For a lifetime career devoted to elevating science to its highest level — exemplified by accomplishments on diverse fronts — as a visionary biochemist, tireless institution builder, and eloquent public communicator.
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.
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.
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.