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….This Little Piggy Stayed Genome
Agriculture and medicine pin high hopes on plant and animal gene sequencing projects.
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| IMAGES: ART EXPLOSION; SUN: ULTIMATE SYMBOL |
Philosophers may fume and physicians may fantasize about the fallout (fair or foul) from the “finish” of the Human Genome Project, but agricultural genomics is really where it’s at for the world at large and in the foreseeable future. (Or at least as long as most of the planet is concerned about full bellies and not just full medicine cabinets.) And even in the area of human medicine, it is likely that the study of the genomes (the total complement of an organism’s DNA) and the proteomes (the total complement of proteins) of plants and animals will be the first and foremost step to understanding and manipulating the intricate nexus of gene interactions that exists in our own genus Homo. The experimentation and analysis still necessary are too complex to bypass in order to start substantially manipulating our own DNA. This holds true even in those rare cases where it might be morally acceptable to play trial-and-error with human genes and gene products.
It is one thing to manipulate single genes to attack those few diseases that they appear to cause. It is quite another to tinker with complex metabolic pathways, hormonal interactions, and cellular development sequences (especially embryonic ones) without being fully aware of what you are doing when there is a human life at stake. The risks seem even greater now than they did just a year ago, since it was only recently determined that there are most likely far fewer genes than were previously assumed (only some 26,000–40,000 rather than 80,000–100,000). Gene interactions; post-translational protein processing; and regulation, regulation, regulation appear to be everything—and much harder to study than single factors could ever be.
That is also why animal, plant, and microbial genomics are so important to human welfare, beyond the intrinsic benefits possible from manipulating them for practical ends. They provide the scientific basis for what is likely to become one of the biggest research fields in modern biology—comparative genomics. To learn how DNA manages to transform from a simple chemical code of four letters into an entire biological entity—from bacterium to basketball star—it will be necessary to understand how genomes operate, not just how genes operate in isolation. Because we don’t know how less than a 2% difference in the genes makes a monkey (pardon, chimpanzee) out of our nearest ancestors and a human out of you and me.
A Chemical Biology
As defined by the National Center for Genetic Resources (www.ncgr.org), a gene is a segment of a chromosome, a piece of DNA with chemical instructions. A gene has to speak chemically or be expressed as a protein before it can exert control over a cellular process. This relationship of genes to gene products cuts across all levels of biology, lies at the crux of evolution, and gives comparative genomics its power.
A large number of human genes were identified by comparing portions of the already known bacterial, animal, or plant sequences for analogous genes with the discovered sequence in the human genome, or they were discovered because portions of the known nonhuman gene were capable of binding to specific sections of isolated human DNA. To sequence genomes and exploit the incredible power of genomics, biology had to transform itself into a chemical enterprise, a world of laboratory instrumentation and computers. From automated protein and gene sequencers and synthesizers to the most sophisticated database-handling power of modern bioinformatics, from genes cloned in bacteria to those massively amplified in PCR, the entire field of gene research and genomics has been made possible by and has proven a spur to new technologies and instruments. Incredible as it may have seemed only a decade ago, genomes are easy to sequence, requiring only a combination of dollars and days.
For all of these reasons, genome projects are and will remain the rage. According to T. A. Brown in Genomes, “As we begin the new millennium, the major goal of molecular biology is to obtain the complete sequence of as many genomes as possible.”
Many of the most valuable potential genomes are found down on the farm. According to the California Institute for Agricultural Genomics (www.genomics.ucr.edu/bag.html), “The potential of genomics research to boost the economy cannot be overstated …. New uses and markets for crops, greater productivity, dramatic reductions in production costs due to less need for pesticides or less damage from pests, and more efficient use of land and water are just some of the expected outcomes.”
Pig of My Heart
Like the characters in George Orwell’s Animal Farm, cows, pigs, sheep, horses, and even lowly chickens play pivotal roles in the future of agricultural genomics—and in the science and profits to be derived (see box, Chickens and Horses and Cows—Oh My!).Not just leaner pork, but humanized swine hearts and blood for transfusions may be produced on the farm (or at least in the laboratory-turned-barnyard pen). The ability to understand and control animal diseases is also a key target for such studies. Comparative genomics and genetic engineering combined will show the way.
As part of the U.S. federal government’s Initiative for Future Agriculture and Food Systems (IFAFS), a competitive grant program was established in 1998 to address critical emerging U.S. agricultural issues related to (1) future food production, (2) environmental quality and natural resource management, or (3) farm income. A key component is the Agricultural Genomics section in which the subsection, The Animal Genome, includes the targets areas: (1) mapping functional genes through analysis of expressed sequence tags(ESTs); (2) developing comparative gene maps across animal species; and (3) strategies for effectively utilizing genomic information to improve agriculturally important animal species. In 2000, awards were given for projects designed to improve meat quality in pigs, to functionally map growth-regulating genes in broiler chickens, and to study the genomics of the immune system in cattle (in hopes of developing new methods of disease resistance). Another study focused on genetic resistance to paratuberculosis, an incurable ailment of dairy cattle that affects 22% of all U.S. herds, with the long-term goal of breeding animals more resistant to the disease.
It’s All a Plant
Weeds and crops are all the same when it comes to genomics. A weed (such as the small mustard variety, Arabidopsis) is, after all, just a plant growing where we don’t want it. (In fact, there are varieties of orchids considered noxious weeds in Indonesia.) Still, what we think of as “weeds” often prove extremely efficient in their ability to grow and prosper under stress—even the stress of our active attempts to kill them—traits that could be very desirable to have in our highly inbred and often comparatively “sickly” commercial crop varieties. Comparative genomics may provide the key to determining what cascade of characteristics and gene and protein processes make some plants more successful than others when faced with the challenges of drought, heat, frost, and flood, as well as insect pests and microbially induced diseases (see box, How Green Was My Genome).
The big news in plant genomes, however, is the complete sequencing of the Arabidopsis genome—the first plant genome to be completely sequenced. The ultimate goal is the identification of every gene in this particular plant species. This will permit analysis of each gene in particular varieties or genotypes, in different environments, and in response to various stresses. As pointed out in the National Science Foundation-sponsored report, Realizing the Potential of Plant Genomics: From Model System to the Understanding of Diversity, “Modern chromatographic methods, coupled with on-line detection by mass spectrometry, are allowing the resolution of increasingly complex mixtures of small molecules and proteins. As a result of these parallel developments, the assignment of surrogate end points for detecting complex phenotypes will become increasingly commonplace and facile.” Thus the technology for doing comparative genomics is at hand.
Using Arabidopsis as a model organism (one that can be manipulated and cloned rapidly under complete environmental control) will provide biological information of profound scientific value for crop species and higher organisms. As the genomes of more and more economically important plant species are deciphered, the practical benefits from comparative genomics may finally justify some of the excessive hype delivered by an earlier crop of genetic engineering cheerleaders.
Barnyard Bugs
Microscopic life and a variety of insect pests also have their place in the realm of agricultural genomics. What makes one insect feed upon our crops instead of the weeds around it? Choose corn instead of beans? What makes one fungus a pathogen and the other just a harmless saprophyte? One bacterium a blight and another a symbiotic companion needed for fixing nitrogen? Why is one virus a bane, the other merely banal?
More importantly, how can these microorganisms be killed or crippled without damaging their harmless peers or other organisms in the environment? Unique gene targets, or points in a panoply of genetic regulation where chemical interference works its worst, must be found. Comparative genomics may be the best means of determining unique targets for our future pesticides. Or it may help to develop environmental or biological controls that eliminate the need for chemical pesticides completely (see box, Cheese It! It’s the Crops!).
As part of the IFAFS grants program as described in the NSF report, microbes, “being of significant importance to the environment, and to agricultural production and processing,” were deemed an “appropriate organism of genomic study under this authority.” An Interagency Working Group on Microbial Genomics (composed primarily of representatives from NSF and USDA) was established in August 2000 and created The Microbe Project to (1) identify science-based priorities for a national microbial genome initiative and (2) plan for a collaborative interagency approach to addressing these priorities. “One of the project’s goals is to develop a coordinated national effort to sequence microbial genomes of broad agricultural and biological importance.”
IFAFS has already funded grants for the genome sequencing and analysis of Lawsonia intracellularis, the cause of proliferative enteritis in swine, and to help support the North American Consortium for Genomics of Fibrolytic Ruminal Bacteria, which studies the gut microbes that help cattle and sheep break down the cellulose in grass and hay, providing nutrients for meat and milk production.
There’s No Place like Genome
Companies such as Celera, best known for their human genome efforts, have also invested heavily in the sequencing of agricultural plants and animals to enhance food production and human health. Numerous consortia with and without federal government participation have also been formed to take advantage of the perceived benefits of genomic science with a plant and animal spin. At the moment it may be mostly hype, but eventually—with such a massive influx of scientific information focused at the very core of biology—our increased understanding of agricultural organisms (and by extension ourselves) will inevitably have tremendous and profound repercussions.
So it seems that ultimately, barnyard biotechnology will merge with biomedicine—at least in the burgeoning comparative genomics field. Henceforth, think genomes, not genes; and think proteomes as well. One of the most predictable transformations in this new millennium is almost a guarantee—our farms and pharmaceuticals will be linked forevermore. The linkage won’t come just through GMOs or nutraceuticals, or through gene farming and environmentally friendly pesticides, but from playing (and comparing genomes) with our food.
Further Reading
(All Web sites accessed June 2001.)
Mark S. Lesney is a senior editor of Today’s Chemist at Work. Send your comments or questions regarding this article to tcaw@acs.org or the Editorial Office 1155 16th St N.W., Washington, DC 20036. |
