1998 Albert Lasker Special Achievement Award in Medical Science

Science communication and education

Daniel Koshland, Jr. has made contributions to the scientific enterprise that few can match. As a young researcher at the University of California at Berkeley, his work on the mechanisms by which enzymes and proteins function resulted in important conceptual advances in biochemistry. Koshland proposed that enzymes change their shape as they react with other molecules, leading to his "induced fit theory" that had extensive ramifications not only for enzymes but also in the control and regulation of biological systems. The induced fit theory postulated that the enzyme changed shape when it reacted like a glove into which a hand is thrust. Koshland has done seminal work on the mechanisms by which cells receive and respond to external cues, and showed through other ingenious experiments that bacteria have a rudimentary memory that affects their response to their environment.

In the 1980s, Koshland and his colleagues discovered essential features of signaling systems among cells. Now he is working on the chemical reactions involved in Alzheimer's by analyzing changes that occur inside the cells of the brain. A complete account of his scientific achievements would fill pages; in fact, they do fill the pages of some of the best biochemistry texts.

Koshland's talent for doing good science extends to a talent for recognizing good science by others and creating an environment in which imaginative research can flourish. In that vein, Koshland took it upon himself to remake the entire biology program at Berkeley, which was no small task as anyone who understands the difficulties of changing academia will appreciate. Historically, the biological sciences at Berkeley developed through 12 small departments with a population of 300 faculty members out of Berkeley's total faculty of 1,000. Of the university's 30,000 students, approximately 10 percent are graduate students or undergraduate majors in biology.

Fired by the belief that good science in the 21st century must cross disciplinary boundaries, Koshland spearheaded a reorganization, combining 12 small departments into three large ones. He was the key faculty leader in persuading the California state legislature to contribute funds for two new state-of-the-art biology buildings and the complete renovation of a third. One of them was named Koshland Hall by the University in honor of his role.

The creation of a new structure in biology made it easy for researchers to work on vital scientific questions without disciplinary limits. The reorganization took ten years to accomplish but the disciplinary walls in biology did come tumbling down. Berkeley biologists now find it easier not only to collaborate creatively with each other, but also to collaborate with colleagues in physics, chemistry, and other areas of science whose role in solving problems in biology is becoming more and more essential.

Koshland is also recognized for his broad contributions to science through his editorship of Science, a post he held from 1985 to 1995 while also maintaining his very productive laboratory at Berkeley. As editor of Science, Koshland attracted some of the most exciting research to the journal and enlivened its pages through his own editorials on research and science policy.

Finally, Koshland's commitment to science communication is evident through a gift to the National Academy of Sciences to build a public science center on the Academy's grounds in Washington, D.C. The center will be named in honor of his wife, the late Marian Elliott Koshland, an immunologist who shared Dan's lifelong concern for the public understanding of science, and was herself a member of the Academy. The center will feature displays that demonstrate how science works.

Dan Koshland's career in science that encompasses research, institution-building, and a commitment to both the scientific community and the public is truly remarkable. As his colleagues say admiringly, "he's one of a kind."

 

Award presentation by Joseph Goldstein

Woody Allen once described his movies as slices of real life with all the boring parts cut out. Daniel Koshland, Jr., the recipient of this year's Lasker Special Achievement Award in Medical Science, would not qualify as an actor in a Woody Allen film because, as far as I can tell, there's never been a dull moment in his 78 years. Dan was born into one of San Francisco's most distinguished families. In 1853 his great great granduncle founded Levi Strauss & Co., the world's largest brand-name garment manufacturing company. His father, Daniel Koshland, Jr., Sr., was vice-president, president, and chairman of the board of Levi Strauss for 57 years, from 1922 to 1979. At Levi Strauss, the elder Koshland pioneered the hiring and training of minority employees many years before the term "affirmative action" was invented.

By the eighth grade, Dan Jr. realized that he was a born puzzle solver, and his fascination for math, physics, and chemistry exceeded his interest in jeans—spelled with a "j." In 1933, the other kind of genes—spelled with a "g"—somehow did not capture the attention of this 13-year-old wunderkind. After all, 1933 was 10 years before Avery, McCarty, and MacLeod, and 20 years before Watson and Crick.

Even though Dan decided not to go into the family clothing business, he followed in the footsteps of his father and grandfather and became the third-generation Koshland to enter college at the University of California at Berkeley, where he majored in chemistry. The next five years, 1941–46, were spent working with Glenn Seaborg at the University of Chicago on the top-secret Manhattan project, where his team purified the plutonium that was used to make the atomic bomb at Los Alamos. At the end of the war, Dan remained at the University of Chicago to obtain a PhD in organic chemistry.

Atomic energy was a perfect outlet for Dan. From early childhood to this very day, he has been notorious for his combination of high energy output, low energy of activation, and catalytic personality. So it's not surprising that in the early 1950s he became intrigued with the energetics of enzymes. He focused on the crucial event in the action of an enzyme: the momentary union that occurs when an enzyme meets its substrate. The fleeting nature of this enzyme-substrate complex held the key to understanding how enzymes speed up the rate of chemical reactions by as much as 100,000-fold. Dan developed new methods to monitor the active site of an enzyme, and in 1957 he discovered that enzymes are flexible molecules that conform to the shape of the specific substrates on which they work. True to his sartorial roots, he likened this interaction between substrate and enzyme to a "hand in the glove," and called it the induced-fit theory of enzyme dynamics. Once the enzyme (the glove) wraps around its substrate (the hand), the substrate induces a rearrangement in the atoms of the active site that enables the enzyme to cleave a chemical bond in the substrate. This new theory flew in the face of the standard dogma of the day—the "lock and key theory" of Emil Fischer, which viewed the enzyme as a rigid molecule that allows only special substrates to fit into its surface in a fixed way, just as a key fits a lock.

Emil Fischer, the recipient of the Nobel Prize in Chemistry in 1902, was a formidable figure for the 36-year-old Koshland to challenge. So its not surprising that most biochemists initially greeted the induced-fit theory with great skepticism. One referee wrote that the "Fischer lock and key theory has lasted over 50 years and will not be overturned by an embryonic scientist." Stirred, but not deterred by the criticism, Koshland devised ingenious techniques over the next 10 years to validate his model. One of his methods, called the reporter group technique, allowed him to monitor the active site of an enzyme by covalently attaching an environmentally sensitive probe such as a flourescent molecule or a radioactive tracer to a region near the enzyme's active site. By the 1970s his theory was confirmed by the X-ray crystallographers, who visualized directly the induced fit of enzymes as they wrapped around their substrates. Today, the "hand in the glove" theory has replaced the "lock and key" theory in all the standard textbooks. Koshland's concept of flexible enzymes whose shape and catalytic activity could be changed by small molecules stimulated Jacques Monod to formulate his famous model for the allosteric binding of oxygen to hemoglobin.

In 1966, Koshland performed the first chemical mutagenesis of an enzyme by converting the serine residue in the active site of a protease to a cysteine using a selective chemical reagent. This single amino acid change rendered the enzyme catalytically inactive. This now-classic experiment was the first example of enzyme engineering, which has now become standard as a result of Michael Smith's invention of DNA-mediated site-directed mutagenesis in 1978.

In the mid-1970s Koshland turned to more complex biological systems and began to study how bacteria respond to chemicals in their environment—a system called bacterial chemotaxis. He chose this system because it exhibited a simple behavior that could be analyzed genetically as well as biochemically. This was a bold and visionary move for a pure enzymologist who was trained as an organic chemist. To make a long story short, Koshland discovered that bacteria swim toward attractants and away from repellents through the actions of two types of proteins: receptors and signal transducers. Receptors on the cell surface detect the external chemicals and transmit their signals to signal transducers, which are regulatory proteins inside the cell. The activity of the regulatory proteins is switched on or off by a novel form of covalent modification called methylation. Methylation was a new paradigm in signal transduction—another example of Koshland's ingenuity and creativity. With the availability of recombinant DNA, the receptors and modifying enzymes that regulate bacterial chemotaxis have now been cloned, and the X-ray crystal structures of several of these proteins have recently been solved by Koshland and his colleagues. At a molecular level, bacterial chemotaxis is the best understood simple adaptive system in all of biology, and it now serves as a model for the more complex sensory systems of higher organisms, such as vision, hearing, and smell.

The American author F. Scott Fitzgerald once wrote that "there are no second acts in American lives." At the risk of being audacious, I will modify Fitzgerald's quote to say that there are three acts in the life of Dan Koshland. I've just told you about Act 1—the visionary biochemist. Now for Act 2—the tireless institution-builder. Historically, the biological sciences at Berkeley had developed around 12 small departments that were scattered all over the campus and involved 3000 graduate and undergraduate students and 300 faculty members (out of Berkeley's total faculty of 1000). This loosely organized structure did not encourage the type of interdisciplinary collaborative research that opens new fields and makes for an exciting ambiance.

In the early l970s the first rumblings of an earthquake in molecular genetics were beginning to be felt in the Bay Area, and by 1973 the Big Revolution in recombinant DNA and gene cloning had exploded at Stanford and UCSF, bypassing Berkeley. Dan Koshland quickly perceived that a New Biology was on the horizon, and if modern biological research were to flourish at Berkeley, a bold and dramatic action was needed: the walls separating the 12 isolated departmental fiefdoms must come tumbling down. This would make it easier for Berkeley biologists to enter into creative collaborations with each other as well as with colleagues in chemistry and physics. Almost single-handedly, Dan became the tutelary spirit to explain the New Biology to the Deans and Powers-That-Be at Berkeley, and with their blessings he spearheaded a massive intellectual and physical reorganization that combined the 12 small biology departments into three large departments. He also led the effort to persuade the California state legislature to provide funds to completely renovate one existing building and to build from scratch two new life sciences buildings, one of which is named Koshland Hall in recognition of Dan's leadership role.

The reorganization took 10 years and hundreds of committee meetings. The end result is a coherent, effective, reinvigorated, and peppy life sciences faculty that now ranks among the leading 3 or 4 institutions in attracting the very top graduate students and postdoctoral fellows. Like UCSF and Stanford, Berkeley is now on the front (fault) line for the next Big One.

Several of the then-young faculty members whom Koshland personally recruited to Berkeley in the late 1970s/early 1980s to assist him in the reorganization include the now-prominent leaders on campus such as the molecular biologist, Bob Tjian; the cell biologist, Randy Scheckman; the developmental biologist, Gerry Rubin; and the neurobiologist, Corey Goodman. All of you in academia who have ever been involved in committee work can certainly appreciate the difficulties and frustrations that Dan faced in his quest to save Berkeley from mediocrity by reconfiguring the lives of 300 faculty members. Thank goodness for biomedical science that Dan ignored Milton Berle's one-liner on committee chairmen—"they're a special breed of people who love to save minutes and waste hours."

Now for Act 3 in the life of Dan Koshland—the eloquent public communicator of science. Dan is widely recognized as one of the grand statesman of science as a result of his 10-year editorship of Science magazine. As editor from 1985 to 1994, he became the voice of science in America and the world. He oversaw the transformation of Science from a good but stodgy journal into the classy publication that we all take for granted today. He expanded the coverage of public affairs to make the magazine our most influential scientific publication in public policy. He also enlivened its pages with more than 200 editorials that he personally wrote during his decade of editorship. Most of his editorials dealt with timely, serious, and controversial topics, such as sequencing the human genome, civil rights and the AIDS epidemic, drunk driving, and spousal abuse. But some had a lighter and more humorous tone. One of my favorites was published in the December 2, 1988 issue entitled "The Golden Median," in which Dan celebrates "tongue in cheek" the glorification of mediocrity that began a decade ago with the abolition of the grade F in high schools and colleges and has now taken over all society, including the Olympic Games in which gold medals are awarded to those who are in the middle of the pack and silver medals to those on either side of the middle person. Fidelity has become more popular because everyone tends to look and think alike, and so there is no temptation to stray. A major medical benefit of the Era of the Golden Median, according to Koshland, is the decline of heart attacks since mediocrity has selected for types who never do today what you can put off until tomorrow. Cancer has also declined since the general lack of exertion has led to less inhaling of ozone. But, surprisingly, despite these medical advances, people are dying at a younger age because all of their neurons have atrophied, a result of the most prevalent disease of the Era of the Golden Median—boredom. A typical example of Koshland wit.

Dan has recently made an extraordinary gift to the US National Academy of Sciences to build a public science museum on the Academy's grounds in Washington, D.C. near the statue of Albert Einstein. This "hands on" museum will be devoted to teaching children how science works and will be named in honor of Dan's late wife, Marian Koshland, an eminent immunologist who shared Dan's deep love of science and passionate concern that it be understood by the public. Like his father, Dan is perpetuating the Levi Strauss tradition of philanthropy and public service—a tradition that is obviously in the genes (no pun intended).

Dan Koshland is a rare bird. His career in science is exemplified by a distinction that is achieved by only a handful of scientists who are held in universally high esteem by their colleagues because of their human qualities of honesty, kindness, unselfishness, originality, and wisdom, and in Dan's case there's also wit. By the F. Scott Fitzgerald standard, Dan has accomplished the impossible in his quest for elevating science to its highest level. He has performed Three Acts in one life—and all have been class acts—the visionary biochemist, the tireless institution-builder, and the eloquent public communicator. And there's no sign yet that the curtain has fallen on any one of Koshland's Three Acts.

Daniel E. Koshland Jr.

Nature Medicine Essay


Interview with Daniel Koshland, Jr. and Robert Tjian

Part 1: Early Interests
As Dr. Koshland discusses his early career with Dr. Tjian, he explains his interest in studying mechnisms of enzyme catalysis. He also talks about the impact of his induced fit hypothesis.

Tjian: What originally led you to direct your studies at mechanisms of enzyme catalysis?

Koshland: That is really hard. I can probably tell you roughly that I was interested really in going into biology when I was an undergraduate. Everyone told me that biology and biochemistry was at a very embryonic stage at that point. Everyone said to major in chemistry. I majored in chemistry and really loved it. I began to get sort of restless my senior year and really wanted to apply it to biology. Then I was interrupted by World War II.

When I went back I really wanted to go into biology. I had all this background in chemistry so I went into graduate school with Frank Westheimer and said I really wanted to work on enzyme mechanisms. He was interested in enzyme mechanisms at the same time. So both of us were trained in organic chemistry and it seemed the most logical thing to one that was interested in enzyme mechanisms. So really I was basically a chemist and asked where can a chemist really contribute at that point.

Tjian: It is interesting how individual scientists have come to do the experiments they do. One is obviously their background. At the time when you went into graduate school, or came out of graduate school and began your own lab, what were the big questions in biology? Was enzyme catalysis one of the major problems?

Koshland: No it wasn't. The time when I went into it, we were really just beginning. There was nobody that interested. In fact I remember the early papers. We did problems that were very interesting so people asked and really wanted to know about mechanisms. On the other hand, they were only peripherally interested in mechanisms. At the time when I started, the big exciting problems were basically pathways. The pathways were just beginning to be understood. The Embden-Meyerhof work and the glycolysis pathway was being worked out. People even questioned whether when you were doing it on yeast if it was the same pathway as in humans. Nowadays we sort of accept for granted that if you do it in yeast it is probably very similar in humans. At that time a lot of the people who were working on mammalian systems said no it would be totally different. That was the big excitement at the time.

Tjian: That obviously changed by the mid 60s. Questions of how enzymes work rather than the fact that they did perform certain functions in a metabolic pathway became really the emphasis.

Koshland: Exactly.

Tjian: So at that point what was it about your work, or other work that was being done at the time, that really led you to initiate this concept, this model, of movement in the protein and this induced fit hypothesis?

Koshland: That is one thing I sort of remember distinctly. ...I was going to a meeting on muscle. I was doing some work with lobster muscles of all things. I was working with kinases and muscles. You know how you prepare a talk; I said why isn't every kinase a hydrolase. Why doesn't water react? If I know the OH group of glucose is essentially no more reactive than the OH group of water, therefore if you have 55 mole of water, every reaction ought to have a lot of water by-product. If you left out the substrate, according to Fisher's hypothesis, it should be a very hydrolase. I started to think about that and I said there had to be some way to prevent water from reacting. Maybe you can think of an easy way to keep ribose out of the active site if glucose was the main substrate. But keeping water out was going to be a big problem. So I essentially evolved the idea that the protein had to undergo some big process like an unfolding reaction in order to really accept the substrate. If that were true then you had to have certain structures for the substrate that would require a conformation change in order to react. That really led to the induced fit. It was sort of the hand in the glove kind of fit. Any hand won't fit any glove. The glove really has to change shape to accommodate the hand.

Tjian: Right. Now this concept which was postulated many years ago; when you first came up with the idea of substrates or ligands actually changing the shape of protein, how was it received? Was it received with great skepticism? Or was it embraced immediately?

Koshland: I would say largely greeted with great skepticism, although it was sort of like the folding problem is today. There were certain people who said that was a very good idea. I was invited to talk at the ACS meeting (American Chemical Society) and C&E News highlighted it as one of their important speeches. I remember as I was walking out, and I was very young at the time, a couple of attractive young ladies were walking out in front of me. One of them turned to the other and said, "You know that Koshland did some work. For him to get senile this early is really too bad." That was a blow to my ego. There were other people who thought it was a crazy idea. I got one review saying that the Emil Fisher theory has been correct for 100 years and therefore some young biochemist out of Brookhaven Lab is not going to over turn it just by doing a couple experiments. It was greeted with a great deal of skepticism by a lot of people. Some people did accept it.

Tjian: Now as you are well aware, it is not only accepted and in all text books, but it has transcended to catalytic side of enzymes and rather is a major component of many protein, protein and protein nucleic acid, as well as protein ligand interactions. How do you feel about that and have you sort of followed through with this model?

Koshland: ...I would like to say that I foresaw all of that. ...I remember in one of the first papers I pointed out that hormones, which always puzzled me because they could take part in catalyzer reaction without being changed chemically at all during the reaction. We realize that it was a technique. The protein folding then, you could have something that didn't react at all affect the folding, or unfolding, of the protein. Therefore it would be very good for regulation and things like that. ...So there was a period in which Allo's theory, which was the regulation of flexible proteins, was as hot as some of the hot fields as recombinant DNA is now. It was lots of fun and I really enjoyed that a lot. We applied it to all sorts of things and then of course it became very important in evolution and regulation and hormones and all those kinds of things. It is always fun to see an idea become more and more useful in other aspects of science.

Tjian: Now, so the final ultimate outcome of the idea of induced fit is nowadays is drug companies are most interested in small molecule protein interactions. This whole concept of induced fit is critical to understanding how to design drugs. How do you feel about seeing your hypothesis and now theory, really being used in an applied way?

Koshland: In fact we are doing it ourselves. It is very exciting. I should be fair in the sense that the induced fit is a reality, as you have said, and is now found that essentially every protein undergoes some kind of a change when it binds another protein; most of the time a fairly major change.

It actually makes drug design a little more difficult. You have to not only say how is the drug binding, but what kind of induced conformational change occurs. Most of our good theories developed like Coulomb's Law, how a positive charge attracts a negative charge and so forth, doesn't really feed into that calculation of how the protein changes shape. In fact, it is confusing drug design. You can still do some but it will be very important to put into the calculation the energy of the conformation change. Actually I am working on that. It is part of our research at the moment; to find how you trace the path of the protein changing shape under the influence of the small molecule.

 

Part 2: A Scientific Progression
Although Dr. Koshland began his career as a chemist, he eventually became interested in the study of progressively more biologically complex systems. Here, he explains his method for selecting areas of study.

Tjian: Although you started off as a chemist and you did very classical biochemistry and enzyme mechanisms, you have moved on to study progressively more biologically complex systems with bacterial chemotactic, mammalian receptors, and now learning process. How do you go about choosing these big problems and what drives you to keep changing?

Koshland: Well, part of it is something that I learned a long time ago; mainly that life is chemistry. I was trained very well as a chemist. It was sort of funny because I had a lot of physical chemistry so I knew a lot of physicists. Physicists kept hoping that life was going to turn out to be physics. It is electrical circuits to some extent in the brain. Mainly even the brain is even largely chemistry. What usually impels me into a new field is that I sort of try to think what the chemical mechanism is. If I find that I can't think of any logical chemical mechanism, it becomes very intriguing to me.

I am sort of convinced that the work I did with chemotaxis, which involved memory and led me to the mammalian systems of memory, was that I couldn't really think of any good method of memory that would be very simple that some simple organism like a bacterium could use. I thought the memory mechanism everyone proposed was sort of that the brain was a little computer. I always thought an E. coli couldn't have a little computer in it. Then it turned out that the E. coli really had a very good memory. It was very important for its survival. ...It turned out to be quite simple chemistry. I guess what impels me into new fields is how you explain in chemical terms how this occurs. If I can't explain it, it seems to be worth going into and finding out what goes on.

Part 3: A Scientific Progression
Dr. Koshland talks about why he often thinks of biological problems in terms of quantitation and theoretical calculations. He also discusses some of his research techniques, as well as the way his scientific emphasis has changed throughout his career.

Tjian: It seems to me that one of the things that you have brought to biological problems, including very complicated ones such as learning and memory, is your notion that you should do experiments in a quantitative fashion and also to be able to think about it in terms of theoretical calculations. Throughout your career you have used these two in ways that most biologists don't do. Do you think that is sort of the fundamental trademark of your scientific philosophy?

Koshland: I think I have always felt that quantitation is very important because if you answer something yes or no, is this kind of molecule the kind, a nucleic acid say the important molecule in such a situation, then if you are just answering yes and no you have a 50/50 chance of being right in any case. That doesn't mean that it doesn't require a great deal of ingenuity to get into a new area. I always feel once you get into a new area answering questions of yes and no, then if you get the quantitation you can really find out whether or not your theory is correct. Plotting a straight line and having points lie on the line, then you have much more than yes and no. If you have a little bit of an error in your theory then the point lies very far off the line. If you get a lot of points that lie on the line or curve or whatever your theoretical evaluation gives you, then you are really pretty sure this theory is correct. I have always felt that is very important in biology for the simple reason we are dealing with very complex phenomenon; maybe even more important than physics in the sense that once you get a theory there are so many variables that if you can then put a quantitative theory on it and all points sit on the line, then you are really fairly sure the theory is correct.

Tjian: Of course it is very difficult to be quantitative in many biological questions.

Koshland: Absolutely.

Tjian: Does that, in part, help you make decisions about what kind of questions you address? Obviously in biology there are many more questions than any individual can address in their lifetime. You have to choose the problems and you seem to have chosen problems where you can apply quantitative analysis and sort of theoretical calculations in a more mathematical sense.

Koshland: I think that is true. I think the reason for that is that my lab really operates with a combination of theory and experiment. In other words, I am doing a little of both. In fact, my lab work is generally deriving the equations while my students are separating the proteins from a complex organism. There is a little bit of a division of labor. I tend to be more mathematical although I have a number of students who at various times are attracted to do the math.

I think all my research, if you really look at the math, it is fairly simple stuff. I mean among biochemists if you do differential equations they think you are doing something very complicated. Among mathematicians that is sort of baby stuff. When I do differential equations it stretches me as much as I can largely because a good deal of my time is devoted to an experiment. As a result my theories have always been very close to the experiments.

Then there are people, who, say are applying theories to the brain and develop very complex systems which then go very far astray from an experimental model. They might end up being right. Then you get more and more difficulty. My math has always been designed to try and explain a system that I knew I could set up an experiment for and check the math.

Tjian: So what you are really saying is that ultimately you are an experimentalist. Although you like to do theoretical calculations, you only do them if you think you can test them out in the lab.

Koshland: Yes. I really like theory because you can put together, let's say in our theory about allostery and our model of how cooperative proteins work, we did a number of things that predicted something like negative cooperativity which had not existed before. The math was very useful. On the other hand you are absolutely right, I was picking a system where I knew I could devise an experimental system to check the math. I am really not that interested in going off to things that are so far away from the experiment that I will never be able to check it.

Tjian: Another sort of general issue about the kind of science that you have done in the last 30-40 years, it seems to me that you tend to change your emphasis or your system about every five to ten years. Is that by design or is it just because you feel you have exhausted the kinds of questions you want to ask about a particular system and then you move on?

Koshland: I think it is the latter. I think that I have a short attention span as you know. What happens is if you do a certain number of things and after awhile you sort of have a good theory and so you pretty well know how it is going to turn out. It will be a little different, say this enzyme will have negative cooperativity and this enzyme will have positive cooperativity, or this enzyme is going to be 40,000 molecular weight and that enzyme is going to be 20,000 molecular weight. I sort of think that is not as adventurous and I tend to get bored. Then I say to myself, what is really one of the problems we don't really understand at all? That kind of problem intrigues me more.

If I get to a point where I think the major problem is not yet solved, then it seems to me that is a good one to do. I do feel that when you think you are on to the answer, you must do a certain number of experiments to convince everyone else and even yourself, that you are really right. You can have a good hypothesis, which may turn out to be wrong. On the other hand after you have done five or six examples and you are sure that the theory is right, then it seems to me the time to move on to something else.

Tjian: Another point from my perspective characterizes the style of science that you have done, is that you don't seem to shy away from using whatever methodology, techniques, experimental strategies necessary. I have seen you go from standard organic chemistry to classical biochemistry to bacteriogenetics to crystallography. How do you do that? How does one person in a lab motivate scientists to carry out experiments in all these different areas?

Koshland: That is a good question. One thing I tell my students is sort of like the crook or scam artist who gets one step ahead of the sheriff. The move that I make from one field to another sort of seems to be bigger when you are looking off in the distance than it really is. In other words, I usually use something that I am an expert in, in one field, to move into another. For example, when I went into chemotaxis, which was dealing with a whole animal, namely an E. coli (whereas before I was with pure enzymes), what I really was looking at was enzyme rates. I had done a fair amount of enzymology but now I was looking at the enzymology in terms of how they were put together in a little bag called an E. coli cell.

The same way the crystallography I had been studying, the pure enzymes, and so the technique of crystallography had recently gotten very good. I realized we really just had to learn that. What I do is essentially do one experiment in which you sort of use the new technique and then just gradually learn it as you are doing it in the lab. It is sometimes the way I do lectures; learn them one lecture ahead of the student. If you can do it, it works.

The fortunate thing about doing research is you don't have to publish until you have gotten a positive result. You really think you understand it.

I think you really have to do new methods and new techniques because I would say in my lab today, I am not only doing experiments, none of which I learned when I was in graduate school, I am even doing techniques that I didn't know existed four or five years ago. I think you are constantly in the modern world, learning new techniques and new approaches that didn't exist a few years before. I think that is going to be a characteristic of the modern scientist; that you really use your background as a platform to learn new techniques. If you think that is a ceiling you are in a lot of trouble.

Tjian: How much do you think that your success in being able to make these transitions into new approaches is due to the fact not only that you want to do it and you see the value of it, but the kinds of people you have been able to attract to your laboratories who have been able to execute these complicated experiments.

Koshland: Oh a lot. I mean a great deal is the students that you attract to your lab. ...I think the professor in any lab has to keep up with the students. He has to understand the general theory and must keep up with the literature so he doesn't have a student working on a problem that has already been solved or using a technique that is really obsolete. You owe that to your students to keep up. On the other hand the students come with really clever ideas.

In many cases, we started out on a problem that I thought was a good problem and the student discovers something that was even more exciting.... Having the quality of students that came to my lab made a big big difference in my career. It made it a career that not only published but it kept me very interested. They come up with such surprising things and they were such interesting people that it really made it lots of fun to come to the lab every day.

Tjian: Now so from that respect, how much do you think it influenced the fact that you were at UC Berkeley, that you were able to attract these high quality post-doctorates and students.

Koshland: I think Berkeley was very, very important. I attracted very high quality people, and if anything, you're pressed by that because you got to, sort of keep up with your students, they're so bright, you have to work very hard to make them think you deserve to be a professor, and they should be in your lab. So that's... also your colleagues are very smart, so it really keeps a lot of pressure on you. On the other hand, it also makes it very enjoyable, it's lots of fun to talk to them. They have lots of ideas. On the other hand, there was something interesting. Before I came to Berkeley, I really got very good people too, and in that case, not as many because my lab was a good deal smaller, and I don't think I could have done the same thing there that I've done at Berkeley. On the other hand, I was pioneering in a new area, namely, applying organic chemistry to biochemistry at the time, and I attracted a number of students who said I was doing interesting stuff, even though the work wasn't very accepted as I mentioned, when I started out. And so I attracted the kind of person who was sort of, was willing to go to work with a place that didn't have as much prestige, namely Brookhaven lab, which is a good lab, but nevertheless not quite the same as Berkeley. So you attracted sort of the original and pioneering type of student. So, I think that there are a lot of places that don't have as much prestige as Berkeley, particularly in the United States now, which are doing very good research. When I go around and give seminars these days, I'm impressed how much excellent science there is at institutions that are not maybe in the top five or ten institutions in the country. So, I think there's no doubt that the big institutions help a scientist's career enormously, but there's excellent research going on in other places too.

Tjian: You began your career in the East. You went to graduate school at Harvard and started your career in New York. Then in what appears to me a very exponential growth phase of your scientific career, you decided to come back to California, your original home. How do you feel about having come back? What brought you back in the first place? What do you think about the last 30 some years that you have been here?

Koshland: I have had just a wonderful time. I love Berkeley. I think probably if I had to say anything it was probably that I had such a great time as an undergraduate here that I wasn't held back to come back to Berkeley. That is not fair to make it over simplified because the faculty was very good and I thought it was an excellent place to come to for my career. Of course my family lived out here so that was certainly an attraction. I was about 40 and the work I had done was fairly good so I was getting offers from a lot of institutions. My wife would really have preferred to have lived in the east because she loved the east. And the thing that probably overwhelmed us was that I really thought Berkeley was such an exciting place, that I wanted to move. So we moved with the condition, my wife's deal would be that at the end of the year, we'd reassess. Was it really as exciting, and if not we would move back east. At the end of that first year, she said that she wanted to stay in Berkeley too. So it really is a very exciting place and I think I was pretending to be objective, but probably I wasn't. My undergraduate career and the people around really influenced the judgment.

Tjian: It seems to me in the final analysis it was a great decision for both of you since both of your careers flourished while here, in completely different areas.

Koshland: That's true. She did very good work in the department of immunology. Fortunately it was really very good because we never really bossed each other in the sense that I didn't know enough immunology to really tell her how to do her experiments.

Part 4: A Controversial Reorganization
In the early 1980's Dr. Koshland began a major reorganization at the University of California Berkeley. Here, he discusses how the changes began and progressed.

Tjian: Now after having been at Berkeley for perhaps a decade or so, both you and Bunny began to think about how to make science and the scientific program in biology better or more progressive. How did that come about and what did it mean to actually reorganize all of the biological sciences; perhaps one of the biggest undertaking in any University.

Koshland: If you had asked me in the beginning and laid out for me how much time I was going to spend and how many years, I undoubtedly would have turned down the first job. The way it occurred was that we were concerned about Berkeley. We had some very old decrepit buildings and had some rather anachronistic science. The Vice Chancellor at that time was a friend of ours. We were having a cocktail at the Faculty Club. He sort of casually asked how Berkeley was doing. Before I could say anything my wife said, "Terribly."

It had just turned out that Berkeley had ended up on the top of the ratings, colleges and other universities and get a compendium of that. Berkeley had ended up the top in about eight or nine. Biochemistry was one of them. Immunology was doing pretty well too. Anyway, the Vice Chancellor asked how I could possibly say that when we had just had this survey. My wife said correctly, that was all very well about the past but we were not getting the good assistant professors, not getting the good students, and it is a bad sign for the future.

Tjian: This was in around 1980?

Koshland: Correct. As a result I backed her up. She was right about that. I thought it was rather rude to say that to a Vice Chancellor. I might never had said it as bluntly as she did. He fortunately, Rod Park, said we should go about doing something about it. I was appointed head of one of the committees to really look into what we could do. That one thing led to another and as a result we thought we would tinker with it a bit here and there. Then we really realized we were going to have to change the whole system. It grew into being a big massive effort as you correctly pointed out. It was sort of digging around in the foundations of a house and sort of seeing a few cracks and things like that. Suddenly you realize you have to take the whole house down.

Tjian: It was a rather radical and unpopular notion that one should take about a dozen different separate departments with supposedly very clear distinctions and combine them into a larger department. First of all how much resistance was there and second of all how did you overcome it?

Koshland: I would say looking back on it quickly now in two ways: first of all I think there are two things in this world namely thermodynamics and kinetics. Thermodynamics is a thing that really decides where you are going to end up and kinetics is deciding how you get there. I think to start out with we really sort of knew...that we really had to get more modern in many of our departments. We had some departments that rated very high but we had other departments that were really considered out of the mainstream at that point. We really had to make some changes. So when we first proposed the radical changes, which was the kinetics and how you get there, a number of people immediately opposed them and were very upset. There were other people who really recognized it. They rallied to the cause and sort of said yes, this is one of the most exciting things and we must do this at Berkeley. It was a bit of am mixed bag. There were some people who really were against it. I give credit to the Vice Chancellor. He did not collapse under the pressure. When you have a big faculty like Berkeley and 15-20 of them are saying these reformers are doing a terrible thing and you have to stop them, it is very easy for somebody in power to sort of compromise and do something half and half. I have always felt that it is really important in the world, politics as well as science, to say if one person says two and two is four and another person two and two is five, two and two equal four and a half is not a good solution to the problem. ...So what happened was gradually as we put forward plans, the faculty was really very good. They opposed it strongly in many cases but they were willing to listen to the arguments and gradually they did two things: They made us be very careful that we had good arguments or go back to the drawing board and say we have to change that because the people are really saying good things. Or, we were able to convince them that we were on the right track. Gradually it shifted. A few people at the very end still opposed the change but as the thing got going and started moving down hill more and more people joined the band wagon.

Tjian: Maybe you should remind us how long it took from 1981 where you first began these discussions, to the implementation of the reorganization.

Koshland: It took about eight years I would say.

Tjian: Eight years. I guess one thing you can take home from this is the fact that it must have been a good idea because it seems like everybody else is doing it.

Koshland: I think that is right. I could have changed my career if I wanted to. I was getting calls from all sorts of other places asking would I help them reorganize their own places. I could have become an authority on reorganization if that is what I wished to do. But having gone through it once, I didn't want to go through the full extent of it again. But I did help a lot of other places, They did call up. And there are certain general principles I learned about reorganization, but I think they're probably things that any good executive of a company knows anyway. It was something that as a scientist, I had to learn, but they were very useful.

Tjian: Let me ask you the same question that Rob Park asked you in 1980; how do you think we are doing now in 1998?

Koshland: I think we are doing very well, at least at Berkeley. At least, I'm very pleased, and I as you know, have sort of stepped down from administration... The best way you test that constantly, in my opinion, is to see the quality of the young professors that we are hiring and the quality of the students we are attracting in the graduate school, at least as far as the research is concerned. Then you look at how you are doing as far as the students are concerned. In all categories, from what I hear, it is very good. We are doing a very good job of recruiting young people. I think the last couple of years, I heard a figure, I think from you that the...people that are our first choices, essentially all of them have chosen to come to Berkeley.

Tjian: In the last three years, that's been true.

Koshland: We don't get every student we want, but certainly, our big competitors; Harvard, Stanford, UCSF, are considered among the top schools in the country as far as graduate programs, and we get our share of them. We certainly don't get exclusively, we lose some very good ones to some other very good places, but at least we're up there competing. Whereas, when we started the reorganization, we weren't competing at all, those students were all going to other places. So, that's the best way I can test.

Part 5: Moving Toward the Future
Dr. Tjian asks Dr. Koshland to offer suggestions on what the University of California Berkeley can do in the future. Here Dr. Koshland offers thoughts on the university as it moves into the next century.

Tjian: What do you think we should be thinking about and doing for the next decade, especially as we go into the 21st century, to make sure that biology on the Berkeley campus does stay in the top ranks?

Koshland: I think the answer is first of all, the fact that you as a young faculty member, a young pup and not anywhere near the elderly statesman that I am, you are now in charge. People of your age are in charge. The fact that you even say to me that you are aware that you should not become complacent and not lean on your past laurels and just stay there, is already a good sign. You have learned the most important single lesson. The second thing is that the system is working very well. The young people and the people who are doing very good research themselves out there are constantly looking at the new exciting developments. I couldn't even name all the exciting ones, or probably even know the ones that are going to be exciting tomorrow and next year and so forth.

What I do know is that you have a very alert faculty that is out there interacting with all those people. They are seeing the new areas so they will hopefully bring back the message that we are really missing this area and we better get some people in that. Or we ought to get the new Magellan's and Columbus' who are going into the new worlds and they should become part of the faculty. I think if your faculty is really alert to the fact that you have to keep changing in order to keep up, and they are getting messages of what areas they need to go into, you are in good shape.

Tjian: Well one of the concerns of all of the great young faculty that we've recruited is of course, how to keep Berkeley's infrastructure, and the resources at a competitive level with our competitors, which are mostly private schools. We're unique in being a public institution. How do you think we can organize ourselves to be more effective in that area, and in particular, how do you think you yourself might be able to contribute to that, the future scientific resource at Berkeley?

Koshland: That's a very good question. I think that the facts are that public institutions and private institutions are becoming more and more similar. That is, private institutions are being helped by taxpayers to a large extent, partly through the federal government giving a lot of money for research, and then... I think private institutions are being helped by government indirect subsidies that pay for tuition and grants and things like that. Public universities are getting help from private donors. In fact, Don Kennedy and I were talking the other day, and he said you know, the difference is that a public institution gets 60 percent of its money from the state and 40 percent from private, and a private institution gets 60 percent of its money from private, and 40 percent from the state. That was a few years ago, because I think the figure for Berkeley was something like 40 percent from the state, at the present time. And so, that doesn't mean 60 percent from private, it means that 40 or 50 percent comes from student fees, and then the remaining part comes from private donations. So, a big public institution is no longer purely dependent on money from the state. On the other hand I would love to keep the tuition low, and the tuition when I went to Berkeley was a hundred dollars a semester, which is a good deal less than it is now. I think that the image of a public institution, even if it has a lot of fellowships, should always be maintained at the level of having the tuition at least accessible for people who are, you know, in middle incomes, not very wealthy people, so it has aspects of a public institution. If you can get enough private money to get a number of fellowships, so that people who were really poor, who really whose parents cannot contribute anything to the education, that kid still has a public institution that he can go to. I think that's extremely important for the democracy in this country and for the chance of everybody having a chance. And so I think it is very important that private institutions, which are already doing that, and doing a good job, but are also augmented in the population with public institutions, where the idea that tuition is a good deal less is really understood by the public.

Tjian: In addition to doing science and research at the basic level, and university administration, you've taken a fair amount of time out to be editor of two journals, first, the Proceedings of the National Academy of Sciences (PNAS), and more recently, Science. What attracted you to these positions, and how important do you think journals are to the field?

Koshland: I think probably I was attracted, because I'm a little bit of a nut. It didn't make any sense to do it, but it just struck me as being an interesting challenge. The PNAS... journal was really not that big of a change. In other words, I could do that in Berkeley, and with the usual kind of help you get from your colleagues and not just the University of California, but across the country, who did editorial jobs and things like that. Science was something different. That was even a much bigger time, and I ended up during that period spending 50 percent of my time editing, and 50 percent of the time doing research in my laboratory. So the answer to that is really, it was really just a big, interesting challenge, and I've always sort of been intrigued to sort of be an editor, and things of that sort. It was one of the things my wife and I discussed that when I retire, I might just become an editor of something, and I was thinking of just a little newspaper in a small town, something very different. Then of course, I was invited then to do this in the latter part of my career. But it was really earlier than I, I've forgotten what age I was, but it was something like 65. I was thinking of possibly retiring in five or ten years. I would really have preferred to have been invited to do it then, but of course, you never get that chance. It came at a certain time, and so I thought, OK, if I'm going to do it I might as well do it now. And it was really a fascinating challenge. The interesting thing in the editing of Science was that I think, unlike the president of the university or something like that, you can do it, and stay in your laboratory. In other words, it was the kind of thing where my continuing to be a scientist was good for the journal, it made me understand what the problems of science were, and it was compartmentalized in such a way that I could really do both. So, it wasn't as big a change as it would've been if I'd just been doing something totally different. But it was different enough so that it involved some strains, but also some very interesting sort of, increase in my general awareness of the world.

Tjian: Having been editor of two major journals in the field of biology, how do you think in the last 30 years and particularly in the last 10 years, journals have perhaps changed the way science is done and how publications affect careers of young scientists. What in general do you think the impact of all these new journals is on the field?

Koshland: I think they are very important. ...As science becomes more universal and more important in all of our lives, it also becomes more specialized. You see it in medicine, of course, that you just can't be just a general doctor any more. ...The same way in science. We just can't learn all the fields. Even in biochemistry you can become a crystallographer and learn about protein structure, or you understand DNA and be interested in transcription or how the DNA is replicated and things of that sort. The literature is so enormous that you really can't be in all those fields simultaneously.

When I started it was still not possible to be an expert in everything but you got some journals, like the Journal of Biological Chemistry where if you skimmed it you got a pretty good idea what all the major things going on in biochemistry were. You of course didn't learn physics or chemistry as well. I think now even in the field of biochemistry is split up so that there is just maybe 100 journals that you really ought to read to be an expert; whereas in the olden days maybe one or two journals you could read and say you had the most big advances. What has happened then is the journals like Science and Nature are sort of taking out the most exciting articles. It becomes very prestigious to get articles in one of those journals. ...The error that can be made is that some of the equally exciting articles are appearing in the more specialized journals. This is partly because if they are highly original people don't even recognize they are that exciting. They turn them down in the more prestigious journals because those journals are swamped and you don't recognize this is a big new development.

Secondly, sometimes if you are doing something very new you have to provide more documentation and more background to convince anybody. ...You have to take the time of a more specialized journal. I think this is something that the journals are going to have to watch. I think that this development means that frequently the specialized journals become too specialized and they miss articles that they really should catch. The people they ask to be referees and editors are themselves experts in that specialty but sort of miss the connection. The problem is that it is sort of an accelerating vicious circle. In the era of computers and recombinant DNA, you have kits for DNA which make it easier and easier to do experiments. You have computers which make it easier and easier to do calculations and to survey the literature. As a result the pace of modern science increases if anything. More and more gets published and it isn't because it is more superficial. In fact most modern articles have more data in them that the old articles did. I think this enormous increase in knowledge and the acceleration of it is a problem that we are all going to have to face.

Tjian: Especially those of us that have to teach it.

Koshland: Exactly.

READ Daniel E. Koshland Jr.'s OBITUARY IN THE NEW YORK TIMES