Ronald Breslow, professor of chemistry and University Professor at Columbia University, is scheduled to present the Priestley Medal Address on March 23 at the awards ceremony during the American Chemical Society's 217th national meeting in Anaheim, Calif. Breslow will receive the Priestley Medal, ACS's highest award, for his distinguished services to chemistry. In particular, Breslow is being honored for his pioneering research in bioorganic and physical organic chemistry, his inspirational leadership as a teacher for more than four decades, and his dedication in promoting public understanding of the positive contributions of chemistry to societal well-being. Following is the text of his address.

I have been teaching chemistry and doing research at Columbia University for over 40 years. During that time, a number of changes have occurred, many of them good. Some of the improvements made my life easier, some of them mainly benefit those who started academic careers more recently.

For example, start-up funds for new faculty were rare when I began my career at Columbia in 1956, and the only equipment I got was a small used UV-visible spectrometer. Now, beginning faculty get funds from the university that let them buy expensive pieces of equipment and hire postdoctorals, so they can get research off to a fast start. In recent times, many funding agencies also make a conscious effort to direct grants to young scientists.

Compared with the situation when I started, many more universities now have the resources, and the ambition, to permit frontline research by the faculty. Thus, the academic job market for those who wish to pursue research and teaching is broader. Our field has also become broader, with many chemists working at the interface with biology, or with materials science. Better instrumentation--including NMRs, mass spectrometers, computers, chromatographs--has also made new areas accessible to research and speeded the progress in classical areas such as synthesis and structure determination.

However, some aspects of academic research life got better for a while, but then turned south. For example, after I started my career, there came a time--in the late 1950s and early 1960s--when the U.S. was so interested in promoting science that we had little trouble finding the funds needed to pursue research. Indeed, NSF and NIH predoctoral fellowships supported most graduate students, so we had almost no need for large grant support. Postdoctorals also generally had their own fellowship support. At one point, my 12 graduate students and six postdoctorals were entirely supported by such fellowships, except for one Hungarian student, a refugee from the anti-Soviet revolution, whom I supported from grant funds.

Now such fellowships have been greatly cut back or eliminated, and faculty members are in the position of having to find funds to support the living costs and tuition costs of most of their graduate students. This means that faculty members have to spend much more time trying to raise much more money just to carry out the normal function of educating Ph.D. students. At the same time, grant money is harder to get than it was in what we now refer to as the Golden Age. My friend Al Cotton, last year's Priestley Medalist, described some of the changes that have occurred in his address entitled "Science Today--What Follows the Golden Age."

Much attention has been called to these problems, and they deserve our continuing attention. We must convince federal legislators and the public at large that adequate funding for research and education is in the national interest. The U.S. needs to be economically competitive on a world scale, but we cannot compete by paying lower wages than in other countries. Our economic strength, and also our military strength, depends on having a strong science and technology base. Such a base needs the trained and educated graduates of our research universities and the discoveries they make and bring with them to their new careers in industry, in universities, and in government laboratories. The role of science, particularly the role of chemistry--the central, useful, and creative science--is central to our nation's strength, indeed to human progress.

In pressing these points, we chemists have an advantage over our colleagues in other disciplines--in truth, few fields contribute as much to human welfare as does chemistry. However, in spite of some of the challenges of modern academic life, we must not forget another key truth: Being a faculty member in a university is still a great profession.

The rewards of a lifetime of teaching and research are truly gratifying. Let me first discuss teaching. Of course, this includes the education and training of undergraduates, graduate students, and postdoctorals who are working in our research groups, but classroom teaching can also be very rewarding. Some critics allege that such teaching is treated as an unwanted burden by faculty who are interested only in their research programs. This is almost never true. On a day when research is going badly, it is a relief to say, "At least I taught a good class." And all of us enjoy seeing the excitement in a student who first grasps the intellectual beauty of chemistry. Those of us who do research are ourselves excited by chemistry, and are usually able to convey that excitement to eager undergraduates. It is no accident that teaching awards often go to faculty who are quite active in research.

Classroom teaching also brings lifelong rewards--for instance when former students tell you, "Yours was the best class I took. It really made a difference to my life." (Of course, they may say that to other teachers, too.) A student who had taken my beginning organic chemistry class once showed up at a meeting of the American Association for the Advancement of Science, where I was speaking about education and training, and he arose to tell the audience how much he had learned from that class. Such situations are truly gratifying.

Sometimes we know what careers our former classroom students have pursued; they may even become famous. One Columbia undergraduate took a seminar that I taught at the beginning of my career. He looked into and spoke on Hückel molecular orbital theory, then went on in his later academic career to extend this theory. He eventually won the Nobel Prize in Chemistry for this work. Chemists will know that I am referring to Roald Hoffmann. Other former undergraduate students in my classes have also become major prize-winning scientists.

We also teach graduate courses. I have taught a course in enzyme mechanisms and bioorganic chemistry for many years, and have been happy to see many of the students and auditors then go on to teach their version of the course in their own academic careers.

We can take some pride in whatever we contributed to students in our classes, but our larger influence is on those who do research with us, either as undergraduates or as our own Ph.D. and postdoctoral students. We deal with them at what is normally one of the most intense and exciting times of their lives, if sometimes also a little stressful. They are launching careers, and sometimes starting families. These are our scientific children. Their success brings us parental pride, whether or not we deserve it. When they are elected to the National Academy of Sciences, when they win awards, when they open up new fields of research, when they achieve major positions in chemical or pharmaceutical companies, we feel almost as good as we do about the achievements of our biological children. Of course, I have fewer biological children--two--than my several hundred scientific children scattered about the globe, many in major academic and industrial positions.

The relationship between a professor and his or her research students is very special, as most of you know. Students come in with intelligence and enthusiasm, but what they learn is how to do worthwhile research. They, of course, acquire some technical skills--in handling instrumentation and in synthesizing and characterizing new molecules or collecting valid data--but the most difficult lesson has to do with choosing a research project. The project needs to be important--if it is successful you will be proud to publish it--and it needs to be novel, never done before. However, important new ideas may also fail. After all, it was once said, "If we knew what we were doing, it wouldn't be research." The trick is to find the balance, a project that is speculative enough to be exciting while not so speculative that it has no chance to succeed.

Research is sometimes described as a conversation with Nature, but that is not quite the right metaphor. It is of course important to listen to Nature, not just to lecture at her. However, except in purely exploratory studies, the interaction is more like the way that litigators conduct cross-examination, using leading questions that can usually be answered yes or no. In much scientific research, we address Nature with questions of the form: "Is it not true that . . .?" The experiments are designed to pose such questions. Sometimes the answer is "Yes, you are right; your theory may be correct." Sometimes the answer is "No, you are on the wrong track." Sometimes, the best answer can be "No, you don't have it quite right; the real situation is the following, much more interesting than your simple idea." If we don't insist that our first ideas be correct, this can be the most exciting result, since it leads us to new concepts. Attorneys have a rule about cross-examination: "Avoid surprises. Never ask a question to which you do not know the answer." Our rule is normally just the reverse.

Research can strengthen teaching, as we convey our enthusiasm and novel viewpoints about the material we teach, stimulated by our excitement over new discoveries. The interaction also works the other way--teaching helps strengthen research. We generally teach a lot of material that is not directly part of the particular field in which we work, and thinking about unfamiliar material can stimulate new ideas.

For example, my teaching about solvent effects in freshman chemistry in the 1970s helped me realize how to use some particular solvent effects, hydrophobic effects, as a tool for discovering reaction mechanisms. This has opened an area of research in which we are still very much involved. As another example, teaching thermodynamic cycles led me to realize that I could use electrochemistry to interrelate carbon cations, anions, and radicals, and thus determine the energies of some very unstable species such as the cyclopropenyl anion.

Research is the part of an academic career in a university that can bring great joy when it is successful. Let me describe some of the moments that have been particularly joyful for me.

One of the puzzles that intrigued me even as a graduate student was the chemical mechanism used by thiamine pyrophosphate, a derivative of vitamin B-1, to perform its functions in various enzymes. The complex structure of thiamine (Fig. 1) held few clues, and the biological chemistry it helped to catalyze was rather special. Luckily, thiamine and some related compounds catalyzed a related reaction in a simple chemical system, so I set out to investigate that system.

I started with some theories about how it might work, and then devised experiments to ask Nature leading questions. The answers were "No"; all our original theories were excluded by the experiments. After several days of hard thinking, I realized that the C-H bond in a thiazolium ring just might be acidic enough to permit reaction there (Fig. 2).

I asked the leading question, "Is the hydrogen on the thiazolium ring easily ionized?" by dissolving a thiazolium compound in D₂O to see if the hydrogen in question exchanged with deuterium. To my delight, an original carbon-hydrogen stretching band in the infrared spectrum rapidly became a carbon-deuterium band. Experiments on a homemade 30-MHz NMR instrument at Columbia (this was some time ago; we have better instruments now) picked up the evidence that the hydrogen I was concerned with was the one exchanging. After this, I showed that this explained the chemistry catalyzed by thiamine, and others showed that they could confirm our idea in the case of the enzyme as well. This work solved a puzzling biochemical problem, and even opened up the new field of stabilized carbenes.

Such sagas are a bit like dramas. In the first act the principal characters are introduced and the action starts, in the second act baffling complications ensue and resolution seems uncertain, and in the third act all is revealed and the protagonist emerges triumphant.

Much of our research, much of everybody's research, has this character. We start with an interesting original idea--the first act. When tested it often turns out not to be completely correct, and sometimes it is not clear how on Earth to solve the problem--the second act. In the third act, we ponder the situation and test other ideas, and with luck we come up with the answer.

While I was working on the thiamine problem, I also decided to study some chemistry of the relatively unexamined cyclopropene system, a three-carbon strained ring with a double bond. I had read a paper in which it was proposed that a hydrogen atom in such a ring was readily lost, but the resulting anion would have four electrons, and I thought it should not be a stable species. This led to two lines of research with my students and postdocs.

In one line, we studied the stability of such cyclopropenyl anions and saw that they were indeed strongly destabilized by cyclic conjugation, having what we called antiaromaticity. At the same time, we examined the corresponding cyclopropenyl cations, which with two electrons should be the simplest aromatic systems. We were able to make the parent compound and various derivatives and show that indeed they had the special stability that defines aromaticity.

We made a very small amount of the parent cyclopropenyl cation (Fig. 3), but at a later point we began to interact with a scientist who was studying microwave signals from gas clouds in interstellar space. His results suggested that one of the molecules in such gas clouds (Fig. 3) was closely related to our cation, and we helped prepare comparison materials to confirm his proposal. I then asked him how much of the relative of our cation he was detecting in the nearest gas cloud, and he said, "Not much. Only about 17,000 Earth masses." Apparently Nature operates on a somewhat different scale from ours.

Over the years, our research programs have built in part on the foundations of these early studies. We have pursued aromaticity and antiaromaticity, and demonstrated them in various systems of theoretical interest. We have also further pursued chemistry that mimics biological reactions, what we have named "biomimetic chemistry." A major goal of this work is to prepare novel synthetic molecules that work like antibodies or enzymes. The progress has been good, and several of our novel molecules are able to catalyze reactions with enzymelike rates and specificities.

Work on biomimetic chemistry illustrates what I think is a useful guide to research: One should select an important goal, one that can be pursued for a long time, even a scientific lifetime. In the course of this pursuit, one can make significant discoveries, significant progress, but the final goal may remain elusive, serving as an inspiration for further research. Our goal--to learn how to carry out with small synthetic molecules all the exciting rapid and selective chemistry that Nature performs in living systems using enzymes--has served us well. We have made good progress, but there is still plenty to do. The continuing challenge keeps me motivated and inspired.

Very important research lines can also arise from collaborations initiated by others. Several decades ago, I was approached by a medical school colleague with the information that some simple solvent molecules are able to induce certain cancer cells to undergo cytodifferentiation--that is, they were transformed from rapidly growing cancer cells, juvenile in character, into adult forms that behaved like normal noncancerous cells. The cells were not killed, they were "re-formed."

I proposed that there might be two neighboring binding sites in whatever was the biological receptor for the molecules, and that if this were so we could get more active compounds by linking two such simple molecules together. We tested this idea, and it was successful. As we developed and modified the new compounds further, we eventually made some extremely effective compounds (Fig. 4) that show exciting biological properties. We have learned how they work by using the technique known as photoaffinity labeling to identify the protein molecule to which they bind in the cell. The new compounds have shown wide activity in cells, good activity in animal tests with human tumor cells, and insignificant toxicity. They are under active evaluation at this moment, and we are hoping for human trials in the near future.

Of course, we write up the results of such work in the usual scientific journals, but in addition, many academics find it interesting and enjoyable to write books. My book, "Organic Reaction Mechanisms," has been translated into at least eight languages. As I travel around the world, chemists in this and other countries tell me that they studied from it, and were inspired by it. I also have written a small book for high-school students, called "How Enzymes Work," that has been widely distributed; and my book published by ACS, "Chemistry Today and Tomorrow," has had a significant effect. There is satisfaction in having an influence, I hope a benign influence, on the thoughts of so many.

Some academic chemists also consult for chemical and pharmaceutical companies. I have done this since my earliest faculty years at Columbia and find it a worthwhile experience in all respects. What I learn has had a clear influence on my teaching and my research; it is good for academics to deal with the real world occasionally. The contacts have been very helpful for my students, looking for jobs. I have consulted with large, well-established chemical and pharmaceutical companies, and also exciting young start-up companies, some founded by former students.

Perhaps my most unusual consulting arrangement was as a member of the scientific advisory board of General Motors, the largest U.S. car manufacturer. I was amazed to see how much chemistry is involved in automobile manufacturing--chemists were the largest identifiable scientific group in the research laboratories of GM--and among the perks was the opportunity to participate in the company's Product Evaluation Program. This program loaned me four cars a year for the seven years of my membership on the board. My relatives, especially the younger ones, thought that the Corvettes and other high-powered convertibles were pretty impressive. My standing definitely went up in their eyes.

We do many things for which the compensation is largely intangible. At Columbia University, I was the chairman of a committee that changed the college from all male to coed, and I also played a role in choosing one of Columbia's presidents. Most of us put in time on government panels and advisory groups for other universities. For example, I was on the board of trustees of Rockefeller University for more than 17 years. We are often on editorial boards of journals, and we serve as officers of professional organizations. I found my own term as president of ACS to be quite interesting and rewarding, and it let me interact with a number of distinguished leaders in industry and in government. The intellectual growth that such professional activities engender is part of lifelong learning, part of a satisfying life.

Another special feature of an academic career in a university is the contacts and friendships that become part of it. Not only do I have strong connections with my own Columbia chemistry colleagues, many of whom are extremely distinguished, but we academics also tend to have warm relationships with other academic chemists worldwide because of our common scientific interests. In contrast to some of my nonscientist friends, for instance, I hardly ever visit a country where I am simply a tourist without local hosts who make the visit more interesting. Academic research chemists tend to know each other, often personally, sometimes simply from their published work.

Life within a modern university also leads to many nice personal relations outside chemistry. There is a wonderful community of scientists in various fields at Columbia, including world-famous physicists, mathematicians, geologists, and biologists. I also interact with scientists in neighboring institutions, such as Rockefeller University. However, there is more to life than science. I have friends at Columbia who are, for example, leading historians, musicians, sociologists, classicists, and specialists in Italian literature and East Asian studies. When I was president of ACS, one of my friends was the president of the American Historical Society, and she and I often compared notes on our respective organizations.

The intellectual and cultural life in a university is also rich, sometimes too rich for the time we all have. Lectures, concerts, and performances by my university colleagues and distinguished visitors are an additional benefit that comes with an academic career. Excellent athletic facilities are usually also available to the faculty.

Of course, there are many other careers that chemists can and do follow, and they have their own satisfactions. Academic positions in small colleges bring fewer research opportunities than we get in universities, but more personal interaction with undergraduate students. One of my former Ph.D.s is teaching science in a big city high school; the country could use more educated scientists who follow that route. One of my former Ph.D.s is an elected government official; it would be wonderful if more of our political leaders understood science.

About half of my former Ph.D. and postdoctoral students are now working in the chemical or pharmaceutical industries. With luck and skill, they may help develop an important product that makes it to the market. A couple of former students are now patent attorneys, and a couple are doing investment banking, using their education to help evaluate new high-technology companies. They are all working to increase the contribution of chemistry, of science, to the bottom line of our economy and to human welfare.

What is my bottom line? It is that young people thinking of academic careers in universities should not be put off by the funding problems so often discussed. Our lives would be better if those problems did not exist, and with effort we will get them solved. However, considering all the factors, it is certainly my belief that being a faculty member in a research university is still a great profession. I highly recommend it.

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