1997 Albert Lasker Basic Medical Research Award

Lambda repressor and gene regulation

One of the great achievements of contemporary biology is its foundation in molecular genetics and the remarkable progress that has been made in understanding how genes work. Genes are nothing more than discrete stretches of DNA that contain within them the blueprint for producing the proteins upon which life depends. The important question is this: What regulates the genetic machinery? The mechanisms by which genes are turned on, and then turned off when their job is done, are essential to our knowledge of development and disease.

Mark Ptashne is an acknowledged founder of molecular studies of gene regulation. For three decades he has kept his scientific eye on this single target and, in so doing, laid the conceptual framework on which many other investigators have built their research. His major accomplishment has been to figure out how "regulatory molecules" control the function of genes. In the early phase of his research, focusing on bacteriophage, a simple virus that grows in a bacterium, he and his colleagues discovered a series of fundamental mechanisms for how genes are switched on and off. Then turning his attention to higher organisms his laboratory showed, much to the surprise of many, that the very principles that explain gene regulation in lower organisms apply to higher organisms as well. These discoveries are now so deeply ingrained in contemporary science that it is possible to forget their wide-ranging significance.

In 1967, exactly 3o years ago, Dr. Ptashne isolated a regulatory protein in bacteriophage called the "lambda repressor." This key regulatory protein controls the genes of a virus, called lambda, that reproduces by invading bacterial cells. Dr. Ptashne's extensive studies of the lambda repressor showed how a regulatory protein can recognize "information specific" sites on DNA. Through studies of the lambda repressor and related molecules, Dr. Ptashne also revealed how simple regulatory molecules can be combined to create a sophisticated "genetic switch" that also allows the virus, when dormant in the bacterium, to dramatically switch on its genes in response to a signal in its environment. Much of this insight required deciphering the molecular anatomy of lambda repressor through the techniques of structural biology, which enabled Dr. Ptashne and his colleague Dr. Stephen Harrison to show in 1987 how the repressor protein bound to DNA atom by atom. This was the first atomic view of a transcription factor touching its DNA. 

Dr. Ptashne's laboratory then turned its attention from bacteria to the more complicated organisms such as yeast and fruit flies. Working on transcription factors from these higher organisms, he defined the structure and function of "gene activators" in these organisms. As is the case for activators in bacteria, gene activators bear regions on the surface that direct the protein to the correct DNA sites and separate surfaces that activate gene expression by interacting with other proteins that bind to DNA. Experiments built on Dr. Ptashne's data and conceptual ideas have shown the universality of regulatory gene mechanisms. The mechanisms are essentially the same in yeast and fruit flies, in plants and people, and gene regulators that work in one organism will work in others as well.

The next chapter in the gene transcription story will be told through the analysis of the thousands of proteins that are part of the complex human genome. Genetic instructions are "transcribed" as the switches that turn genes on and off enable cells to interpret information for development and homeostasis. Dr. Ptashne has laid the foundation for the complete biochemical reconstruction of the machinery of transcription and for deciphering the complicated gene regulatory networks that underlie development and cell functioning.

Understanding gene regulation in the same detail that computer experts understand microcircuits, for instance, is basic to all recent success in science's growing comprehension of how multicellular organisms, like human beings, develop and how things sometimes go awry. In this regard, Dr. Ptashne's work over three decades is a perfect paradigm for the relevance of very basic research on simple and primitive unicellular organisms to human disease. We now know that many genetic diseases are caused by faulty gene regulation Among these are developmental disorders, such as a pituitary hormone deficiency in which growth hormone is not produced; thyroid hormone defects that lead to mental retardation; cancers that develop because an "onco" or cancer-causing gene is turned on (leukemia due to chromosomal translocation, for instance); and cancer caused, oppositely, by the inactivation of genes whose function is to keep cell growth under proper control. Certain tumors of bone, breast, brain and even the eye are known to occur when the "repressor" molecules in the regulatory system fail to repress. Researchers have identified a host of oncogenes, with names like Myc, Fos, and Jun that are known to cause cancer because of errors in gene regulation. When these and similar errors of regulation are finally explained and treatable, Dr. Ptashne can take pride in this accomplishment.

For elegant and incisive discoveries that provided a conceptual framework for understanding how regulatory proteins control the transcription of genes, Mark Ptashne is honored with the Albert Lasker Basic Medical Research Award.

Award presentation by Joseph Goldstein 

In an interview on BBC Radio in London, Francis Crick was asked, "What is the key to scientific success?" His reply went something like this: "Be bold and adventurous. Make bold theories and take a bold approach to experimentation. Don't get bogged down in details. Think big and adventurously."

The recipient of this year's Lasker Basic Research Award, Mark Ptashne, passes Crick's boldness test with flying colors. When Mark began his scientific career 35 years ago, Jacob and Monod had just advanced the theory of gene regulation by repressors. Identifying repressors became the Holy Grail of molecular biology. An understanding of repressors would tell us how genes are turned on and off in response to hormones, growth factors, drugs, and other environmental signals. Many scientists searched for repressors, including Jacob and Monod, but in the end only two scientists had the "bolds" to complete the job: Walter Gilbert working on the lac operon repressor defined by Jacob and Monod, and Mark Ptashne working on the repressor of a tiny virus that infects bacteria called bacteriophage. Mark isolated the repressor in 1967. He showed that it was a protein that specifically bound to a small stretch of DNA. These experiments earned Mark a full professorship at Harvard at age 31. Mike Brown and I had to wait until we were 36 to become full professors—and that was at the University of Texas Southwestern Medical School, not Harvard!

Shortly after Gilbert and Ptashne isolated the first repressors, Gilbert left the field of gene regulation and went on to develop a new technique for sequencing DNA, for which he received a Lasker Award in 1979 and a Nobel Prize in 1980.

Like Gilbert, Ptashne did not rest on his Harvard laurels. He continued to work on gene regulation and soon made his most notable discovery notable not only for its significance, but also for its elegance. To shorten a long story, Mark delineated the molecular basis of the lambda switch, which explains how the repressor and another regulatory protein called Cro interact with the DNA of the bacteriophage virus to switch genes on or off in response to two different environmental signals. Upon infecting a bacterial cell, the virus decides between two developmental pathways, called lysis and lysogeny. When the switch is ON, the virus multiplies exponentially. It commandeers the bacterial cell and kills it by lysis. When the switch is OFF, lysogeny occurs. The DNA of the virus inserts itself into the chromosome of the host bacteria and remains quiescent until the switch is reversed by signals from the environment.

Mark's work explained beautifully how the lambda switch is constructed and how it is modulated by a positive and negative feedback system controlled by the two DNA-binding proteins, repressor and Cro, interacting with DNA and other components of the genetic machinery. Elucidating the lambda switch opened the field of transcriptional regulation as we know it today and provided the first general model to explain the switching between two developmental pathways that occur during the formation of embryos and cancers in higher organisms, including humans.

In 1985, Mark and his colleague at Harvard, Stephen Harrison, solved the crystal structure of the repressor bound to its DNA-binding address. This was the first atomic view of a transcription factor tickling its DNA. So over the 20-year period from 1965 to 1985, Ptashne pushed the lambda repressor from an abstract genetic concept to a purified protein molecule to an atomic structure. Not bad, even for a bold (and now bald) Harvard professor.

In more recent experiments, Mark used his insights from the lambda system to analyze gene regulation in higher organisms such as yeast. In typical Ptashne fashion, he formulated powerful new ideas that continue to influence all scientists working in the transcription field today. Let me briefly tell you one example of Mark's influence. While studying the genes that allow metabolism of sugars in yeast (the so-called GAL4 system), he and his colleagues showed that transcription factors in higher organisms are constructed in modules. A typical transcription factor is made up of two discrete regions or domains; one domain directs the protein to the correct binding address on DNA, and a separate domain in the same molecule touches other proteins that activate the genetic machinery to turn on the gene. This discovery paved the way for other scientists to invent a powerful new technology—the so-called yeast two-hybrid system—that allows the identification of new proteins that interact with each other in the living cell. Using the yeast two-hybrid system, scientists have just recently discovered the master switch protein that directs the formation of the heart during development of the embryo.

The field of gene regulation, which began with Mark's work on the lambda switch, deals with a subject that is central to all biology. As many as 15 to 20 percent of the 100,000 genes in the human genome encode transcription factors like the repressor and Cro. And not surprisingly, the transcription field is the most active field of basic research today, bar none. During the last 12 months, 11,000 papers on gene expression were published in the scientific literature—4,000 more than on cholesterol! The next chapter in the gene transcription story is now being written by biochemists who are reconstructing, in the test tube, the complex protein machinery of transcription. The ultimate aim is to show how multiple transcription factors and their various co-activator proteins interact to generate the serpintiginous networks that underlie normal cell development and function. Once this goal is achieved, it should be possible, one day, to learn how these networks are deranged in human disease, as in newborn babies with birth defects and in patients with cancer.

One final comment about Mark Ptashne's boldness. Not only is Mark well known for his virtuoso performance in science, but he is also an accomplished violinist. According to legend, Mark decided to buy a Stradivarius violin in the late 1970s. Even though he had a good Harvard professor's salary and had acquired some prize money, he still could not afford the Stradivarius. This was before his side ventures into biotechnology. So in typical Ptashne fashion, he approached the President of Harvard, Derek Bok, and attempted to convince him that Harvard should make him a loan. He argued that Harvard made special loans to faculty members so that their children could attend college. Ptashne had no children, and he argued that owning a Stradivarius would be the closest thing in his life to a child. I'll leave it to Mark to tell us whether or not President Bok flipped the monetary switch ON or OFF!

 

Mark S. Ptashne

Interview with Mark Ptashne and James Watson 

Mark Ptashne began a brilliant scientific career by studying lambda, a virus that infects bacteria. In a September 1997 interview with friend and colleague, Nobelist James D. Watson, President of the Cold Spring Harbor Laboratory, Ptashne talks of his work and teaching.

Part 1: Love for the lambda prompts a leap of faith
Mark Ptashne leaves the field of fly genetics to pursue his PhD and learn lambda lore. The Lasker Award winner discusses the scientific community and tells how determination, friendly competition and a unique perspective lead to eventual success in the search for the repressor.

Watson: ....the ambition to find the repressor.

Ptashne: Well, you know, in fact, I had it before I came to Harvard because I had worked -- I went to school at Reed College in Portland, Oregon and well, let's see, if we go back to my sophomore year, my introduction to the field was working as a fly geneticist with Ed Novitsky. We went to Crested Butte, Colorado and Ed, despite his continuing enmity with all things molecular, had the good graces to say look, if you really want to do science, you should go into molecular biology and you should meet Frank Stahl and Aaron Novick. And that was my introduction.

So I spent at least one summer with Aaron and Frank and that was really the generative thing. Of course, Aaron had studied with Francois Jacob and Jacques Monod in Paris, and the whole business of the repressor was very much in the air. It was the great intellectual issue, and I can even remember once mixing up some test tubes and absolutely thrilling Aaron because he thought we'd disproved the French—and of course it was just that I'd screwed up. And so then, when it came time to graduate and go do a PhD, they said well, the real person to go study with is Matt Messelson. So, I went to Cal Tech and met Matt and he said I'm going to Harvard. So that's why I went to Harvard.

But from the beginning, I said I wanted to isolate the repressor. And Matt said, well, that's fine. But first you have to get a license, you have to do your PhD. So that's why I set about learning everything I could about lambda and did the initial thesis on lambda, so that I could get into a position when I got my PhD to then spend full-time doing what, of course, everyone thought was a waste of time because it couldn't be done.

Watson: Now, when you were doing this --

Ptashne: Oh, and by the way. One of the things that was so encouraging is that as I was on the sidelines doing this other stuff and supposedly all these great labs, the Pasteur and so on, were going to isolate the repressor, they all failed. And yet, if you looked carefully at what they had done, you could convince yourself they just hadn't done it seriously enough. In other words, they didn't fail for what I thought were good reasons, but had anyone succeeded during that period, of course, then I wouldn't have done it.

Watson: Did they fail because they weren't rigorous or did they not just work as hard as you?

Ptashne: I don't think they were willing to do things as bizarre as it turned out we had to do. Because don't forget, there must have been 10 different things we tried, both me and Wally, and none of them were classical chemistry nor classical molecular genetics. They were all quite bizarre. And finally, as you probably remember, in our case, in the lambda case, we had to do this completely unheard of thing of giving vast doses of radiation to cells so that they were essentially just bags of protein synthetic machinery and then stick the DNA in, that is, by adding the virus and let it make the repressor. So there was this very elaborate, complicated thing that depended on a lot of luck and Nancy Hopkins' particular touch with the cells and correlations with genetics. Looking back on it, it's not surprising that most people --

I think having Wally there as the competitor, where the two of us were spurring each other on, is what made it possible. Otherwise, I think after a while, you try all the standard ways of doing it and then give up. So in other words, what finally worked was so bizarre and unusual, it could not have been predicted when we started, both of our methods. And it required that special kind of effort.

Watson: Did the sort of conventional lambda PhD, was that actually useful? I mean, in the sense that if you hadn't done that, you wouldn't have done the experiments you finally did? That is, it just gave you the background of --

Ptashne: Yeah, I think so and you learn the culture, you learn the --

Watson: That is, I guess what I'm asking you is if you'd started two years earlier, would you have gotten the answer two years earlier?

Ptashne: You mean if I had started on the repressor two years earlier?

Watson: Yes.

Ptashne: Oh, I see. Well, I doubt it. I don't know, but I sort of doubt it. Certain mutants had to be developed and certain things had to be clarified before it was possible, I think, to go ahead, but my recollection isn't detailed enough to know for sure.

Watson: So, it was a discovery --

Ptashne: But, certainly, I mean one of the things that outsiders can't appreciate is the extent to which when you do these things, you're part of a community. In the lambda case, there were these fancy mutants, these N-mutants, and there were these virulent mutants. There is a small group of people, Italians and French and Englishmen and Americans and so on, who talked this curious language of "lambda lore," and certainly just being part of the culture and having that group of people with their knowledge to draw on, all that's very important, you know. These things don't happen, as you know, in a vacuum.

Watson: Well, do you think today, when people are so commercially minded for their implications, that there's any group of people who sort of share information the way it was done with the lambda group?

Ptashne: Well, I must say groups are so much bigger now. My impression when I went to a meeting run by Christiane Nüsslein-Volhard on fly development was that there certainly is a large group of people who are very open and very cooperative. Even the fly community now is so large that it's hard to generalize. But certainly, amongst this subgroup, I was very touched by the very serious—in fact, I said at the time, it reminded me of the old lambda meetings where people would stand up and honestly say well, what we used to believe is wrong, and argue about what the real interpretation of the experiments is and so on.

And I'm told a lot of the worm world is like that. Certainly a lot of the yeast world. The thing is, each of these worlds has become so big that I'd be reluctant to make generalizations. But, for example, as you know, indirectly if we talk about the field of transcription, which is a vast field...if we have a meeting, you can expect a million people there. But then we had this wonderful meeting at your place, when was it, last year or two years ago?

Watson: It was just last December.

Ptashne: Yeah, last December. Where 35 people came and it was marvelous, I mean, I thought with one or two exceptions. I mean people were just extremely good humored, extremely open, very generous, very smart. It may be a problem of size and getting a small enough group. But, of course, one doesn't want to be nostalgic for the old days, but it is true that there is a different sort of pall. The terrible problem of supporting labs. It used to be if you were a serious person who had done something seriously or had good ideas, you would be funded. And now --

Watson: Automatically.

Ptashne: Yeah. And now, skipping my own stories because everyone's got his own horror stories, it's heartbreaking. You hear about people who you think are the most intelligent people in the field, and whether they get a grant or not is completely whimsical....And sometimes they don't and they suffer and they're under tremendous pressure and so on. So this has to influence things, and so I guess I would say the fact that you still find these pockets of such good will and such intellectual seriousness is actually quite a touching and positive thing. And it shows you the real power of this field and why it's so wonderful to be part of it in its best manifestations.

Watson: Because science is no fun unless you can sort of convince someone else of your own ideas.

Ptashne: Science is a totally social thing. I've never had any patience with—never could understand people who think they want to keep a secret. There are people who want to keep a secret of what they've done. I can't even see the point of keeping a secret of what you want to do. It's just no fun. The only fun is if you have an idea, to tell everybody and to try to see what they think. Now, I can see where there are. I must say I think that the other side of it is that because of these pressures of money and jobs and so on, it's not so easy to say and a person who's achieved, who's in a more secure position, I guess, as I am, can be a little more casual about this.

But I believe that the only way to run a lab, for example, is by day-by-day total openness. Everybody must know what everybody is doing. Everybody must be subject to constant criticism from others and it's the way people respect and like each other the most, when there are those kinds of interchanges. And the people I admire the most are the people who have always been the hardest on me, and I respect them for that.

Watson: But I think, looking back at the lambda field, there were people who might have claimed—you know, they had something that wasn't strong, but there really were no people you wanted to kill. There weren't any, to use a word, shits.

Ptashne: Well, maybe because the stakes weren't that high. I mean, it didn't matter, you know, maybe in some way? Except the people who believed in it like a certain kind of cult or something. And the other thing, the other characteristic that I think really should be mentioned used to amaze me. You'd go to a meeting and there would be these people who were your peers and there would be this rapid-fire discussion that you were perfectly at home in, then if you didn't go to the meetings for two years, you'd come back and two things would have changed. First of all, there'd be a whole new group of young people that you'd never seen before and secondly, they'd be talking a language you'd never heard because there are new mutants, new ways of thinking about things. And where they came from and how they learned all this is dazzling.

And then, of course, what is both the exciting thing, the most extraordinary thing about science that distinguishes it from, let us say a cultural endeavor like the arts, is that the world that you're in—especially if you are good and people are serious—gets destroyed. So, in other words, there's a certain period where there are wonderful ideas and wonderful ways of talking and so on. But as soon as the next level of discovery is made in which you can interpret those genetic phenomena—say in terms of some chemical thing—then suddenly that old way of talking becomes irrelevant. And there's something, on the one hand, exhilarating about that, but on the other hand, it also can be depressing.

And so you see how some people can get caught into perfectly understandable reasons of not wanting to solve problems. Because if a problem gets solved, that particular world that's been created around those problems gets destroyed, and now there's a new world. And I think it takes a certain kind of psychology to embrace that as opposed to resist it. Am I making myself clear?

Watson: Yes. If you see the newspapers now about genetics, it's almost as if the genes are getting bad press because they make things go wrong, whereas when we started out, genes were wonderful things because all these genes work together so that [(inaudible) could come out and there was subtle control mechanisms so they were all good. But now, human genetics is dominated by bad genes—that is, when a gene doesn't function. You can see you might keep it secret. You don't want to admit you have a bad gene. What people are studying is something you don't, in some sense, fear, and so this is a completely different world.

And then, of course, it brings you to the fact that people are sick and you want to cure them, and it's a different world. I don't know if it's changed, but one has the feeling that the people aren't shits, but they act like it because they aren't going to tell anyone else because it'll help someone else. You know, there are five people wanting to find that bad gene, whereas I think it is there's a limit to the number of bad genes but an awful large number of good genes. So that if you're studying good genes, there's almost enough for everyone. But in bad genes, you focus on one bad gene and all these people are trying to get the bad gene. It's very different, and I think from a test field, you shouldn't be in it if you're a student because you can't talk.

Part 2: Not just a job
Science is serious intellectual work, but Ptashne says trying to decipher how the same genetic material combines to create life forms as diverse as yeast, flies, worms and human beings is fascinating and fun.

Ptashne: Well, I think there's another side to that which I really believe. When I entered the field, following the pathbreaking, pathfinding work of you and many others, still, back in those days, we all believed that if we studied profoundly some small part of the world, whether it was a bacterium or whatever, that we would learn something of general relevance. But it was a matter of belief. We'd argue it and intuition and the people who didn't believe it, you just had to ignore them and so on and so on.

Now the world has just changed dramatically. Because of the progress that has been made in the human genome, you see the human genes are the same genes that you find in flies and in yeast and bacterium and worms and hope, not always and so on, but to an astonishing extent. And the real hope of understanding how those things work, how those proteins work, is going to come from studies in those simple organisms. And so it's a wonderful sort of full circle. In other words, now that the beginnings of the real look at the human genome are happening, it now becomes clear that basic research on the simple organisms is more relevant than ever.

And, in fact, I think even things you and I would have thought were boring, whether they were mismatch repair or recombination, all of these matters now are of incredible interest, and the intellectual challenge as to what they do and how they work and all this wonderful stuff...there is simply no basis for denying. In effect, it's quite the contrary that these discoveries are going to be relevant to understanding how humans are put together.

I think the real cultural message should be that more than ever it's clear that serious intellectual work—by that I don't mean to take the fun out of it, because that's the fun part—understanding really how things are put together, how development works, what the real business is in flies and in worms and even in yeast and bacteria is now more fun and more important than ever. It would be a great tragedy if people think that if they go into this field, they have to just start doing what everyone else is doing. Where the ideas are no longer limiting, as you say, and just have a race to isolate this or that gene. Because it's not the kind of science we like.

Watson: Exactly. I would find that very disconcerting because when I was at Harvard, I think I didn't mind one competitor, but the thought that three or four people were doing something. And generally, you wanted a competitor that you talked to once every two or three months, not every day.

Ptashne: Sure. But I think we somehow have to convince people that working on good genes is more important than working on bad genes, but it sounds just the opposite because most likely...something like mismatch repair, which is a good gene, you see bacteria surviving....So I think this sort of "bad genes" should be for older people, you know, this is sort of a (inaudible) phase in your life. The real fun is how does a bacteria—how do you put together 500 proteins? Just 500 genes and microbacterium?

And I actually think the most—it strikes me that the most amazing thing, if this turns out to be correct, is the way it seems that rather small changes in the numbers and kinds of genes has such fantastic phenotypic effects. I mean the difference between us and a chimpanzee is not very many genes, as far as we know. And who knows how many genes would have to be changed to make a chimpanzee talk. You only learn these things by studying.

Watson: Or what is the fundamental difference between Neanderthal man and Homo sapien? I mean, could the Neanderthal man speak? What was the mutation which suddenly gave voice to Homo sapiens, which certainly was a very important thing in letting the culture develop?

Ptashne: And all these things, you know, these arguments about evolution which so many would strike one as sterile...I think the really extraordinary insights are going to come when people get more examples of how you, for example...let's see if I can recall this. There was a talk I heard six months or so ago about how photosynthesis has been invented several different times in evolution. It turns out that all you have to do is put one cell—a certain housekeeping, ordinary, garden variety enzyme—next to another cell making a garden variety enzyme, and then by the miracles of chemistry, you get this effect that you could never have predicted. As we learn more and more about how you take these simple systems and combine them, what extraordinary things will come out? And that will tell us a lot about the process of evolution.

Now, suddenly, evolution is sort of compared to development, how you can suddenly, with almost the same set of genes, look totally different, function in a different way. And I guess I think about why would I want the cost of DNA sequencing....

Well, the other thing is that, you know, I don't know much about this, but the little I've read in it, the thing pioneered by this guy, Lark, Darwin's finches. You know, this business where he....

Watson: Yes, luck.

Ptashne: Luck. Sorry. David Luck, that's right. Where if the recent developments are right, it turns out that the variation that's within a population is really quite extraordinary and the ability of evolution to change things over very short periods of time. I mean, as the genome progresses and one learns how to measure this kind of thing, one's whole attitude about what a species is and what a race is and what evolution has to play in all these things certainly may change.

Watson: Well, I think what we're doing now is sort of defining the sort of fundamental actors. They put a phosphate on or take a phosphate off and they change their shape, so these are the actors. But this has to have different clothes and so if they have different clothes, they attract a different molecule and so then they function slightly differently. You change your clothes and you're a different person, even though deep down you're the same but your opportunities for doing something are very different. That comes from just, you know, changing one single amino acid, and suddenly you've got a new partner.

Ptashne: Well, not only that. I think it's even more of a problem than that. So let's think back about the lambda days. As you know, the virus infects the bacterium and it can either lyse the cell or it can turn its genes off. Lysogenize. And so you could say well, it makes this decision. Now, we know a fantastic amount, in fact it's probably the most highly developed system in terms of what molecules do what on the genes as these two processes. But if you ask, well, when all is said and done, what environmental effect really tells the virus whether to lyse or lysogenize, we can't say very much. I always used to make the joke that that's a problem for a psychiatrist, not a scientist. Now, when you think about the questions people are asking—you know, what causes a cell to become cancerous, which is related to a question does the virus grow or not grow—you're dealing with contingent matters of such complexity that it's just very difficult.

It's not that we know so much, it's that we know so little....I go back to my thing is understanding what all the players are, learning how they work in different settings and why does one set of these guys working in a fly give you a fly? Now, you take those same proteins and you use them in a slightly different way, you get a worm, and what is the thing? So, in that sense, if we can get rid of the unpleasantness, you know, the whole thing is at an even more generative and exciting stage than it ever was.

Part 3: The teacher talks about his students 
Ptashne recalls some of his students. He describes the love/hate relationship between instructors and students as young scientists seek maturity and struggle for independence.

Watson: What's [the next] task? You've stayed with this transcriptional control mechanism as your whole career. You've had a series of good students. Have they stayed with the same problem, or have they branched out into totally different ways?

Ptashne: Well, let's see. There have been so many wonderful people and I have to go through them. Nancy Hopkins, of course, worked on animal viruses and is now doing zebra fish; Sandy Johnson is a prominent figure working in yeast who started working on yeast just about the time my lab started working on yeast, and has done very important work there; Carl Pabo is a distinguished crystallographer in many areas, not just related to what he began to study; Bob Sauer has stayed more or less studying fundamental aspects of protein structure; Tom Maniatis, of course, has branched out in many different ways; Lenny Guavente is now studying aging and yeast. But with all these people, you still see a certain thread. For example, Lenny, I notice, uses the same wonderful kinds of genetic arguments that we [use]. There's a certain kind of style that you can see applied in these many different problems.

Ann Hachscheld actually has made, I think, some absolutely profoundly important contributions by going back to bacteria and reaffirming or establishing how many fundamental things work. Who else would I -- Of course, Roger Brent is applying things far more generally. I think the straightforward answer is none of them, except in a sense, Ann, but certainly none of them have stayed simply working on...Barbara Meyer is of course a distinguished experimenter in worm development.

Watson: So, in a sense, you're not competing with your students.

Ptashne: Oh, no. Not at all.

Watson: That's what I was trying to -- the right student sort of has to reject his professors.

Ptashne: Oh, yes.

Watson: And completely move in some way.

Ptashne: Yes. I mean, in the short run, I don't think your students are there to love you. They're there to become the best they can and if they do, in the long run they respect you, they like you....

Watson: They get at your guts and then they....

Ptashne: Well, they have to assert their independence. Absolutely.

Watson: The sort of sooner they do it, the better. So I think probably you can sense that—what students, by the time they've got their PhD, they've already sort of had enough of you.

Ptashne: Oh, absolutely. Yes. And they don't really want to do things that would please you but their aim now is just to please themselves and I guess that's the—and of course, that's what pleases me the most.

Watson: But you see, when you were doing your PhD, you really weren't doing anything to enhance Matt Meselson's career, you were doing something to enhance yours.

Ptashne: Well, I also think that's a tribute to Matt. But that, I think, was one of the wonderful things back in the old days is that there wasn't this big effort and you didn't sort of see your students as the way to get your ideas expressed. You provided a sort of bench where students could hopefully develop their own ideas. And so, I think, that's a sort of worrisome thing. I see students that are around for six or seven years and their names are on large numbers of papers with their supervisor, and their whole supervisor's career depends on the success of the students—whereas 30 years ago, people did their own thing.

Watson: Well, again, you know it's like being a politician nowadays. Either the politician gets elected and all he worries about is how he's going to get re-elected. So you get a grant and all you worry about is how you're going to get the next grant. If you don't have students who are doing something, it's.....

Ptashne: So that is the changed thing. So you see the student as a way of whereas looking back into the 19...

Watson: I do think, though, that there are all kinds of people who are students. And with some, you put them on the ground, they just run. But others really...it's very important that they be part of a supportive group, that they not be isolated, that they....

Ptashne: But if you really asked those people who are part of a supportive group, do they ever really make it in the long term? I mean, are those students ones that, you know, you tend to forget because you really...one thing we worry about is almost too many scientists. All these postdocs. Are we really training too many?

Watson: Well, maybe so.

Ptashne: Are we in this situation where if you really have to be supportive for a student, you shouldn't have him. I mean, you'd never be supportive (inaudible) or Joan Steitz or some of these super students I had. I saw it more as just seeing they had the money to do what they wanted and then by the time they left, they never really were that emotionally dependent on you for keeping going, and then they could go off and they were perfectly good. So, I'm just wondering that people essentially have too many students because everyone is worried now. What are we going to with postdocs as old as the staff as sort of workers, rather than scientists, and I don't know how to break the thing. It may be an inevitable consequence of the simple fact that the field is so successful, that important things can happen by turning the crank. Let's face it.

Watson: We know how. Recombinant DNA certainly, and everything that has followed from it.

Ptashne: Sequencing and all the rest of it. I mean, this is true. I actually was a little shocked to learn from one—you know, I'm moving from Harvard to Sloan-Kettering, and some of my lab is coming, and one fellow couldn't come because of a family problem, and I thought it would be trivial to get a job in industry. Well, it turns out now that as many companies as there are, there are hundreds of applicants for every good job in these companies even, I gather. But I think the other side of the coin, let's face it, is I think I don't want to be too gloomy about this, but an assistant professor starting at a university which typically will give very little support beyond just setting them up has a pretty daunting task. In the old days, you were an entrepreneur and you could do it if you had some pizzazz.

Watson: One of the reasons why it's so hard to get a grant is so many people are applying.

Ptashne: Yes.

Watson: And so we're creating a situation where we're almost....

Ptashne: And the people who are judging are not necessarily most sympathetic....

Watson: And so the system, in a way, is killing itself by the sort of like the peacock's tail. It gets longer and longer because there's a selection (inaudible), but it's not really doing any good. You know, when you came to Harvard, you know, Matt probably had four or five people working for him and that's what I had and Wally and I put together, we were about 10 and now, any of the—I was back at Harvard and I didn't have 20 people working for me. I would be in a mess because when—you could say I was competing with Norton Zinder or Chris Lipman or something like that, I knew the size of their groups and I was about the same and it still let you take summer holidays and know people and this bigger and bigger thing really will just generate a worker class in science. And I don't know how to stop it, but I think we might really ask how many students should we have if we're going to give them a real chance to go out in the world and get self-confidence? If you have 10 students, you probably have two or three favorites and the others that are there, you don't quite know what to say to them because....

Ptashne: One of the most important things, I think, generally and certainly to me, personally, is this thing we'll call emulation. In other words, I went into science because I read a paper—one of the reasons, I read a paper by Jacob and I thought my God, that's what I want. That's it. That kind of prose style. I read your stuff. I read Matt's stuff. I said that's the way the sentence works, the whole style. The way of thinking (inaudible). That's why I came to Harvard. And here, I was surrounded by these people that I vastly admired, you, Wally, Matt, all of whom were different and individuals, real personalities. And nothing ever gives me more pleasure than starting out a paper by saying, "Following in the footsteps of X, Y and Z." I just wonder, that seems so much to have disappeared from the world.

It's almost as though you read papers nowadays and I'm just talking about other people, and then you see it's like pulling teeth to get them to say that instead of a matter of pride that they were inspired by somebody, it becomes almost a matter of pride that they weren't inspired by anybody. And that's no fun. It's not honest, it's not fun. But you know, that's why one does something. I'm always shocked to think of myself—you know, I've always thought of myself as the youngest guy at the party. Now I go to these meetings and I'm the oldest guy at the party. It's a little depressing. So, whether it's our failing or whether the world has changed, one doesn't—in other words, I would never have appeared and said to you and Matt well, you show me why should I study in your lab? I regarded it as just an incredible thrill that I could be around.

Part 4: Changing times don't change an eternal principle
Scientific institutes have changed and scientists face many struggles. But the impetus in science, intellectual fun, is still the same, says Ptashne.

Watson: I think we should bring this to a close. But if you're a young scientist, it seems to me what you should be doing is try and go into a field where you find that you're working for yourself and not for someone else. I never felt that I was working for (Inaudible). I don't think he ever thought that, and I think that's why I had the self-confidence afterwards to take on difficult problems.

Ptashne: I certainly think that was the atmosphere at Harvard when I was there, yes.

Watson: Yeah. And it just may be that with so many genes we can do so many things that we've moved to this other way, but I guess I wouldn't want to be a student faced with those pressures. I would move to a slightly more offbeat field. But I do think that brings us back...really, can the way in which we thrived at Harvard in the 60s have a future? I think the answer is no because I think the institutions have to—if you want to support science, the institution has to provide an infrastructure and really take it very seriously. If it just thinks it's renting space, there's no loyalty to the institution, and you don't get that sort of long-term development.

Ptashne: I think the way Harvard worked in those days that you're referring to was a noble and wonderful thing. We were a department of equals and nobody had power; everyone was on his own but was a formidable individual in his own right. And the world has changed now so much that it's just very difficult to maintain that without, as you say, much more of an institutional involvement.

Watson: When I was at Harvard—George Bundy, he was very sympathetic. We had a president who had no interest in science, but he was told we could get government money, and Harvard never has to put any money into it except pay your salary for nine months, and it worked. But that's not true any more. I think you just have to have a situation where there is some support for young people and infrastructure, and if a university really wants to do science, it's got to put in the same amount of money it's going to put into its football team. And I don't think they realize it yet. That worried me, because these young people won't really think someone wants them. They'll just be used, I mean, wanted for their brains and because they're going to help them, and I think it's --

Ptashne: Do you think that if that were available, the culture is such that young people...if not the numbers, the percentage will be willing to devote their lives to some intellectual challenge and take great risks and do all the things that we all did?

Watson: Yeah, I think they would.

Ptashne: You don't think that's changed?

Watson: I don't think it's changed. I think it's great fun, but you've got to put them in something where—you were never going to work for someone else, I was never going to work for someone else. I think that's the right way.

Ptashne: I agree.

Watson: But still you've got great faith that relatively young people can do very important experiments. You made the discovery for which you're most famous when you were a postdoc. I did the same. It wasn't that you had to go on because now most postdocs are just working for someone else, helping someone else make a discovery. I think at that social level, your PhD should be a program by which you acquire techniques and sort of get a feeling for what's the big thing to do, and then do that. And that's where I think those institutions that triumph see that people at that age really can do something good, and it's a question of how you're going to finance it—to what extent will private philanthropy...that you're going to have to find some of these billionaires who just decide that maybe a good use of half their fortune would be to support ideas.

Ptashne: Despite what we were saying before about the relevance of basic research, the only motivation that really works, that really matters is the intrinsic excitement of the ideas.

Watson: Yes. And that's the important—you know, Dudley Herschbach, I love this line of his. He says that the most important product of basic research is ideas. I think it's exactly right. If it's done for any other reason.

Ptashne: I remember when I had my first idea. It was wrong but you know. It was my second year of graduate school and I said gee, I had an idea. I always try to tell my students that it's important to sound dumb. Of course, they're always telling me I'm the dumbest one, but that's fine. I would like them to have lots of bad ideas because it's only by having lots of bad ideas you can have a good idea.

Watson: Yes.

Ptashne: The problem usually is that people are afraid to have ideas, period. And you want them to sit there and just think all the time. Maybe the world works like this, maybe the world works like that. There's always somebody, if they're smart enough to just go talk to people, who will tell them it's nonsense, if it is nonsense. And they'll probably be told it's nonsense if it isn't and then they have to have the character to realize it.

Watson: Yes.

Ptashne: The problem is to have the ideas, not to have good ideas. One in a million will be a good idea. The problem is to have any idea.

Watson: Well, this is great fun, talking again.

Ptashne: Great.

Watson: Yes.