GENOME INTERVIEW TRANSCRIPTION: Walter Gilbert, 10/1/90
SUBJECT: Walter Gilbert, October 1, 1990 at Hilton Head
INTERVIEWER: Robert Cook-Deegan
WP 5.0 FILE: WGILBERT.TAP
TAPE NOTES: Interview begins about 1/3 through tape side A. Interview stops about 2/3 through tape side A, and resumes 1/3 through tape side B.
MISC NOTES: Proper names, acronyms, and unclear phrases are placed in parentheses, ending with a question mark, e.g. (Markowski?). Uncompleted sentences or pauses are marked with an ellipsis (..).
*** START OF INTERVIEW
COOK-DEEGAN: This is an interview with Walter Gilbert, we're at the Hyatt Regency on Hilton Head. .. Wally, I'm interested in trying to document the early history of the genome project, and in particular in your case, you were there from the Santa Cruz meeting and beyond, there are a bunch of ways I can get at that, one way to capture that is to ask you what defines the genome project and how it has changed from the period between 1985 and 1990.
GILBERT: It's changed because it's now defined through a national program rather than through a simpler idea which was essentially the direct sequencing of the human genome.
I'll give you a rundown of history as I saw it, as my memory serves. In 1985 I
1 was invited to that Santa Cruz meeting. The point of the meeting was to bring together a group of people to discuss whether or not a project like sequencing the human genome was at all feasible. Bob Edgar and Bob Sinsheimer did the invitations.
I went to the meeting thinking this is nonsense, what a silly idea, but not having anything else to do, I went to the meeting out of curiousity. In the course of the meeting, both by talking to Bart and George and arguing about how the sequencing might go and becoming more educated as to how the mapping was going, I concluded that it would be possible to sequence the genomes. I had very much the same attitude I have today, actually, that it would be possible with a reasonable increase in speed of the basic technology that existed in 1985, or the multiplex technology that George has suggested, or the technology that I'm going to use which was already essentially formulated at that meeting.
The basic intrinsic speed of the sequencing at that time was about 100,000 bases per year per person for the best sequencers, and therefore I expected that essentially a production line approach would move that to about a million bases per year, which is about a 10 cents per base figure. So I wrote an essay right at the end of the meeting, I concluded and the groups concluded that the sequencing project was certainly reasonable.
We argued to Sinsheimer that we could set up an institute there to do that. I, Bob and others also argued that they should not go to the government for money, because we worried about the conflict of this sort of project with the usual uses of money. It would be much better funded separated as a separate institute. I wrote an essay to Sinsheimer, essentially saying, why don't you set up an institute that would have about 300 people in it, and thus would cost about 30 million dollars a year, that about half of those people would be involved in sequencing, mapping and that technology, and half would be involved in research around the general theme of human structure. By having half involved in research
2 you'd have a reasonable structure at the university; by having half involved in sequencing, supported essentially on endowment funds, at such an institute, you could plan to make deep inroads in the sequence, and you could plan to do the sequence over a about 30 year period, at that sort of level of expenditure. Which then comes to something like spending roughly 300 million on the sequence, but thinking of it as starting on interesting genes, moving on to small regions, chromosomes, and gradually doing the rest as the technology improves.
I left that meeting with a (?) that conclusion. Sinsheimer, as far as I know, did not try to get, energetically, private money for it, but sort of approached the government, and nothing really came of it. At the meeting he sort of vaguely approached me, would I come there to do that sort of thing, I said "no, I wasn't going to move."
I went to the Gordon conference right after that meeting and at the Gordon conference, sort of gave me a few minutes to quote summarize this sort of possibility, and probably to express the sort of thoughts on the cost of the genome, not the low figure but maybe the cost of doing the genome at current costs would have been something like 3 billion dollars.
Naturally when I first event (figured?) at the Gordon conference or a little later at the Cold Spring Harbor meeting, the Cold Spring Harbor meeting was probably - because that was a year later, I'm not so sure..
COOK-DEEGAN: That was June, the Gordon conference would have been in August or something like that - August '85..
GILBERT: Gordon was in '85, that's right, Cold Spring Harbor was the next summer..
COOK-DEEGAN: June of '86..
3 GILBERT: That's right, June of '86. Across '85, '86 I guess nothing much happened.
COOK-DEEGAN: You gave a talk at New Hampshire, right..."Genes and Computers", whatever.
GILBERT: Yeah, that probably would have been the summer of '86, and I...I'll have to look at the records. I gave some talks on the theme during the summer of '86, and I'm trying to remember when I talked at a AAAS meeting, whether that was the summer of '86 or '87, it may also have been the summer of '86.
COOK-DEEGAN: I think that was actually the beginning of '87.
GILBERT: That's right, somewhere around that ... autumn.
Across that time also, a little later, I interacted during that '86-'87 period, a bit with a fellow who was then president of the MacDonald Foundation.
COOK-DEEGAN: (Lutenski? Matenski?).
GILBERT: (Matenski?). Actually talked up, at that time trying to maybe setting up some sort of institute at Harvard, ..my interest in the project grew stronger, ..and our discussions in terms of financing that institute, that foundation (MacDonald?) or maybe Hughes doing it, finally led him to a strong interest in sponsoring the NRC group.
I participated in the NRC group, but about half way through that, after several meetings, I became terribly disappointed with how the government program, the national program, was moving, in the sense that I had talked with nobody who was moving with any sort of speed; and I left that, and tried to set up a company to do that privately. The company I almost managed to fund, but the funding for
4 that collapsed entirely at the end of '87 in the crash, I gave up that whole sort of theme for awhile.
My own perception of what happened across that period is that there was an active group separately pursuing the idea in the DOE, and that several meetings were called with DOE, a number of which I went to. My cynical view of what happened is that the DOE was intensely enthusiastic about it when they thought it was going to cost 3 billion dollars, but they cooled off tremendously when they were sort of offered figures of 300 million dollars. They then got enthusiastic again later when they thought, again they sort of scaled the figure up. The NRC figure of 3 billion dollars again I didn't have anything to do with, that's a figure probably again conditioned in everybody's thinking by that original figure of, "it's 3 billion dollars at the current price, can we run a program which may cost roughly that, but will finally lead to doing the sequencing at some other price". That's some summary of the history as I see it.
COOK-DEEGAN: There are a couple of things, just focus on, your role was distinctive in several respects, one was I think you were the person who brought the idea of the genome project from Santa Cruz into kind of the mainstream of molecular biology. The other was, you seemed also to take a burden of public..
GILBERT: I appeared as a public spokesman a number of times yearly, I wrote an article on it which I think was influential, which was in that national, now defunct I think, National Academy magazine. And I've taken a certain public burden in just giving talks around the country on this general theme, in being a cheerleader for this project, starting both at that AAAS meeting, and then in fact a series of talks around the country on the general theme of the human genome project, actually both here and in Europe.
COOK-DEEGAN: Could I ask your assessment of the costs and benefits of that?
5 GILBERT: Of the project, or of my giving talks about it?
COOK-DEEGAN: Of your giving talks about it.
GILBERT: Well, I don't think I did the project any harm, I'm not sure I have a cost-benefit analysis.
COOK-DEEGAN: No, I'm not asking you to assess your impact on the project, I'm interested in what, one of the things I'm interested in .. is the degree to which that plays in the scientific .. there's a schizophrenia in science in my own view, there can be, about, there is clearly a need for public support of science, it's kind of on the federal government, on the other hand there's a reluctance to play the role we play, we can be penalized for taking such a high profile on an issue, we can be accused of grandstanding, etc.
GILBERT: Well, I was a little safer from that when I wasn't actually doing a project. See, actually I was quite safe from that for a long time because I was outside the genome project thing and now that I've actually gotten involved in doing a project, it's a touchier, it is a touchier issue, because now what I say is far more self-serving, before it was purely objective, I had no particular interest.
On the other hand I am a rather high profile person in science and I've taken positions before against the general view of the community, some of these I've won on, so I don't regard it as a sort of serious issue that way. And, there's some other things on which I have positions that are much more against the establishment view than let's say, the genome.
The genome .. when I first took a position on it, it was more against the establishment view, it was against this sort of thing, at that time we were at the Cold Spring Harbor meeting. A chunk of the establishment actually have swung
6 over to entirely to my view, and in fact all the establishment swung over by the outcome on the NRC committee. Once I had left it as a polarizing force, which everybody was then sort of arguing against me, once I had left everybody came over to sort of that viewpoint .. almost unanimously, even the staunchest opponents.
There was a discussion in I guess the New Mexico meetings, about a question of how do you mobilize public opinion, and sort of arguments, and some input from people from outside the community in terms that you do need to have a general view of public opinion and then a general mobilization. And there is a sense in which, from the public viewpoint, I've always thought the genome project was in fact a very persuasive one, easily understood, easily comprehended, benefits easily comprehended, nature of the problem very easy for anybody to understand, impossible not to do from that side -
I often found myself, it was very amusing, there was a meeting after the NIH got some money, for the genome project, they had had a meeting to say "how are we going to spend this money", and that meeting included a discussion about, "well maybe we shouldn't call it human genome, because that's too popular, we should call it something like model systems in development or some other phrase", totally wrong I think, in fact they should be playing to congress, explicitly responding to very general interests.
The scientific community has - there's another element in this, in which I am at odds with pieces of the community, but that's based on my different experience having gone in and out of industry. A great chunk of the molecular biology community still sort of prides itself on an ivory tower position, it was very very strong in, let's say, the early 70's. The biotechnology industry had to grow out of people who broke away from that, and so it was said, "well damn it all, the ivory tower is all very well, but if you do something for humanity, can actually doing something that's relevant, you've got a duty, practically a duty
7 to demonstrate that it can be done. And, those of us who got involved in biotechnology actually had deliberately made a decision, by the time I got involved in BioGen in 1978, and the whole group who got involved in BioGen, essentially each of us as an individual at that moment, had to decide "we will get involved, we'll get out hands dirty in a sense, in the practical world, because it behooves us to demonstrate that this technology is useful.
Well you have a lot of that still floating around, you have the (Jim's?) comment about the drosophila group, they're above this, they're pure, they don't want to do anything practical, all the model systems are still there saying "we're studying model systems, we're studying drosophila because ..." and they lose track of why they're studying it. We're studying drosophila because it's the best system for studying development, but they've lost track of why are they studying development, they're studying development in drosophila because we cannot study development in human beings, but what we're interested in is the development of all animals, specifically the human being because that's the one we're most interested in; that's actually the underlying motivation for doing most of biology.
That motivation of course is strongly what the human genome, human project's about, and that's the motivation behind the project that I recognized from the beginning, and one of the reasons I've argued for it. Occasionally I'll argue specifically, generally not publicly in these terms, but realize that one of the reasons for having the sequence is that it focusses the science on the human model, and makes the human a model for what you do, and centers your discussion finally on human development, in a way that feeds into the applied research and the pharmaceutical and the medical side, but in a way which I don't think harms the basic biology but simply reflects a transition that I think is going to happen in the basic biology over this next period, as the methods become so powerful that one can essentially look at the human model as part of the vertebrate, and see aspects of vertebrate development because they apply to the
8 human, or see aspects of invertebrate development and reflect them up to the human. And that's happening very rapidly now, it wasn't happening in 1985, but it was sort of visible, the first glimmers of that were visible at that time.
COOK-DEEGAN: Going back to 1985 again, what was it - you said you came in sceptical and then you went away enthusiastic, what was it specifically that caused that transition?
GILBERT: It was thinking seriously about how efficient the sequencing was, and what the intrinsic cost was, which was a sort of dollar-based figure. Realizing the power of the production setup; realizing that the problem was a pure production problem, and realizing that the cost of mapping technology, essentially as (Learop?) was trying to advance it, I concluded was powerful enough that we could have positive maps of the human being with a perfectly finite amount of work, a few years work for 20 or 30 people, and that then one could reduce the sequence.
And I distinguished in my own mind something which is not fully distinguished in the population at all, and is part of the confusion today about what the human project means. Because I essentially realized very early that the problem of reducing the genome sequence was an exercise in applied science or engineering, it was a production problem that reduced an information resource. The problem of understanding the sequence is a far more difficult one, but was essentially equivalent to the the problem of developmental biology, and so that whole formulation of the sequence as a tool for that, I've been saying since 1985.
I have a certain number of adherents, people who realize that that's what's happening, everybody who gets close to the problem in a certain way realizes if you should bake the sequence, if you just do it as a production problem and then you should understand it, but a lot of the project is terribly confused, in the question of how do you understand the sequence, and you must understand it before
9 you get it, because otherwise it's meaningless. And you can hear that discussion going on in this meeting, it's been going on for several days. It's going on just now with Jim (? ) because (Serning?) is saying "if you can't understand it, what's going on?" Whereas there's no reason to understand it at day one because it's a permanent resource, and he knows it's a permanent resource, but he's still so caught up in the "I've gotta give them the answers right off the bat".
There's a danger in the human genome project that it gets sold to Congress, as not only the sequence, but the complete understanding of the sequence. I always try to talk about it, I didn't here because I didn't give the full talk, I gave a little talk to the pharmaceutical companies forum, but if I generally give a talk on the human genome I always start off with this theme of the genome sequence as a tool, and you will understand it in the next hundred years of research. And I was saying that in essentially the same words since 1986, and it still strikes everybody as a surprise when I say it, so it's (?).
COOK-DEEGAN: One other contribution you made was to the rhetoric of the genome project, and that was the holy grail..
GILBERT: The grail image..
COOK-DEEGAN: Where did that come from, how seriously did you mean that?
GILBERT: Well I meant it in an offhand way when I said it, I can't remember, I may have said it at Cold Spring Harbor, I don't remember where I said it. Of course I said it with an offhand allusion, the holy grail in that offhand form was something that somebody sought, it was just the object of a search. And the .. even using that image at all even unconsciously reflects probably my attitude toward the meaning of DNA sequence, which does reflect in fact my attitude toward doing biology or molecular biology, in that, in getting attracted to molecular biology, what I was most attracted to is this notion that genes determine things,
10 that genetic structure is determinate, and what we do is look at the DNA to ask, "how does it function, how is it controlled"; and the epitome of that is finally that you then can look at the sequence, which is the ultimate statement about the DNA structure. In that particular structural view we can talk about (admixture?) structure of genetics, there is an ultimate structure, it is the DNA sequence, there is nothing as I say, more primitive, more basic to the organism. Everything else in the organism is essentially, that which is dictated by .. biology is dictated by that structure, either the organism or its appearance, or somewhere.
From that viewpoint the challenge of "can you work out the DNA structure of an entire organism", has an alternate character. Jim summarized this in one of the meetings by saying "it's a monumental theme, it is a once and for all, you work out the human genome, you have made a statement about the nature of humanity that essentially stands forever. There is nothing more that you can say in that particular direction, of the variation across the species, which is significant, but in the case of humanity it's only a tenth of a percent of the variation of what's there in the sequence, so that you've made a 99.9% statement by having done that, even counting all the (polymorphis?).
Someone had asked me about the grail image, and I immediately remembered a little more about the grail image, which is that the point about that search in the Arthurian legends, is that it was to revitalize the country. Again talking about a superficial view of the Arthurian legend, but the search for the grail was the search for something that would make the gardens blooom again, this sort of thought. That's a very pleasing image, in terms of the role of the human genome sequence, in terms of what you do with it as a tool in biology, and it's something that you use to create a efflurescence of knowledge in biology, and that plays again to this notion that it's a tool, and that it's akin to the accelerators in physics which are tools in which you do research.
11 To the extent to which I know more about the Arthurian legend now, having recently read the grail saga, the grail is an object of Christian mysticism, a highly mystical object, and represented the search for essentially union with God, and it was a search which only the most perfect and purest heart could finally succeed in. And in succeeding in the search (one that debt?) because that was the nature of the cumulation of experience represented by the grail, so it's not necessarily from that viewpoint a good image if we go too deeply into it.
COOK-DEEGAN: Well of all those things which you did in connection with the genome project, what would you characterize as your most significant role? How do you think you fit in to all this?
GILBERT: Well I think I fit in very significantly as an enthusiast from outside, for a long time, and therefore essentially as a Nobel Prize winner speaking out as a sort of, one of the ones to polarize opinion, (Del Beco?) also played a strong role just in this form, just by speaking out in an article in Science, and actually had I written more I would have had a more effective role, to have provided a more sort of popular thing, to have probably the role that I should have played, had I been smarter about influencing the course of events.
In some ways by not being part of the project, and by being such an extreme proponent of, let's say, the commercialization of the project, I provided I think actually a useful polarization, a useful "bogey man" out there, you know, "better get the government project going, because maybe Gilbert will do it out there", I'm coming in a little bit from the cold but as you can see from this meeting, maybe I'm still sort of dancing around as a danger on the side. I'll be very interested in seeing how the project goes, because now I am involved in doing a sequencing project, and we'll see how successful that is, both on the line in the sense of "can I do the project as effectively as I've promised", even more on the line, in the sense of "can I do the project as effectively as I think I should
12 be able to do it", but that's my goals rather than the (?) obvious goals, and we'll see what happens.
COOK-DEEGAN: What's your sense about whether the genome projects will succeed or not, first of all what would be the criteria that you would (talk?) about when you decide whether (it's?) capable or not?
GILBERT: First of all, I think it certainly will succeed; I do think, I think in certain ways, the genome project, in the sense of knowing the genetic makeup of humanity and of life forms on earth, is inevitable as the science moves forward, and the issue is really one of timing. Is it going to be 50 years from now, or is it going to be 10 years from now, or 5 years from now. The genome project is actually as I always have seen it, the attitude is worth accelerating that time forward, because it is so useful to have that information, that rather than wait until you have a PhD thesis doing the human genome, you should actually do it now when it's a lot more work, and a lot more effort.
I think that view is gradually winning around the world, you can actually see it, you can see it move in Europe, you can see it gradually move in Japan. It moves because individuals like (Del Beco?) and myself influence areas; it moves because people realize that .. popular minds realize that this is a good thing, politicians realize it's a good thing; it is a persuasive idea. And in fact the (nadir?) you shouldn't have this knowledge is a very tricky conflict, because it's part of that deep conflict between the know-nothings and the knowledge- makers, and that conflict is actually what is also being fought out around the world, and is probably the major threat to the human genome project, but it's a major threat to biology and technology in general, and actually I regard it as a very serious threat in Europe.
I was very pleased on my my last trip to Europe to discover the EEC is actually now sponsoring genome projects, the vast move quite forward in the last year from
13 looked like total stasis to now considerable setting of the projects across Europe. The French are organizing a genome project, the British have been involved in one. I expect it to move. By now I have become hardened to the view that it will take a long time, that it's slower than I thought, in terms of the world moving in that direction, or the governments moving in that direction. The arguments against it, the sort of Bernie Davis, last week, Bernie Davis and these others, I do think are exactly like the arguments that were had in '85 and '86, they come from exactly the same sources of "maybe my money is being taken away", and I don't think it'll be persuasive, they don't answer the question for Congress, they're very damaging in terms of Congress; except that I think that .. I think actually there's one level which I think Congress will laugh them out of court because Congress knows there's more money in the NIH, and it knows there's more money going into the system.
*** END OF INTERVIEW ON TAPE SIDE A. *** THE LAST 1/3 OF TAPE SIDE A IS UNUSED. *** INTERVIEW RESUMES ON SIDE 2, WITH THE FIRST 1/3 OF SIDE 2 UNUSED.
*** INTERVIEW RESUMES
COOK-DEEGAN: If you were looking back over this 5-year history of the genesis of the genome project, what would be your major chapter, what would you think is the most significant thing in getting the genome project launched? Actually, before you answer that..
GILBERT: Yeah, I don't know ..
COOK-DEEGAN: Let me ask, maybe I should give you a running jump at that, and maybe it'll come to the surface then. One thing that I'm puzzled about, although
14 maybe it's not so puzzled, but, just to get your views on it, why 1985 to 1990, why not a decade earlier or a decade later, what was it in that period that Bill (Deco?), Phil (BC?), Sinsheimer more or less independently..
GILBERT: That's right, there are a number of themes that must have been independent. Well, back in that period, right I think early in '85, right after that meeting there was in fact even a New York Times editorial with a line about "how about sequencing the human genome?". I think it was actually in that period, it almost had to come out of something else in the round of conversation. I think in some ways it's the growth of the sequencing technology.
You see, such things were unimaginable before 1975. By '75, we have the fast sequencing methods, but you're just beginning to do genes. The actual amount of DNA in the databases doesn't begin to be appreciable until again the middle 80's. It's like the figure I just .. it's 60% growth a year, with 25 megabases of sequence this year, '85 at 2 and a half megabases, '80 there were 20 or 50 kilobases of sequence put in the database. At that level of sequencing it's unimaginable to talk in terms of millions of bases. It isn't until the world has moved a level of magnitude up, that suddenly people begin to think that maybe something different is even possible.
Again, across this period, I was going to make another comment about this sort of objection to the genome project; across this whole period, from 1980, molecular biology was still a separate part of science, a third part of biology, it was not fused with the rest of biology. It represented a group of people with a separate discipline, working with molecules of DNA in sequences, but the ground-level biology followed its own rules, "drosophila genetics" sort of followed its own rules, evolution followed its own rules, ecology its own, everything was separate. By '85, the molecular biology had begun to penetrate throughout developmental biology and medicine. And that penetration, the first wave of that penetration was already complete by 1985, so '85, the ideas that the
15 Hughes foundation, saying "what should medical research do", we'll take as an example, it should clone genes. Then (Brown and Goldstein?) are the examples of what ideal medical research should be. Genes should be looked for..
By now, of course, the fact that genes are being found, genes that disease the population are being found with frequency, has penetrated everywhere. '85 was just the first beginnings of this, but enough so groups .. there had already been a transition in the medical community. Across the late 80's, the DNA science essentially penetrated all of biology, so that not only does all development look at DNA, evolution looks at DNA sequences, ecology looks at DNA sequences. You would ask what bacteria grow in the ocean, you look at DNA sequences; you want to ask whether lipids on the coast move up and down, you look at DNA sequences; you want to ask who's the rapist, you look at DNA sequences. DNA sequences have become, are said to be the underpinnings of all of biology. I think actually of course, as I generally say when I talk about this now, that we're in the last throes of molecular biology existing as a field of science, as opposed to a service technology. And that I expect everything, DNA sequencing, cloning, all of this to move out of the laboratories. I don't know if you've heard me give this talk, if I talk these days to generally any group of scientists on the genome, genome theme, I would make that argument. And, that argument is actually the argument that if you're not careful, your rice bowl's about to be broken. If you think that you're out there honing and sequencing genes, that that's what the meaning of your science is, when you do biology today, then you are wrong, that is not the meaning of your science, and it's about to disappear, completely as science. So if you train the graduate students to do molecular biology, and you train them to follow instructions in the (Maneaus?) cookbook, they won't have a job 3 years from now, because that's not science, and they really should learn to do something else besides just follow the cookbook.
This is actually very effective when I use this, when I talk this way, and it
16 does shake people up in the audience, and in fact if I talk at Syracuse, or I talk to place all over the country, it has the result of people listening to it, stopping to think "well what am I teaching my students, what is really going on" and this sort of thing.
In part, what needs to happen in biology will happen both quickly and slowly, it'll happen quickly in the sense that some of the technology will move, at the major research institutes, into services. It needs to happen quickly in the sense of this much higher networking computer connections, and yet that's still moving very slowly for the general population, although some people are sort of running very fast and up to date.
COOK-DEEGAN: One other thing I think would be very helpful, is sort of tracing the development of your views on the role of the government, in science in general but using the genome project in particular.
GILBERT: Oh.. well see my role of the government in science in general: until I got involved in private industry, I would have thought of government as probably the sole support of science. And, when I got involved in industry, some of my attitudes changed a little bit, in terms of where I saw some of the power of the capitalist system. But my attitude still is, that the only sensible long- range support of science is the governmental support. And, that, in fact, that's why we need the governmental support of science, is to support the long-range changes; if I were to talk about that, when I do talk about that I'd use an example where the government support of science essentially creates the industries of 20 years from now, or 50 years from now, and that that's why we do it. If you want a direct return to society by doing that support, it's in fact exactly in that long-range economic shift, rather than in the short-range industries of this next year, or the industries of last year.
The.. My view of even why, to what extent let's say Congress thinks of that
17 government support of science as a direct support of industry, rather than a support of knowledge, has certainly shifted, and my whole experience with Congress on the human genome project has made me much more aware that I think they are likely to look for short-range rewards in industry, technology transfer and that, out of the science they do, rather than the long-range connection. A problem that one simply has to work with.
COOK-DEEGAN: One of the places where government support in that regard in the domestic context, those values of science as knowledge, and as a return on something you're investing in as a nation, they don't usually come in conflict. They do come into conflict in the international context. And..
GILBERT: Yes, they come into conflict specifically with Congress, the international conflict, in the international arena, and that's again a "are you supporting American know-how as opposed to foreign". The .. We have very, I suppose, in fact our government has very confused and mixed views of whether we should have tariff barriers or whether we shouldn't, does one believe in really free trade or is that working against us, should one try to block imports and the import (sparing alloy? Jay and Jacobs?), or should one be free trade and let everything go around the world, the devil (take get it?), the (hindmost?) open capitalism? In some ways, I'm probably more partial with (Jay and Jacobs?) tariff barriers, including you should actually try to build your stuff at home.
I'm much more free trade as a scientist, I view the scientific effort as a sort of worldwide intellectual endeavor, but in some ways I view the free-trade extreme view of capitalism as a overstatement.
Congress simply.. I remember the first time Congress came close to actually supporting a human genome project, over the objections of NIH at that time. That bill actually had a sort of lean to make sure that it was used solely for american industry statement.
18 There is a problem with the sequencing of the human genome project, and that has been coupled with this element of when people could see the advantages of the mapping; they couldn't see the advantages of the sequencing. And Fred Blackner, I think single-handedly, dealt the human genome project a tremendous body blow, in the early days, by writing a letter to Nature, suggesting that the way to do the project was to do random sequencing on the human genome in every laboratory in the world. And that was so insanely foolish that it both gave sequencing a bad name, convinced everybody that the theme of the genome project was that they should sequence, it was a foolish effort to rip the government off for money, in such a transparent and explicit way that there was no way in which it would ever work. And it did a lot of damage.
And in fact we're still fighting our way out from that sort of view, that the smart thing to do was random shotgun sequencing of the whole thing for 30 years, and then get some information off the end, which actually ignores the whole power of DNA sequencing, which is that it is in fact a linear method, you can start at one end of a piece of DNA and go to the other. And the power of that sequencing from the very beginning, in the hands of the people who wanted to exploit that power, was always that, unlike protein sequencing, it was a rational, linear approach. And you could always start at one end of the gene and go to the other, and stop anywhere you wanted, and have the information just that you wanted, you didn't have to give up and do everything randomly and hope for the best.
COOK-DEEGAN: I wanted to play out this industrial theme, I didn't state my question to elicit what I wanted; I'm curious about in your day-to-day conduct of research, you had the opportunity to be a university professor in the 1960's and 1970's context, and then at BioGen, and then back in the university setting doing (R01?) research again; to what extent do you think that the structure of science is changing, in connection to the demands that are being placed on it, the changed expectations from policy makers.
19 GILBERT: Oh, I don't think it is, in general; I don't think the structure of science has changed particularly. I do worry that the scientists' confusion over what a project like the human genome project is about, may damage the structure of science. I think the policy makers are actually quite reasonably clear as to the difference between (R01?) basic research and building accelerators, building a space station, this sort of thing. It's the scientists which are confused about the differences between an applied project, short-term specific goals, so well-defined goals that you can specify the steps and know that they're going to happen, you can order the breakthroughs, and a basic project in which you can't order them, because in fact what's needed are really breakthroughs, not just slight changes in technology. Policymakers are perfectly aware of that difference.
So, the scientists that get confused about that difference, those who haven't thought about the difference between applied research and basic research, getting involved in industry made me very conscious of that difference. What I do at the university is basic research, what you did in the companies are applied research, you simply knew the set of goals, the problem was to actually work to those goals, and I began to do applied research in certain directions, in the insulin problem, and in the problem expressing genes in proteins and bacteria, knowing that it's applied research. And that research in the late 70's, it's that research that finally became the companies. I went back to the university, a great chunk of the research I do there is basic research, in evolution of the themes, not applied. Structured actually as basic research has always been structured, funded on grants as basic research has been funded on grants, the only problem that I see is a.. in certain ways because of the shift in funding, the tightness of money, the community gets confused as to how it should review grants from basic research and things published like that. We could talk about that, but it's.. the problem's there. But those problems I think always arise.
20 The human genome project is an applied project to the extent.. that's why I disagree with Jim, fundamentally, see; I would have preferred to see the project actually done with DOE as an applied project, outside the NIH, no connection; we do basic research here, you can do applied research, use different forms, not get confused on .. that it's equivalence to basic research. Putting it in the NIH, philosophically to try to make it equivalent to the basic research we do.. Some of that's useful, the technology development is basic research, but most of the project, from the bulk of the mapping to the bulk of the sequencing, is going to be applied research, that's going to require dedicated groups doing it on somewhat different rules.
The groups giving out the money begin to perceive this, but haven't yet perceived the structures that the government's put into place, don't clearly perceive these, and that's been one of the reasons that there's been such confusion about what's been going on for the last several years, and there'll continue to be confusion, in part because there's a deliberate effort to.. actually there's not a deliberate effort to produce confusion but there's enough confusion in people's thinking..
COOK-DEEGAN: Thinking about the project that you're proposing though, for example, just taking the (capracovin? caprapolin?) project, you could sell that project as a basic project..
GILBERT: Well I actually did, I phrased the grant in both forms. I had to, by the nature of the way it was going to get reviewed; except that, you see, there is a.. the grant itself doesn't support the basic research side of the (capracovin?) project, except insofar as it supports some of the computational research and database, that is actually basic research that will feed into that. The grant supports basic research in the development side, although it's hard to even call it basic research, because it's very closely tied to production development. And, I shouldn't actually call it basic research, it's actually
21 applied research. There are only two basic research themes in that grant, as I look at basic research themes, and they're both identified as things that could be done by graduate students. One was actually analyzing the genes of (capracovin?) by experimentation, and the other was working with database, as part of computational science experimentation, and those were in that grant actually factored out as graduate student themes, and everything else was sort of described as applied research, much more focused.
COOK-DEEGAN: One other basic research question that falls out of that approach though, is almost a prototype of going into an organism knowing almost nothing other than the sequence, you don't have the genetics, you don't have the sets of tools with the same richness that you have in other organisms, and essentially saying that we can reconstruct the biology of an organism starting from sequence, and that we can do it better that way; that's kind of a fundamental question..
GILBERT: That is a basic research theme, but it's actually not fully addressed in that grant; that grant doesn't have resources to solve that problem, it has a little resources to work a bit on it. It's.. I do regard that as the interesting basic research theme that comes out of this. And in fact in doing this, ..in the laboratory adjacent to my own, it might appear to be what the future holds, let's see from my own laboratory, where I will find, a year downstream that in fact I've taken five graduate students into the basic research side of this.
..It's most likely actually, I'll talk to new graduate students about this project in the sense of what's going to (fare a lot?) and I think we'll do it fast enough so that a year from now there'll be graduate students flying down to.. trying to work on exactly that theme: "how do you understand the organism".. both in the computational sense, and in the experimental sense, "can you go in, change the genes to order, if you have a novel gene can you dock it out, can you over-express (?) it, what do you do to it", all that sort of thing.
22 I think actually that'll go very fast and be quite fascinating. So, it's..
I'm very pleased with the idea of doing a micro, really micro, microorganism and being able to get past these things. I think this..
Well I think this is a problem throughout the genome project, we're seeing in fact in this discussion with Craig. Craig gets involved sequencing a (conscript?). If he were actually thinking clearly about his role in the sequencing laboratory, he would be sequencing another conscript for that group, but instead he wants to say "no, I've got to find out what that does, I've got to now stop the sequencing, and expand and try to solve the (Huntington's?) problem, driving his collaborators wild of course, rightly so, they should be furious, they are disgusted with him, cutting himself off from doing the rest of that, that's the sort of macho science, "I'm going to do my part, the hell with anybody else, and if you collaborate with me I'll slap your hands" sort of thing.
COOK-DEEGAN: Can you think of anything else that I should have asked you but I didn't?
GILBERT: No, yeah, you didn't ask me what I thought the most important themes were in going the human genome and I'm not sure what they.. I don't know that, think I know what the real.. what the real influences were, I mean it's a .. I mean I was at a number of meetings, and although a number of meetings went against me, (Bob Hurst? Barber?) sort of pushing that meeting that the Hughes group called, sort of over that way. Things could have gone faster in that sense, than they..
There were some amusing meetings, there was that meeting of the National Academy out at Woods Hole, I try and remember who finally said to me, "I hate it, but it's going to be so exciting I want to be a part of it!" And so you have this
23 sort of tension in all of it, in the sense that, I think that the moment that..
I think what's really needed for the project, is that transition to sequencing as a service. I think that'll happen within a few years, and once it happens it's going to change everybody's relationship to sequencing, in what I think will be a very healthy way. Because there's this tension, of "sequencing is boring, I don't want, why am I doing this?" When of course everyone knows you don't want to be doing that, you want the answer. But throughout science, you actually have to have a.. great ability to withstand the boring, everyday routine of experiment, you've got to be able to take joy in the colorimetric reaction, spinning the DNA (alnay? RNA?) on a glass rod, or all of just the brute acts of doing the experimentation. If you can't enjoy those, it gets very frustrating. And there is almost too much of this, "gee, actually doing the experiment is boring", which is this sort of mandarin impulse in science, and it's a very bad one.
COOK-DEEGAN: Just to defend that view for a second: if this were 1961, and we're just making the transition from physics into molecular biology in 1990, 30 years later; if you were a young person, if you chose the genome project as being your field, what would you, you wouldn't want to do DNA sequencing as a service, would you?
GILBERT: The.. if I, were coming into the genome project as a graduate student today: for the next couple of years, for example, in the genome project, there's going to be a fascination in making the first complete (yak? YAK?) maps. (I?) already have a graduate student at work on maps for zebra fish. In fact it's decided that it's probably going to be enough fun for a graduate student, right now it's going to be a lot of work, but the result comes out I think sufficiently rapidly that the (YAK?) map of the mouse, the (YAK?) map of the zebra fish will probably be single theses, as done around Cambridge, Harvard and MIT.
24 Immediately after that, making a (YAK?) map is going to be so dull that nobody will want to do it again. Actually, see, let me give you that parallel: in 1935, Nancy (Mazell's?) thesis was the first 50 bases of lactose messenger. By 1976, Phil (Farboe's?) thesis was the complete sequence of the repressor gene. In 1977, (Greg? Sutcliff?'s) thesis was the complete sequence of (PBR-322?). That was the last DNA sequence thesis we did, nothing, I did a few genes, as theses, (trans-s.. s.. somrase?, irvade kinase?), and that was it. And even the group that did, first we did (trans-s.. s.. somrase?) not only had to go float a novel gene, find the CDNA, sequence the CDNA, find the (genomoclone?), sequence the (genomoclone?), express the gene in e. coli, modify the protein, (the chedio??), get a (?) experiment changing the enzymatic activity, that could be considered a thesis. So, the science changes very rapidly.
And just sequencing a novel CDNA, I don't consider, even if you have to invent the sequencing method, it's not something I have to do, what I'd have somebody do as a thesis in my laboratory. Devising novel sequencing techniques I don't think is particularly a thesis for a young person wanting to get involved in the genome project. On the other hand, the computer analysis, I think that's a field which is going to expand fantastically, ideal thing for somebody to get involved in, with enough feeling for experiment to make it meaningful. The interplay between computer and experiment in understanding the organism, all these are things which one could get involved in.
.. There a sort of comment I'm making is one that I've noticed, picked up from Eric (Landire?). As (Eric?) sort of formulates what they learned in setting up the MIT center, is that they assumed that none of the bright people would want to do this, and they worried in setting up the center, and then they realized in setting up the center, that both.. with a little cleverness, the first projects are intensely interesting, and they are great fun to do; and that's why the next mapping stage will go like a boom.
25 The group that I have actually doing the sequencing lab, my attitude on that has actually changed, because I think that lab is going to change its technology so rapidly in the course of a few years that it's going to be fascinating for anybody to be associated with. I can't quite see ways of factoring it into graduate student problems, but just in terms of experience, it'd sort of be an experience of a lifetime for these guys, because it's just going to go from sort of impossibility to multi-megabase home organism sequencing in the course of a blink of an eye.
The problem is always, coming out into a field as a graduate student, how do you find a field which is.. how do you get out to the front of a field, far enough in front so that you can do something that's novel, and yet do something in only a few years, it's always a difficult problem, and it's.. And as I said, most of my graduate students are doing different things than this. I (must?) solve that problem for this. I don't think the genome project itself is particularly good for graduate students, at (Harvard?), except in so far as that next cycle of information that's rolling. So, .. you've got down your list?
COOK-DEEGAN: You've certainly covered everything in here, plus some, so.. well thank you.
GILBERT: I hope this worked, I had a fine time talking...
*** END OF INTERVIEW. END OF TAPE SIDE B.
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