codes With Error Correction for DNA-Based Data Storage. IEEE Trans Inf Theory 2021, 67 (8), 5602– 5613,  DOI: 10.1109/TIT.2021.3066430
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      Blawat, M.; Gaedke, K.; Hütter, I.; Chen, X.-M.; Turczyk, B.; Inverso, S.; Pruitt, B. W.; Church, G. M. Forward Error Correction for DNA Data Storage. Procedia Comput. Sci. 2016, 80, 1011– 1022,  DOI: 10.1016/j.procs.2016.05.398
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      Tang, Y.; Farnoud, F. Correcting Deletion Errors in DNA Data Storage with Enzymatic Synthesis. In 2021 IEEE Information Theory Workshop (ITW); IEEE, 2021; pp 1– 6.
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      Lu, X.; Kim, S. Design of Nonbinary Error Correction Codes with a Maximum Run-Length Constraint to Correct a Single Insertion or Deletion Error for DNA Storage. IEEE Access 2021, 9, 135354– 135363,  DOI: 10.1109/ACCESS.2021.3116245
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      Press, W. H.; Hawkins, J. A.; Jones, S. K.; Schaub, J. M.; Finkelstein, I. J. HEDGES Error-Correcting Code for DNA Storage Corrects Indels and Allows Sequence Constraints. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (31), 18489– 18496,  DOI: 10.1073/pnas.2004821117
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      HEDGES error-correcting code for DNA storage corrects indels and allows sequence constraints
      Press, William H.; Hawkins, John A.; Jones, Stephen Jr. K.; Schaub, Jeffrey M.; Finkelstein, Ilya J.
      Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (31), 18489-18496CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Synthetic DNA is rapidly emerging as a durable, high-d. information storage platform. A major challenge for DNA-based information encoding strategies is the high rate of errors that arise during DNA synthesis and sequencing. Here, we describe the HEDGES (Hash Encoded, Decoded by Greedy Exhaustive Search) error-correcting code that repairs all three basic types of DNA errors: insertions, deletions, and substitutions. HEDGES also converts unresolved or compd. errors into substitutions, restoring synchronization for correction via a std. Reed-Solomon outer code that is interleaved across strands. Moreover, HEDGES can incorporate a broad class of user-defined sequence constraints, such as avoiding excess repeats, or too high or too low windowed guanine-cytosine (GC) content. We test our code both via in silico simulations and with synthesized DNA. From its measured performance, we develop a statistical model applicable to much larger datasets. Predicted performance indicates the possibility of error-free recovery of petabyte- and exabyte-scale data from DNA degraded with as much as 10% errors. As the cost of DNA synthesis and sequencing continues to drop, we anticipate that HEDGES will find applications in large-scale error-free information encoding.
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      Dong, Y.; Sun, F.; Ping, Z.; Ouyang, Q.; Qian, L. DNA Storage: Research Landscape and Future Prospects. Natl. Sci. Rev. 2020, 7 (6), 1092– 1107,  DOI: 10.1093/nsr/nwaa007
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      DNA storage: research landscape and future prospects
      Dong, Yiming; Sun, Fajia; Ping, Zhi; Ouyang, Qi; Qian, Long
      National Science Review (2020), 7 (6), 1092-1107CODEN: NSRACI; ISSN:2053-714X. (Oxford University Press)
      The global demand for data storage is currently o utpacing the world's storage capabilities. DNA, the carrier of natural genetic information, offrs a stable, resource- and energy-effient and sustainable data storage soln. In this review, we summarize the fundamental theory, r esearch h istory, and tech. challenges of DNA s torage. From a quant. perspective, we evaluate the prospect of DNA, and org. polymers in general, as a novel class of data storage medium.
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      Hosseini, M.; Pratas, D.; Pinho, A. A Survey on Data Compression Methods for Biological Sequences. Information 2016, 7 (4), 56,  DOI: 10.3390/info7040056
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      Vishwakarma, R. High Density Data Storage In Dna Using An Efficient Message Encoding Scheme. International Journal of Information Technology Convergence and Services 2012, 2 (2), 41– 46,  DOI: 10.5121/ijitcs.2012.2204
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      Choi, Y.; Ryu, T.; Lee, A. C.; Choi, H.; Lee, H.; Park, J.; Song, S. H.; Kim, S.; Kim, H.; Park, W.; Kwon, S. High Information Capacity DNA-Based Data Storage with Augmented Encoding Characters Using Degenerate Bases. Sci. Rep 2019, 9, 6582,  DOI: 10.1038/s41598-019-43105-w
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      High information capacity DNA-based data storage with augmented encoding characters using degenerate bases
      Choi Yeongjae; Ryu Taehoon; Choi Hansol; Lee Hansaem; Park Jaejun; Kwon Sunghoon; Ryu Taehoon; Park Jaejun; Lee Amos C; Kwon Sunghoon; Song Suk-Heung; Kim Seojoo; Kim Hyeli; Park Wook; Kwon Sunghoon; Kwon Sunghoon
      Scientific reports (2019), 9 (1), 6582 ISSN:.
      DNA-based data storage has emerged as a promising method to satisfy the exponentially increasing demand for information storage. However, practical implementation of DNA-based data storage remains a challenge because of the high cost of data writing through DNA synthesis. Here, we propose the use of degenerate bases as encoding characters in addition to A, C, G, and T, which augments the amount of data that can be stored per length of DNA sequence designed (information capacity) and lowering the amount of DNA synthesis per storing unit data. Using the proposed method, we experimentally achieved an information capacity of 3.37 bits/character. The demonstrated information capacity is more than twice when compared to the highest information capacity previously achieved. The proposed method can be integrated with synthetic technologies in the future to reduce the cost of DNA-based data storage by 50%.
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      Ren, Y.; Zhang, Y.; Liu, Y.; Wu, Q.; Su, J.; Wang, F.; Chen, D.; Fan, C.; Liu, K.; Zhang, H. DNA-Based Concatenated Encoding System for High-Reliability and High-Density Data Storage. Small Methods 2022, 6 (4), 2101335,  DOI: 10.1002/smtd.202101335
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      52
      DNA-Based Concatenated Encoding System for High-Reliability and High-Density Data Storage
      Ren, Yubin; Zhang, Yi; Liu, Yawei; Wu, Qinglin; Su, Juanjuan; Wang, Fan; Chen, Dong; Fan, Chunhai; Liu, Kai; Zhang, Hongjie
      Small Methods (2022), 6 (4), 2101335CODEN: SMMECI; ISSN:2366-9608. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Information storage based on DNA mols. provides a promising soln. with advantages of low-energy consumption, high storage efficiency, and long lifespan. However, there are only four natural nucleotides and DNA storage is thus limited by 2 bits per nucleotide. Here, artificial nucleotides into DNA data storage to achieve higher coding efficiency than 2 bits per nucleotide is introduced. To accommodate the characteristics of DNA synthesis and sequencing, two high-reliability encoding systems suitable for four, six, and eight nucleotides, i.e., the RaptorQ-Arithmetic-LZW-RS (RALR) and RaptorQ-Arithmetic-Base64-RS (RABR) systems, are developed. The two concatenated encoding systems realize the advantages of correcting DNA sequence losses, correcting errors within DNA sequences, reducing homopolymers, and controlling specific nucleotide contents. The av. coding efficiencies with error correction and without arithmetic compression by the RALR system using four, six, and eight nucleotides reach 1.27, 1.61, and 1.85 bits per nucleotide, resp. While the av. coding efficiencies by the RABR system are up to 1.50, 2.00, and 2.35 bits per nucleotide, resp. The coding efficiency, versatility, and tunability of the developed artificial DNA systems might provide significant guidance for high-reliability and high-d. data storage.
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      Tabatabaei, S. K.; Pham, B.; Pan, C.; Liu, J.; Chandak, S.; Shorkey, S. A.; Hernandez, A. G.; Aksimentiev, A.; Chen, M.; Schroeder, C. M.; Milenkovic, O. Expanding the Molecular Alphabet of DNA-Based Data Storage Systems with Neural Network Nanopore Readout Processing. Nano Lett. 2022, 22 (5), 1905– 1914,  DOI: 10.1021/acs.nanolett.1c04203
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      Expanding the Molecular Alphabet of DNA-Based Data Storage Systems with Neural Network Nanopore Readout Processing
      Tabatabaei S Kasra; Liu Jingqian; Aksimentiev Aleksei; Schroeder Charles M; Tabatabaei S Kasra; Schroeder Charles M; Pham Bach; Shorkey Spencer A; Chen Min; Pan Chao; Milenkovic Olgica; Chandak Shubham; Hernandez Alvaro G; Aksimentiev Aleksei; Schroeder Charles M; Schroeder Charles M
      Nano letters (2022), 22 (5), 1905-1914 ISSN:.
      DNA is a promising next-generation data storage medium, but challenges remain with synthesis costs and recording latency. Here, we describe a prototype of a DNA data storage system that uses an extended molecular alphabet combining natural and chemically modified nucleotides. Our results show that MspA nanopores can discriminate different combinations and ordered sequences of natural and chemically modified nucleotides in custom-designed oligomers. We further demonstrate single-molecule sequencing of the extended alphabet using a neural network architecture that classifies raw current signals generated by Oxford Nanopore sequencers with an average accuracy exceeding 60% (39× larger than random guessing). Molecular dynamics simulations show that the majority of modified nucleotides lead to only minor perturbations of the DNA double helix. Overall, the extended molecular alphabet may potentially offer a nearly 2-fold increase in storage density and potentially the same order of reduction in the recording latency, thereby enabling new implementations of molecular recorders.
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