00:00:00 The symposium will begin at 1 p.m. Eastern Standard Time, and will conclude at 2 p.m. Eastern Standard Time.

00:00:30 Our plan for the afternoon is really straightforward, and that is to try to make

00:00:59 sense of a number of the issues that were raised this morning, and do it by taking questions

00:01:06 which you raised in this array of papers that were handed in as a way into the question.

00:01:13 In some cases, I'll direct a question initially to one or another of the panelists, but I

00:01:18 will invite all of them to come in at any point. I would love to see the variety of

00:01:25 interpretations where there is variety, or a consensus where there's a consensus on

00:01:29 critical issues. I'll move across the range from maybe back and forth between things which

00:01:35 may be considered more technical to those which may be considered more social, which

00:01:42 may have to do with industrial development, but try to deal with the richness of the issues

00:01:49 that came out of the discussion this morning. One of the first I want to turn to is a question

00:01:56 submitted by an old friend and colleague in the history of science, and I won't read

00:02:00 off the names in all cases, but he went right to the point that is obvious as you look at

00:02:07 this group, and that is to ask the extent to which biotechnology is exclusively an

00:02:15 American story, as this commentator says, looking at the panel. Well, that is the question

00:02:20 of choice of panelists who could get here, but there's more than that, and that is the

00:02:24 extent to which there were patterns in the development of science in the United States

00:02:29 in the post-World War II period which seemed to strengthen the American role. We'd begun

00:02:38 discussion of this last night informally around the supper table, and I'd love to move into

00:02:43 that first, and then I'm going to have a couple of hooks on it. After the general American

00:02:47 story is, what about California? And I don't mean the general California phenomenon, but

00:02:56 links to phenomena like Silicon Valley, which several of you mentioned, the role of place.

00:03:02 Do you get a convergence in place that makes a difference? I know, for example, that the

00:03:09 first conference I ever ran as editor of the Journal of the History of Biology, when someone

00:03:13 gave me a small amount of money to bring together both working scientists and historians, where

00:03:19 did I head? The conference site at Asilomar. I'd never seen it, but I'd heard about it,

00:03:25 and this was before the recombinant DNA discussions, but it had a lure. So I want to ask then,

00:03:33 and let me turn first, if I can, Paul, to you, because you and I were discussing it

00:03:37 last night, and perhaps to George, who was also in our last discussion. To what extent

00:03:42 is the emergence of biotechnology largely an American phenomenon? And if it is, what

00:03:50 were the characteristics that you say, see as being important? Paul?

00:03:55 Well, I think if you dissociate different parts of the origin of biotechnology, you

00:04:01 talk about the scientific base. I don't think it had a specific locale in California. I

00:04:07 think it was an international effort, and as I told you last night, I took great delight

00:04:13 in pointing out to President Mitterrand at one occasion that, in fact, a large number

00:04:18 of the American scientists who played a major role in development of biotechnology were,

00:04:23 in fact, trained at the Pasteur Institute. And, in fact, they, in turn, trained the next

00:04:29 generation of people. So the Pasteur Institute in Paris and the MRC in Cambridge were major

00:04:36 players in the development of the technology and the ideas. The adoption of that technology

00:04:43 or its implementation into the industry, I think, clearly is more of an American phenomenon.

00:04:50 And even to this day, 20 years later, the amount of biotechnology companies in France

00:05:00 or England are infinitesimally small compared to what's happened in the U.S. And Japan,

00:05:09 which has certainly also been a major player in molecular biology, also has very little

00:05:15 in the way of biotechnology. So we have to ask, what are the characteristics of the American

00:05:22 entrepreneurial system, if you will, which promoted it in this country? And I think that

00:05:30 the fact that Silicon Valley already had been established as a center of innovation and

00:05:36 venture capital and the whole idea of risk and starting new companies, particularly in

00:05:41 the computer and electronics areas, I think made starting biotech companies easier there

00:05:48 than anywhere else. And, in fact, I know from experience that the venture capitalists were

00:05:54 on the prowl. They were constantly prowling the corridors of the university looking for

00:06:00 ideas and tempting people to form companies. And Bob Swanson, I think, Herb's recounting

00:06:09 of Bob Swanson coming to him and saying, let's start a company. Now, where did Bob Swanson

00:06:14 come from? He was in the venture capital business. And so he immediately was looking for entrepreneurial

00:06:18 opportunities. But just as an aside, on a trip to Japan some years ago, I was asked

00:06:28 to meet with a large group of business people on the southern island of Kyushu and wanted

00:06:33 to know, how is it that California became the center of development of biotechnology

00:06:39 in this country, and what was necessary? And so I began to paint a picture that the funding

00:06:46 of biotechnology was an enormous risk. And, in fact, it was akin to gambling, is that

00:06:52 venture capital people essentially accumulated other people's money and then bet on certain

00:06:58 kinds of opportunities. And they know they're going to lose on most of them. And as George

00:07:02 pointed out, if they hit on one out of ten, they've done gangbusters. So the question

00:07:09 is, the rejoinder from the Japanese was, but what you describe is illegal in Japan. In

00:07:18 other words, somebody taking other people's money for investment purposes without promising

00:07:25 them specific returns or dividends or interest, but in fact putting it at risk at the chance

00:07:31 that they will lose it, is just unacceptable. And I think to the extent that I've talked

00:07:37 to people in Europe, that same issue still pervades the financial markets in Europe,

00:07:47 is putting money at risk without getting some opportunities to call on it or recover it,

00:07:53 is something that is largely unacceptable. The second thing is that investors in Europe,

00:07:58 I am told, expect to be able to cash in at any time they want. They want to be able to

00:08:04 get at their funding. And you know investments in biotechnology companies are not going to

00:08:09 bring that kind of an opportunity. You're putting your money out there for long term

00:08:14 with the likelihood that you're not going to get it back until maybe five or ten years.

00:08:18 And again, the capital markets, as I understand it in Europe, don't accept that format. So

00:08:26 we've acquired a culture. It has been probably more accentuated in California than it was

00:08:32 in Boston. But the area around Boston and Cambridge has certainly developed. And now

00:08:37 the East Coast certainly has an enormous number of biotech companies. But as I understand

00:08:44 it, I think two-thirds of the American biotechnology companies are centered, in fact, in California,

00:08:48 largely in the Bay Area.

00:08:49 George, do you want to add something?

00:08:51 Well, Paul's stated it very well. I think a couple of points. The first is I think what

00:08:56 is exclusively American, though it wasn't for science, although it was performed extremely

00:09:00 well and was very broad-based here. But what is exclusively American is the idea that the

00:09:05 vehicle for doing great things with biotechnology is the small biotech company. And that was

00:09:11 not a given. As I pointed out, the small biotech company had to do a lot of things that were

00:09:15 already in existence in larger companies. So it's not surprising that what I think happened

00:09:20 in Japan, for sure, and Europe to a degree, is the expectation would be that one of these

00:09:24 big companies, and they all got interested in biotech. Japan Tobacco was interested in

00:09:29 it. The food companies were interested in it. The beer companies started quite independently.

00:09:33 Then one of them tied in with Amgen and did very well. But they didn't really believe

00:09:37 that a small biotech company would be the vehicle for exploiting biotechnology. And

00:09:42 yet it turned out to be true. So that gave us an exclusive in that we were the country

00:09:46 that had the small biotech companies, and they were multiplying rapidly. And if we then

00:09:52 say that was essential to the success, as it turned out, we have to say that the venture

00:09:56 capital availability was essential to that success. I don't think that despite the fact

00:10:01 that big companies have bought into pharmaceutical companies, I mean to biotech companies, big

00:10:05 pharmaceutical companies, and others, and even oil companies in the early days, the

00:10:10 vehicle that really attracted, that really got many companies started so they could prove

00:10:14 they had an opportunity for public investment was venture capital, many times in conjunction

00:10:19 with big companies. And I think that the venture capital system, the risk capital system in

00:10:23 general, and I extend that all the way over to the public marketplace, where there are

00:10:26 many investors who are willing to take the risk that Paul just said is not willing to

00:10:30 be taken in Japan, and sometimes not in Europe. I think those are the key points. So it's

00:10:34 a, I think it's a, it's a marriage of wonderful science with this wonderful availability of

00:10:38 risk capital.

00:10:39 Great. Bill, did you want to add a word? Just to comment on the science itself. Whereas

00:10:45 I fully agree with Paul that good science was being practiced in Europe and other places

00:10:50 as well, I think we had in the United States a system, an infrastructure, which allowed

00:10:57 explosive development after a finding was made of relevance. The labs, big labs in Europe,

00:11:08 largely, I would say, clearly were up to date in the things that were going on, but the

00:11:14 ability to translate laterally across a large group of individuals was perhaps easier in

00:11:20 the United States than elsewhere. Then just a couple of points to amplify what George

00:11:27 has said. We've mentioned the availability of venture capital, perhaps as an, as a trailing

00:11:37 effect of electrical engineering increases the semiconductor industry, and that was particularly

00:11:45 vibrant in California. But I think the other important component of that is the public

00:11:52 market and NASDAQ. That kind of public market for which you can essentially recover risk

00:12:01 capital, venture capital to reinvest doesn't exist in any of the other countries in Europe,

00:12:09 and especially this doesn't happen just now. They're beginning to establish a small cap

00:12:17 market in the public level. And a couple of weeks ago, I was speaking with Robert Jennyard,

00:12:23 who was one of the key financial investors in Credit Suisse First Boston. I was talking

00:12:33 with those folks, and I was asking him whether he thought there would be a viable public

00:12:38 market in Europe that would be generated for technology-oriented efforts. He said,

00:12:43 not in our lifetime. He still believes that that aspect, which is crucial, is absent from

00:12:50 Europe, and most of the companies want to get on the NASDAQ or some other American exchange,

00:12:55 and as a result, by the drive is toward a relationship with America. Let me fine-tune

00:13:02 this one. Please, Arthur. This is for the sake of history, and that is that biotechnology was

00:13:11 actually more advanced in Japan in the sense, not simply making beer, but when I visited there in

00:13:18 1957, I was astonished at the kilogram quantities of vitamins, amino acids, nucleotides that we had

00:13:28 only available in milligram quantities. And so, the capacity to engineer organisms in the ways

00:13:38 available then was very advanced in Japan. And so, we might add that as a footnote, that that

00:13:45 kind of science and technology was available years, years before here. Well, they didn't

00:13:50 capitalize on it. This is one of those aspects that has come out neatly. The science can be

00:13:58 there, but unless something's done with it. And here, several of you pointed to what looked like

00:14:05 particular characteristics of the American capital markets, American financial system, which allowed

00:14:11 it. Let me push this a little bit further in terms of some fine structure. A couple of people wanted

00:14:16 to know whether a local place, San Francisco, University of California, San Francisco, Stanford,

00:14:24 is there something that you would look at, or is it largely individuals, or was there something

00:14:31 built which allowed these places to excel the way they did? And Herbert, you've crossed both

00:14:38 parts of that line. Well, stimulated by the discussion prior to this, I wanted to introduce

00:14:50 the possibility that there is an additional factor involved here in terms of the science,

00:14:58 and that is a generational difference. And that rather than geography and nationalism,

00:15:05 although what I'm going to say does have a lot of nationalism involved in it, but I was sort of

00:15:12 trained around the time of the big push forward by the Sputnik and the competition between

00:15:20 countries to put us in a position where we started to train large numbers of students in

00:15:26 basic sciences. I came out of that period, and I might say a lot of good talent came out of those

00:15:40 days. But our background was such that we were very much influenced by the academic environment

00:15:50 of all of us, which was to a large extent, for good or bad, very negative towards business,

00:15:58 capitalism, and so on and so forth. So there was, in my generation, a lot of, or at least colleagues

00:16:06 I happen to be associated with, there was a lot of anti-government and anti-business sentiment,

00:16:13 and our views could be, I suppose, described as very liberal. And so when I can remember

00:16:26 around the time of trying to start Genentech, that I was very much concerned with how to recruit

00:16:36 scientists out of academia, because I knew of this sentiment that many of my colleagues had.

00:16:45 But I was quite surprised by the people, the scientists we tried to hire at that time. I

00:16:54 remember being very much impressed by several scientists coming to me and said they would like

00:16:58 to do something like this. They'd like to get into business. They saw it as a very fruitful way

00:17:05 of exercising their education and pursuing their scientific career. And I think that this had a

00:17:16 lot, I think they probably had a little better education in terms of a broader education than

00:17:23 some of us were exposed to. But that, I was very, I just happened to think of this while you were

00:17:28 discussing this issue, that there is a generational difference in the scientists of the period where

00:17:36 I was trained and the ones that are being trained today. A business and industry, biotech industry,

00:17:44 whatever, is a very viable option for many of these people, as opposed to the day when I was

00:17:51 a graduate student when we were very, we looked down our noses at the science being done in the

00:17:57 pharmaceutical industries. So I think there's a difference there. As far as geography is concerned,

00:18:03 I don't, I don't know if one can really paint a valid picture for that. I would like to think

00:18:12 that the Bay Area was very important to the development of technology, not, I think it was

00:18:18 an accident that the biotechnology industry started there. There was certainly a big contribution from

00:18:25 the venture capital atmosphere there, but just the right combination of people came together who

00:18:33 did the work and went ahead with that. But many of the people that we have attracted to Genentech,

00:18:45 I think, and I think probably speak for other companies as well, is that they come to the Bay

00:18:50 Area not just because of the company, but because of the intellectual atmosphere provided by Berkeley

00:18:57 and Stanford and UCSF. So I think that's a big magnet and drawing point for many of these people.

00:19:04 Good, thank you. I think you've hit on a number of nice points. I particularly like the implications

00:19:08 of the generational shift, and we may come back to that in a couple of minutes. I want to give it,

00:19:13 Charlie and then Stanley. Yeah. I want to throw something else into the mix. All of these biotech

00:19:19 companies were university-linked and based in terms of where the knowledge was coming from, and

00:19:24 the United States has a very large number of research universities over a vast territory. I

00:19:32 think if you take a look at the early companies in the field, you'll probably be surprised that

00:19:37 they weren't just at the universities that happen to have been mentioned today, east or west coast,

00:19:43 but at places all over the country. And as the field developed, that's the way it has been. In

00:19:49 Europe, there are fewer research institutions, and there are many more countries, and these are

00:19:57 investments that are made. Yes, there are multinational corporations investing, but it's

00:20:03 generally there are different conditions, different regulations in various countries, so that it might

00:20:08 account for the difference. I think it's something that ought to be studied. I don't think we're

00:20:12 going to put... Thank you, Charles. Yeah, Stanley. There's another issue, Everett, to respond to your question

00:20:16 about whether there was something special about the culture at Stanford and UCSF. I think there

00:20:21 was, in that it's noteworthy that neither Herb nor I thought initially about patenting recombinant

00:20:31 DNA, DNA cloning, and we were approached by the Office of Technology Licensing at Stanford, and

00:20:38 the fact that Stanford at that time was one of the few universities that had an Office of

00:20:42 Technology Licensing in place has something to do with the culture at Stanford, a legacy of its

00:20:50 involvement in the electronics industry in Silicon Valley, and UCSF also had a small Office of

00:21:00 Technology Licensing in place at that time as well, which of course has expanded since, and based on

00:21:07 the models at those universities, analogous offices have been set up now at universities

00:21:12 throughout the country. So in addition to all of the things that have been already pointed out, I

00:21:19 think there was something special about the cultures at these specific universities that

00:21:25 contributed to the early days of biotechnology. That's a very nice point, I think, the nature of

00:21:32 the university's own approach to just these issues. I mean, I can remember the discussion

00:21:37 at Harvard, which grew out of our own banning any classified research on campus after the Second

00:21:45 World War, one of the things Conan brought back with him from Washington, and the spillover from

00:21:49 that was often, well, shouldn't we also therefore not get involved in commercial research? It was

00:21:54 fascinating. Now, other changes were made, but there is a, at times, different university cultures,

00:22:00 and I know a lot of our colleagues who wanted to do research which required defense

00:22:06 classification left Harvard to do it, because they couldn't do it within the university, in

00:22:11 their laboratories. Yeah? I was going to make just a little footnote to an event. When the

00:22:18 Asilomar Conference was planned, you remember I mentioned that it was initiated by a so-called

00:22:24 moratorium request. The people who signed that letter, three of us are up here, the actual ones

00:22:33 who drafted the letter were a group of seven, subsequently joined by Stan Cohen, Herb, David

00:22:40 Hogness, and Ron Davis. What we were asking for is everybody to put a hold on the experiments

00:22:49 they were doing, in contemplation of this meeting at which we would review whether there were risks

00:22:55 or not. A week or ten days before the conference was to open, Stanford announced the patent claim

00:23:03 for the Cohen-Boyer discovery. You can imagine how I felt. I was the organizer of the, or the

00:23:12 chairman of the organizing committee, and I know that I was inundated with telephone calls and

00:23:18 outrage. Outrage at what seemed to be, to outsiders, a call for everybody to stop the work while

00:23:26 Stanford proceeded to apply for the patent. And I had quite a to-do with the trustees and the

00:23:35 president of the university about this issue. I lost in the end, because I felt the patent should not

00:23:40 go forward. And perhaps later in our discussion, I will tell you my own views on patenting in

00:23:45 general. But that's just a little footnote to that particular announcement, which was really

00:23:52 almost the first time that anybody who was doing basic research and contributing to the field, that

00:23:59 their university now took their thing and were going to make a big claim on it. And bear in mind

00:24:06 that although Herb and Stan did key experiments, it was based on an enormous amount of information

00:24:12 generated by a large number of people, and also a lot of input from people in my own department. So

00:24:19 there was a little bit of misunderstanding about why the patent claim should have emanated from

00:24:25 Cohen and Boyer and Stanford, when in fact this had been a community effort in many respects.

00:24:32 Let me take this a couple of steps further, because many of you asked about the patenting

00:24:37 issue and related questions. And rather than defer it, I'm quite willing to attempt to be

00:24:41 flexible. And I want to push it in two ways. Before that, do you want to come in?

00:24:46 Yeah, I think it's why has this emergence been an American phenomenon? And I don't want it to be lost

00:24:57 that the explosive growth of basic biomedical science is due to the NIH.

00:25:05 That these discoveries were made exclusively in academic laboratories, as Bill and others have

00:25:11 pointed out. They were not made in pharmaceutical companies. They were not made by venture capitalists.

00:25:16 These were discoveries in academic laboratories supported almost entirely by the NIH. That is an

00:25:23 American phenomenon. Yeah, I wanted to pick this up, and I was actually turning toward you, Maxine,

00:25:28 knowing your role in the NIH, and particularly what you see as the culture of the NIH, both in terms

00:25:36 of where it turned its grants, but then in terms of what its research scientists were doing

00:25:41 in this aspect. Actually, I was going to comment on something else which is not totally unrelated

00:25:49 to that. I suppose it's very hard for all of you sitting out there listening to this

00:25:55 to recognize that 25, 30 years ago, when all of this was going on, we didn't have the gray heads

00:26:02 that we have now. And because of who we are sitting here now, it's hard to recognize

00:26:12 that a very important component, which Herb sort of talked about but not really explicitly,

00:26:19 is how young everybody was. It wasn't just the scientists who were young. It was also

00:26:24 the people who were starting, the scientists who were starting the companies. It was the people who

00:26:30 were bringing the money. Bill mentioned how old Swanson was. I'm sorry, Herb mentioned how old

00:26:38 Swanson was, 29 you said. And I think that adds, that's another reason why so much of this happened

00:26:48 in the United States. And that's because, without any question, it is the country in the world where

00:26:55 young people have always had the biggest opportunity. People with money were willing

00:27:02 to give money to young people to start things. The NIH was always supporting young people.

00:27:08 Now, in part, it was a function of growth at the time. And I think this played a role in the fact

00:27:16 that things concentrated in California, because it wasn't until after the Second World War that

00:27:22 the population of California began to go up. The universities grew enormously in size in the years,

00:27:29 so that the faculties at the universities were on average somewhat younger than they were in the

00:27:36 East. And so it was a whole kind of concept of youth and trust of youth, which doesn't go on

00:27:43 in European countries to this day or in Japan. And I really think that that played a very critical

00:27:51 role in the whole development. And with respect to the NIH and the way things have developed,

00:28:02 partly because of NIH policies and partly for other reasons, it is becoming increasingly

00:28:08 difficult in the United States for very young scientists to strike out on their own.

00:28:13 We find people with postdoctoral fellowships that keep them in multiple postdoctoral fellowships

00:28:20 sometimes still in such positions when they're in their mid-30s, whereas most of the people

00:28:26 sitting at this table had their own labs well before that. And I think that's a very significant

00:28:34 thing and something we ought to be worrying about, in fact.

00:28:37 That's a nice point also. Let me take this in one other direction. There's been success now in terms of

00:28:44 biotechnology in the United States, and you've indicated reasons for it, and they ring true.

00:28:52 Surely there's then a feedback from this success as to what kinds of topics, what kinds of research

00:28:58 will be done in the United States as compared to Europe. Is Europe now, or Japan now, out of

00:29:06 some key areas because they've been usurped so completely by the success of biotechnology

00:29:13 in the United States, both at the industrial level and the support that gets into universities that way?

00:29:21 Paul? Well, I think the name of the game today, at least in many people's minds,

00:29:29 is the emergence of what people euphemistically call genomics.

00:29:33 And I think by far the largest number of biotech companies and even the large pharmaceutical

00:29:44 companies are betting on this enormous amount of information which will emerge from the solution

00:29:50 of the sequence. Somebody mentioned the necessity for doing the physiology, and I think it's through

00:29:57 the genome sequence and the recognition of the identification of genes that people will be able

00:30:02 to explore the molecular basis of disease and physiology and so on. And there too in this

00:30:11 country we've taken the lead. We are far out in front of almost everywhere else, and what I see

00:30:17 is when I go around in Europe and Japan is all of them groping for how they can get into the game.

00:30:24 And the game today, at least as it's being funded in this country, is so far ahead of anywhere else

00:30:32 that it's catch-up but not very efficient. And so I see as we move forward that the U.S. is almost

00:30:41 going to increase its lead in terms of the key discovery. Now, the important point which I think

00:30:48 has to be looked at is are we distorting the research enterprise in such a direction that

00:30:54 is becoming more and more oriented to coming up with applicable solutions or discoveries

00:31:03 and ignoring the areas which we cannot yet discern the importance of but which may be the grounds

00:31:11 for the next generation of advances. And Charles, I just want to remind you that there's a map

00:31:18 that was once published of the U.S. which shows by black dots the location of each biotech company

00:31:25 in the United States. And what you see is that the west coast from virtually Seattle on down

00:31:30 to San Diego is black, and from Boston, Cambridge down to Washington, D.C. area is black, and then

00:31:37 you see occasional spots or clustering of spots at the research universities. And the question

00:31:43 you can ask yourself is where is the next massive development of black dots? And it's going to come

00:31:50 to places which are making some new breakthrough discovery. And we don't know where they are and

00:31:54 what field they're going to be. And that's why I think the importance of having an agency that's

00:31:59 still willing to fund pure, unadulterated, curiosity-driven research is so critical

00:32:07 because it's from that direction that the next breakthrough will come. Nobody predicted the

00:32:11 recombinant DNA thing. We were cooking along doing interesting molecular biology and then suddenly

00:32:17 a technique gets developed that opens the world. Where is the next technique going to come from? The

00:32:21 next insight? We don't know. But we need a system for funding that opportunity. And I don't know, I think

00:32:28 the point was made, Europe and Asia and Japan certainly doesn't promote that either because

00:32:35 they don't bet on young people or because they're not convinced yet that that's the way to develop

00:32:41 Almost CNRS, the Max Planck Institutes, the Pasteur, don't they compete in some way?

00:32:48 Pasteur now is much involved in biotechnology. They've converted a large part of their activities

00:32:54 to more applicable things. So you think they're being distorted as they try to catch up?

00:32:59 Yes, I think American universities are. I'd like to make a few comments with respect to what

00:33:06 Paul has just said and Arthur as well. And that has to do with what I may inappropriately

00:33:15 interpret as an effort to delineate the contributions of NIH versus biotech and other

00:33:25 components of the endeavor. And I don't think that the reason we're here today is because

00:33:33 there are linear pathways for science, business, and development. I think they're all connected

00:33:40 and it's actually a circular pathway. I believe that NIH in-house and through its extramural

00:33:49 grant programs, largely responsible for training generations of scientists, which have been

00:33:56 very contributory. I have no doubt that NIH and academic institutions and universities, research

00:34:06 institutions, can develop the technology that's made available through basic scientific research.

00:34:14 I don't see a big difference actually between basic science and applied science. I think

00:34:20 it's muddled quite a bit and there's a lot of good science that goes on in industry,

00:34:26 not in the basic science programs, but in developmental projects as well.

00:34:31 So it's a circular pathway, I think, which feeds on itself. And I think

00:34:38 the findings and contributions made in, for lack of a better term, the golden age of molecular

00:34:45 biology were such that they provided a framework for the introduction of a new biotech industry.

00:34:55 That biotech industry in and of itself, whether or not it funds academic research, which it does,

00:35:01 it pays its taxes, it returns money to its investors, but it also provides new problems,

00:35:09 provides new materials, research material, which can be used to stimulate thinking and

00:35:18 academic research. And I think hopefully this will continue to circulate. This might be a

00:35:25 naive way of looking thing, but I'm not particularly sure that one can make linear pathways for

00:35:35 academic science and industry. They have to be connected in my mind. And I think a lot of credit

00:35:42 has to go to the system which allows for this, which is the system we have in the U.S.

00:35:52 And I don't want to be overly nationalistic, but I think that system was put in place by a number

00:36:00 of wise people 40 years ago, and it's paid off. And I share the concerns that Arthur and Paul and

00:36:08 the rest of us have that, you know, this system does need public support. And in order for it to keep

00:36:17 it going, we have to make sure that happens. You know, you raise a number of interesting

00:36:21 questions, some of them historical, which we may come back to, remembering Vannevar Bush's

00:36:27 projection that something like 5% of all R&D money ought to be put aside for things which were not

00:36:33 explicitly a goal or mission directed. The NIH had a more checkered history in terms of what its

00:36:40 mission was, and a lot of it was seen as mission, but it was dealing with disease, which was a very

00:36:44 broad category. The question that emerges, though, is not only the money coming in, but also where is

00:36:51 the prestige now for the younger investigators? Where are they going to get the recognition?

00:36:57 Are many of the people who are coming through the departments of molecular biology now being

00:37:02 siphoned off into the industrial sector because that's where the fast action is, and the

00:37:07 remuneration? You told us earlier today that you made it worthwhile in your recruiting,

00:37:12 as well as giving a nice atmosphere. Well, what is the sense in terms of whether we're going to

00:37:18 leave a population among the best and the brightest in the universities and the technical

00:37:23 institutes as compared to the very active research sector? Sam? Well, that all depends on whether

00:37:29 we're successful in providing the vehicle for funding young people that are starting out. I

00:37:35 mean, one of the problems for the past several years has been the inadequacy, particularly during

00:37:40 the past several years, the inadequacy of federal funds. And I know that many of the excellent

00:37:47 laboratories at Stanford and other first-rate institutions are turning out people who cannot

00:37:54 easily find positions and, in some instances, cannot find positions at all in academia. And

00:38:02 whether or not we are successful in attracting these people to academic positions, to answer

00:38:10 your specific question, really depends on, in my view, how successful society is in recognizing the

00:38:17 need to provide resources to attract these people and fund their grants and perpetuate

00:38:27 the educational system that has produced what we've been talking about today. Yeah, we can

00:38:34 leave some of these. I want to switch gears for a minute just so that people in the audience who had

00:38:39 other more science-oriented historical questions in mind can get some of them brought forward.

00:38:45 A couple of questions came forward which had the intent of really asking the difference between

00:38:51 the biochemical orientation, in part I'd say the kind of thing that Arthur Kornberg was alluding

00:38:58 to in his opening remarks, as compared to the more focused molecular biological, molecular genetic

00:39:04 orientation. For example, what if instead of the group we have today, the mix included

00:39:11 Erwin Chargaff, Seymour Cohn, Korana Ochoa? Would the story of the development of molecular

00:39:17 biology, biotechnology look different with that mix of people, or would it look the same?

00:39:23 You're smiling, Herbert. I just want to recount something that was attributed to

00:39:29 Chargaff. Actually, he said that a molecular biologist was practicing biochemistry without

00:39:35 a license. Yes, yeah. Well, in most cases, the translation of molecular biology

00:39:46 to something useful in the commercial domain requires chemistry, ultimately requires chemistry,

00:39:54 because a product has to be defined in chemical characteristics if the product is used

00:40:01 as a single or a combined molecule. And secondly, as targets become better developed, the structural

00:40:09 information becomes an important aspect about the development of products which interact with

00:40:15 those molecules. So, more and more, this industry and the science itself is a coalescence of these

00:40:25 several disciplines, going from physics, chemistry, and biology, because integrated they form a whole.

00:40:33 Please, Arthur. I guess the burden of what I had to say this morning

00:40:38 was a reflection on the fact that science is driven by fashion,

00:40:46 and it isn't to say it's not without purpose or intellect, not simply hemlines and that sort of thing.

00:40:55 And these fashions are overwhelming. They have social, economic, and all kinds of personal

00:41:04 components, and so it's natural for a bright young person to go where the action is, where

00:41:12 there are meetings, there are symposia, there are jobs, there are grants, etc.

00:41:17 And the consequence of this is that areas deemed unfashionable are neglected.

00:41:25 And I've realized that history isn't reversible, and the new wave of enzymology will take a

00:41:35 different direction from the one that we took. But ultimately, with all the genomics and all the

00:41:43 enormous information that we get from gene sequences and arrangements and homologies and

00:41:50 motifs and whatnot, we will, as F.G. Hopkins, my hero in science in the century, said that

00:42:00 chemistry or biochemistry won't explain life, but without its input, life will not be explained.

00:42:09 And so there's a plea that in one form or another, that there be support, and the support

00:42:17 herb has to come from the federal government. With all due respect, the biotech venture is in

00:42:25 business, and it's not in business to do research, it's in research to do business and to be

00:42:35 profitable. And large companies may sustain some little alcoves or recesses where people can do

00:42:43 what they wish, but largely that's not the case. And so if we're to pursue knowledge for its own

00:42:49 sake, just to understand nature, it's got to be in academic institutions by and large.

00:42:55 Thank you, Walter. Yes, Stan.

00:42:56 Yeah, I think, Everett, it's a little bit artificial to present this as a dichotomy

00:43:03 between disciplines. Clearly, biotechnology is an outgrowth of biochemistry and genetics

00:43:11 and microbiology, and all three components have an important role in what we've been talking about

00:43:17 this morning. And I think that I would view it as not saying, well, there's a biochemical approach

00:43:23 and there's a genetic approach. All what we've been talking about really is an amalgam of multiple

00:43:30 approaches and disciplines. To pick up for a moment on what Arthur said about fashionable,

00:43:37 I agree strongly that unfortunately there is a tendency for students, especially young scientists,

00:43:47 to pursue what they deem is fashionable. On the other hand, I would point out to those of you

00:43:54 in the audience who are young and trying to decide what you want to do that there's some merit in

00:44:00 pursuing something unfashionable. One of the reasons that I became interested in plasmid biology

00:44:06 when, as Maxine pointed out, we were all very young, was because it was an area which was not

00:44:13 very popular. And when I was a postdoctoral fellow, I worked on bacteriophage lambda, which at that

00:44:20 time was one of the most competitive areas of molecular biology. And I once did a calculation

00:44:26 of the number of scientists working on lambda and the number of nucleotides in the lambda genome

00:44:33 and concluded that there was a scientist for every hundred or so nucleotides. And I thought

00:44:39 that was pretty crowded, but it was worse than that, because scientists were interested in

00:44:43 particular genes, and in those genes it was even more crowded. And you'd look, I mean,

00:44:51 scientists was every 10 nucleotides or so, and it's pretty crowded to look 10 nucleotides away and find

00:44:56 that there's someone else working on exactly the same thing you are. So I decided at that time,

00:45:03 since very few people were interested in plasmids, and plasmids were a very unfashionable area of

00:45:09 molecular biology, that that was an opportunity. And I think that that's often overlooked

00:45:17 these days in terms of young people pursuing things that are fashionable.

00:45:22 I can hear the hands going up, I don't see them, but they're going to ask you,

00:45:25 what are those unfashionable areas which I ought to head to because they're going to be good in a few years?

00:45:32 Yeah. Do you want the answer? Oh, well, please. Well, I mean, in a sense, Everett, I've

00:45:39 tried to do that in multiple aspects of my career. I think that, as some of you may know, I currently

00:45:48 work on RNA decay, and that's, until recently, has been a not a very fashionable area of study.

00:45:58 People have been interested in the front end of gene expression, things that control gene expression

00:46:03 at the level of transcription and translation, and they've considered RNA decay to be a kind of

00:46:09 default mechanism. On the other hand, there are very interesting mechanisms that are involved in

00:46:15 this aspect of regulatory regulation of gene expression. I don't know whether this is the

00:46:19 place to go into other areas as well, but there are many areas where there are interesting and

00:46:25 important scientific questions to ask that are not as crowded as the fashionable ones.

00:46:32 That's very helpful. To follow up in a way, one question came, Herbert, directed exactly to you,

00:46:39 and it follows this in a way. And the question was whether your initial interest in restriction

00:46:44 enzymes was generated by an anticipation of their potential for being able to purposefully

00:46:51 modify DNA. In other words, someone is trying to find out what the pathway of your thinking was

00:46:57 as you turned toward restriction enzymes.

00:47:05 It might be a little difficult to express it, but I think you'd have to have gone through the

00:47:13 experience of being a graduate student to know that you were more or less relegated to what

00:47:20 your advisor decided you were going to do in your thesis research. And this observation that I had

00:47:29 made as a graduate student was one that I made all by myself, and this guy, my mentor, wasn't

00:47:35 interested in it. And on the side and in the evenings I tried to learn a little bit more

00:47:42 about it. And so I guess my initial interest was, one, it was a very self-fulfilling gratification

00:47:51 that this was something I had discovered. I wanted to find out what it was. So that was my

00:47:57 initial interest. And then as I progressed through postdoctoral fellowship and what have you,

00:48:07 I became clear, as I said through the work of Arbor and DeSwal, that there was a lot of

00:48:13 specificity involved at the DNA level. And this presented the opportunity to look at a unique

00:48:21 model for protein-DNA interaction. And secondly, if it did make—we didn't know in those days

00:48:29 whether the breaks were—how specific they were, what the recognition was. But that had—

00:48:41 I think there was some thinking at that time in my mind about how it might be used to dissect

00:48:50 small chromosomes. But it was a very fleeting thought. I think I may have put it in my original

00:48:56 grant request, but I don't remember. But I never thought about the commercial possibilities until

00:49:06 Stanley and I had done the initial experiments. And as Bill, I think, said,

00:49:19 most of the large companies were not interested in the technology at that particular time. And I

00:49:23 remember talking to at least one liaison person from a drug company who used to come through

00:49:32 the department every once in a while and talk to people. And I tried to get him interested in this.

00:49:35 And he said, oh, it's very nice what you're doing. It's interesting. But it's 10, 20 years away.

00:49:41 Just keep on doing what you're doing, and we'll check in with you now and then and see how it's

00:49:46 going. So it was at about that time that I started thinking about possible ways to

00:49:55 use the technology to make drugs. And I won't go into any little stories.

00:50:01 No, very nice. Thank you. Yeah, Paul, you wanted to come in.

00:50:05 Yeah, I want to comment a little bit on a thing that Stan put up and one that I—I

00:50:12 got my early training in enzymology. In fact, I was a postdoctoral fellow with Arthur for several

00:50:17 years. And at one point, I guess I did what we all said, maybe one of us has to branch off

00:50:26 completely to go into a different field. And I chose to go off on sabbatical and work on tumor

00:50:32 viruses. And I recall—I won't mind if I recall—that he told me I was wasting my talent by

00:50:43 leaving enzymology in the tried-and-true path of E. coli enzymology.

00:50:48 That's true. It's still true.

00:50:50 It's still true. And that I was really jeopardizing a career by making this transition

00:50:59 to a murky system that was going to have to work with cells and not purified enzymes and so on,

00:51:04 and so forth. But I guess like, as he said, I was young and brash, and I was ambitious,

00:51:12 and I wanted to do something different. And I frankly thought that the route to doing something

00:51:19 different was to move to animal cells and ask whether the themes and paradigms that had been

00:51:23 developed with E. coli were also true of higher organisms. And working through viruses was a

00:51:30 procedure that had worked with the phages in understanding E. coli and certainly would do that.

00:51:37 Now, SV40, which is the virus I work on, is a circular DNA. And one of the things that I had

00:51:46 learned from my colleague, Gail Kaiser, was that the lambda chromosome is a linear molecule

00:51:53 and therefore has defined ends. And you can map things along relative to those ends,

00:51:59 relative to their distance. But if you have a circular molecule, you have no reference point.

00:52:05 And so in 1968, when I came back from the Salk Institute sabbatical, I heard about restriction

00:52:12 enzymes. And I thought, well, maybe restriction enzymes actually might cut the DNA and provide us

00:52:17 with a reference point. And so I called Herb and asked him if he could, actually, I think it was

00:52:25 not Herb, but Matt Messelson, who sent us two of the enzymes that Herb said don't make specific

00:52:33 cuts. And then we heard about EcoR1. I called Herb. He didn't give us buckets, but he gave us

00:52:42 some enzyme. And John Morrow, a graduate student in my lab, showed that EcoR1 did, in fact, cut

00:52:50 the DNA once and did, in fact, open it at a unique site. And for the first time, we had a reference

00:52:56 point to which we can map both physical features and genetic markers and genes. And so in terms

00:53:06 of using restriction enzyme, not to paste things together, but in fact, to just do a job of cutting

00:53:13 the DNA and opening it up. And I'll just tell one other little footnote because it relates to what

00:53:19 Herb also mentioned, and that is one of my students, Janet Mertz, and one of my colleagues

00:53:27 on department, Ron Davis, actually began to explore this cut SV40 and found that it cyclized.

00:53:35 It formed circular molecules under certain conditions, but these could be melted out as you

00:53:41 raise the temperature. So if you raise and lower the temperature, the molecule goes from a circle

00:53:46 to a linear molecule. And the deduction was quite clear on the experience with lambda that it must

00:53:51 have cohesive ends. And we called Herb, who was then working with Howard Goodman, and told them

00:53:58 of our result. They dashed down to Stanford and we discussed the thing and divided up the

00:54:04 problems in two ways. One was to explore the implications of the so-called cohesive end, and

00:54:10 the San Francisco group determined the sequence at the cleavage site. Now somebody earlier mentioned

00:54:17 the place, and it's very clear that the fact that we could communicate so easily, we had met

00:54:24 at many seminars, we had gone from Stanford to UCSF and back, that the proximity, the friendship,

00:54:31 the relationship, made it easy to do things, not in a collaborative sense necessarily, but helping

00:54:37 each other and doing that. And I would venture to ask whether you two guys, Stan and Herb, would

00:54:43 have actually collaborated or even sort of sat down and had your pastrami sandwich in Hawaii,

00:54:51 over which you cooked up this experiment, and then made the collaboration easy. Because now

00:54:57 if you'd been on the east coast and Herb on the west coast, it's a real question about whether this

00:55:02 collaboration would have matured in the same way. I think it's a very good point. I think it's a

00:55:09 good point too, and I just point out that at this conference, prior to my discussions with Stanley

00:55:16 Cohen, I had talked to Stanley Falco, who was also a plasmodologist, and Stanley, I think,

00:55:23 was in Washington at that time, and Stanley said, we're too far apart. He says, Stan Cohen's,

00:55:29 you know, very close by, and he's interested in doing this, and he's much smarter than I am, so

00:55:35 I was happy that Stan was agreeable we could do that. So I think it does have, I think that's a

00:55:41 good point. Good point. Thank you. I'd like to shift gears again for a minute, if I may,

00:55:49 and turn back to a question which we begun addressing but hadn't gone into directly,

00:55:55 and that is the question of patenting, what it is and what the differing views are. And here I'd

00:56:01 like to begin by turning to Charles Weiner, who has been engaged in this discussion at one level,

00:56:08 and to George Raftman, who obviously is right smack in the middle of it in his leadership

00:56:15 in the industrial sector. What about the implications for the way in which science

00:56:21 is done for university industry relations if patents are granted for whole genomes,

00:56:29 for DNA sequences, even without knowing their function, or for organisms themselves? We've

00:56:36 now had, what is it, 1980, we said the first patent was given for an organism. We've now had

00:56:42 17 years of experience. What are the implications now, particularly as we watch in those 17 years

00:56:49 this enormous burst of energy in the biotechnology field? Charlie, why don't you start?

00:56:56 Originally there was a great deal of resistance to patenting in the academic world,

00:57:02 in particular in biomedicine, and of all fields this was felt that if any patenting was allowed

00:57:09 in other fields that you'd have to be very careful in biomedicine. This goes throughout

00:57:13 the 20th century, and there was certainly the position in the UK and in the US. There were

00:57:20 statements by medical people, by university researchers, said we should not profit from

00:57:25 the public's ills. Where there was patenting, there wasn't an aggressive approach, and there

00:57:32 were considerable controversies in universities over a number of medical devices and

00:57:39 pharmaceuticals as well. It doesn't mean that universities, professors, didn't consult for

00:57:44 companies, but there was strong resistance to it. So when the Supreme Court decision

00:57:53 came down in 1980, it opened up a very large discussion not only

00:58:02 where the leaders of major religious groups wrote a letter to the President of the United States

00:58:07 saying that this raises very serious implications because not only is it in the field of

00:58:11 biomedicine, but specifically it has to do with genetic manipulation and tinkering with life,

00:58:16 and it raised for them the deeper moral issues, and a presidential commission was

00:58:21 appointed to consider those issues on the basis of the patenting decision. At universities, there

00:58:27 was a very great amount of confusion over the effect of this on the informal communication,

00:58:36 as I mentioned this morning, and the free flow of information, the free flow of cell lines and

00:58:42 bacterial strains and plasmids, and pretty soon people were signing agreements and specifying that

00:58:49 if I give this material to you, which I've always done, now you'll have to sign a form on it so that

00:58:57 I know that you won't, as the President of Stanford said at the time, that you won't clone it and

00:59:02 patent it. So you found a great deal of resistance to it and a great deal of confusion. Coming back

00:59:10 from that older tradition about is it appropriate for a university professor to engage in commerce

00:59:16 and to profit from federally funded research, university professors traditionally, even though

00:59:22 there had been involvement, on the whole they had said over the years that we want special privileges

00:59:28 as academics, we have a special ethic, we'd like to be left alone to choose our own research

00:59:34 problems so that we can be protected from the, and we are protected from the marketplace, so you can

00:59:39 trust us. Now there's a rich tradition and history of science showing where that changed, but this was

00:59:45 the overall ethos. Jumping from there to the more recent period, patenting is the norm. There's a

00:59:53 new status quo. Universities have aggressively set up technology licensing offices. They encourage

01:00:01 and in some cases pressure their faculty to patent and then approach them about starting companies

01:00:07 where the university would, as the owner of the patent, if you work for a university, the university

01:00:14 can't apply for the patent, but they encourage you to and then you assign the rights to the university.

01:00:20 You may get a percentage, a small percentage usually, of the royalties should any be forthcoming

01:00:26 if the university was able to license that patent. Universities now are saying we will provide

01:00:33 the patent to you and we'll help you raise venture capital to set up a company and what we want out

01:00:39 of it is some return, so their venture capital that they're bringing to it very often is the patent

01:00:44 itself. It's a very large change. It sets up questions about do you hire faculty because of

01:00:53 their ability to bring in patents, because of their entrepreneurial nature, who makes those

01:01:01 decisions, what about the effects on young scientists, and so forth. So there's been a real

01:01:05 shift in the status quo and the issues are not settled. Those same issues persist.

01:01:14 Thank you, Charles. Yeah, George, you must look at this from a very different direction, so I'd be

01:01:19 interested in your own take on the subject. Well, first of all, they're much better qualified people

01:01:23 here to come in on the pros and cons of the attitudes about professors if they're being

01:01:28 stimulated to do patents, how they're going to be recruited, how they're going to be

01:01:32 rewarded, and I really don't think I can look into that carefully enough, but I can tell you

01:01:37 what the impact on a biotechnology company is, and that is we're forced to think about how we can

01:01:46 get a return on the investments that are being made. Our investors are risking their money.

01:01:50 They're looking for a better than average return, so that guides us in certain ways. One is that if

01:01:55 we're going to have a success, we better be able to protect it, because we certainly aren't one of

01:01:59 the bigger companies around, and that goes even for Amgen, and certainly goes for the new company

01:02:04 I'm associated with, Icos. If we don't have something that gives us an extra shield, we will

01:02:09 not be able to return a profit from even good ideas. If you look also at the enormous amount

01:02:14 of money and the connection with the exact place where people may think patents have some ethical

01:02:19 overtones that are negative, it's exactly that place where you're going to spend four or five

01:02:24 hundred million dollars to get a product approved, and if someone can cherry pick afterwards which

01:02:28 ones were successful and which ones were not, and they would have very little trouble,

01:02:33 even if you didn't disclose the nature of what you're doing, to retro-engineer, take a piece of

01:02:38 the material, clone it, express it without much time, and so you wouldn't really be able to protect

01:02:43 anything in the face of much stronger companies, so it's absolutely essential. It also induces us

01:02:49 to do hard things and new things, which I think is very, very productive, because obviously if

01:02:55 patents aren't going to be important, then maybe you're much better off to copy somebody else

01:03:00 instead of doing something new. And lastly, the patent system, as a lot of people understand,

01:03:05 and I certainly understand it, is an astonishingly good communicator of implementable facts concerning

01:03:12 every invention, and these days the stated situation is that if you want to have worldwide

01:03:17 protection, and you certainly want that because you'd hate to encourage a big competitor coming

01:03:23 out in Europe or Japan, so you look for worldwide protection within 18 months at the outside 20

01:03:29 months from the time you filed your U.S. case. If you filed overseas in a timely way, it will be

01:03:35 published overseas, and eventually it'll be published in the United States, as we now know

01:03:38 that there's some changes underway. So the idea of that enormous delays in communicating from

01:03:44 scientist to scientist are occurring is not true. Now that's not quite the same as

01:03:50 as Herb and Stan talking to each other about their latest result, which does happen when there is

01:03:56 academic collaboration. It does not always happen when there isn't academic collaboration. There's

01:04:00 not a huge incentive for a scientist to tip off a fellow scientist as to what might be the next

01:04:06 most fruitful experiment to run, and I don't think it necessarily happens in real time, but it could

01:04:11 happen in less than 18 months. On the other hand, those disclosures that go into the patent office

01:04:16 by law and for a valid patent have to be total and implementable and enabling, and that's a pretty

01:04:22 fine disclosure, sometimes better even than what's in a publication. So the enormous downside that's

01:04:28 seen by some doesn't seem near as significant as the downside of just frankly leaving a

01:04:35 biotechnology company with wondering what the heck they would work on if they didn't hope to be able

01:04:39 to protect something with a patent system. Yeah, let's get Bill and then I'll come back to you.

01:04:45 As I mentioned this morning, I think that in the early 1980s, personnel moved primarily from

01:04:53 universities into small or large companies, not vice versa. I think there's a fair degree of

01:04:59 movement now backwards, and that fact isn't necessarily to prosecute research for which

01:05:08 patents of value are developed. It's because of an intrinsic interest in the science that

01:05:13 goes on in universities, and there's a vibrant interaction now. I also would make the point

01:05:19 to sort of supplement the other comments that have been made. I believe nowadays that research,

01:05:26 though dominantly supported by the NIH, is substantially and significantly supported

01:05:31 by complementary research in companies.

01:05:36 Certainly, for example, the discovery of hepatitis C, which happened to occur with us,

01:05:41 would have been quite difficult in a singular laboratory in the university,

01:05:46 although it would have happened at some time. Other kinds of things that are going on,

01:05:51 the development of the facility to measure a single or small number of molecules of nucleic

01:05:57 acid, the development in companies like Affymetrix to do matrix displays, which are going

01:06:04 to be important for research in general, as well as commercial research. All those kinds of

01:06:10 activities indicate a kind of complementarity which exists between those two organizations.

01:06:16 Finally, I'd say that if you took a look at the research which is going on in universities,

01:06:21 do we have a real distortion that is aimed at providing patentable materials and therefore

01:06:30 commercial rewards? Well, perhaps to some degree, but I would posit to a very small degree. We have

01:06:38 a vibrant, interesting group of young people who are interested in science per se, in systems which

01:06:45 are unlikely to give a patent per se. Really understanding biology itself and human biology

01:06:52 is a commanding interest by a majority, I think, of people in science.

01:06:59 Yeah, please, Herb. Yeah, we want to get in and I'll come back.

01:07:01 Just give you a few personal anecdotes. I can remember when Stan called me with the

01:07:09 request from their patent and licensing office that they wanted to patent this technology,

01:07:15 and my first words to Stanley were, that's illegal. And even though I had signed a piece

01:07:23 of paper when I joined the faculty at UC dealing with patent issues, I don't think I even read it.

01:07:29 All I want to do is get in the lab and do research, and I signed a bunch of papers.

01:07:33 And so I'd been totally unaware of what patents were, had no idea they played a role. I'd heard

01:07:39 about them. I'd heard about Thomas Edison, whatever, but never paid much attention to

01:07:44 the particular role it played in commerce. And when Stan and I got involved with the patent

01:07:52 process, I learned a little bit about it, but I couldn't stand all the little details that had to

01:08:00 go into writing a patent. And fortunately, Stanley was very good at that. He gives us the credit for

01:08:05 putting that effort into it. Patents have a history from the 15th century, and I think

01:08:16 they serve a very valuable and commercially valuable mechanism for industry. They were

01:08:28 introduced to Venice by the dogees, primarily in the glassware business as a way of attracting talent

01:08:36 and in turn jobs and commerce to Venice. And they had to do so by providing an incentive,

01:08:43 and that incentive dealt with providing them with some form of payment if they would divulge their

01:08:50 information. This system spread throughout Europe and impressed such people as Thomas Jefferson,

01:08:57 who incorporated into the Constitution right here in this city, as one of the features of

01:09:03 the Constitution, that patents are a viable system of our country. And I had myself and I think many

01:09:12 of the scientists of that generation were totally ignorant of exactly what a patent was. And it took

01:09:20 a long while, and we had to put up with a lot of criticisms from various individuals about how

01:09:27 we were going to destroy science and communication and so on and so forth. And many of them thought

01:09:34 that they would not be able to use this technology in their laboratory unless they paid a royalty to

01:09:41 UC and Stanford, and there was a great deal of misinformation. Fortunately, I think that

01:09:47 has been taken care of today. But I think patents do encourage innovation and risk-taking.

01:09:58 There are some examples. There was a family of Dutch physicians that were actually obstetricians,

01:10:06 and one of them invented the forcep method of delivering babies. And this was a closely

01:10:14 guarded secret, which they kept in the family for many years and therefore was only used by

01:10:18 royal households because they could afford to put forth all of the appropriate monies to satisfy

01:10:24 these individuals. So if they'd had a way of patenting this, they might have been able to

01:10:31 have been more widespread. But I just close by saying that our patent attorney said that,

01:10:41 which I think is a true statement, a patent is nothing more than a key to the courthouse door.

01:10:48 And the fact that you have a patent doesn't mean that it is actually valid or enforceable. It will

01:10:53 be challenged, and the more broad it is, the more impact it has, the more challenged it will be by

01:11:00 your competitors. And I might say that a lot of the issues that we originally started out with,

01:11:05 I think, are going to be adjudicated and dealt with in the courts. And I think there has been

01:11:13 some recent decisions which are taking a much more narrow focus towards the patents in the

01:11:21 biotech industry. Yeah, Herb, you've left us at a very good point. My managers tell me that it's

01:11:28 important for us to take a brief break now. So let me thank you. We can pick this up because I

01:11:34 think there are elements of patents and what has got to be the two-way relationship between industry

01:11:40 and university which are worth further exploration. But thanks a lot for this start. We're going to

01:11:45 take a 15-minute break and then be called back. All right, let's come back to the second half of

01:11:51 our discussion. As we broke, you remember, we were right smack in the middle of what I thought was a

01:11:57 fruitful, if somewhat hot, exchange on patenting and what it means. There was the question, in a

01:12:04 sense, of patenting from the industrial side. Charlie raised the point of patenting from the

01:12:10 university side. And I felt around me some urgency to get some things out. Paul Berg, you were about

01:12:17 to speak. Well, I think it's terribly important to understand the distinction between the legitimacy

01:12:25 or value of applying for patents from the industrial side. That's the intellectual capital.

01:12:31 They have to protect that. There's no argument. Nobody's ever raised any question about whether

01:12:36 a new company that makes some discovery that they think has value of patenting. They're doing it

01:12:42 aggressively. God bless. The question, I think, that was raised is what's the consequence of an

01:12:51 aggressive patenting policy on the part of research institutions like academic or even

01:12:59 the NIH, let's put it. And there, I think, I do have some real concerns. And let me start off by saying

01:13:07 that I think the Stanford-Cone-Boyer patent set us on a bad course. So I'm going to say that

01:13:16 right off. Because I think the reaction on the large part of many scientists was,

01:13:23 hey, wait a minute. I mean, where does Stanford and UC get the entitlement to this whole thing?

01:13:29 Because the broadness of the patent that was actually approved essentially preempted almost

01:13:35 any kind of cloning operation. It said, in all possible hosts, in all possible vectors, joined

01:13:42 in all possible ways with all possible DNAs. And that left nothing for anybody to explore.

01:13:50 So there was a certain amount, I certainly heard it, resentment. One reaction to that resentment

01:13:56 was a tit-for-tat one. So Columbia then applied for a patent for being able to introduce DNA

01:14:05 into mammalian cells, something that we were all doing and had been relatively routine.

01:14:12 So now Columbia had preempted. So anybody who wants to now introduce DNA into mammalian cells,

01:14:18 any commercial or for-profit thing, has to now pay Columbia royalties. And I think both of those

01:14:27 have set in train a whole attraction. It's not difficult to see that an enormous income flow

01:14:35 can be generated from a successful patent, especially if you can make it broad enough to

01:14:40 include everybody having to pay your royalties. It's become very licensing offices in universities,

01:14:48 I think, have become more and more aggressive in pursuing patent opportunities. So in fact,

01:14:54 they are having a hand in directing some of the kind of research that goes on.

01:14:59 Because as I was recounting earlier, my own experience is I had a student who made a

01:15:04 discovery which he thought had commercial value, and he called up the licensing office on his own.

01:15:10 They sent over a battery of lawyers, and they sat with him for a week figuring out how to capture

01:15:16 this mythical invention. And in the end, he had to do experiments to satisfy their needs

01:15:25 to validate the claims that they were putting forward. And I was astonished because that was

01:15:31 not his role. He was there as a Ph.D. student, and it wasn't his job to try and figure out how

01:15:35 to make some future income from his discovery. He was there to explore, I thought, the relevance and

01:15:43 physiological significance of this protein that he had discovered. More and more, what I find is,

01:15:50 as Herb alluded to, patents are an incentive. Well, they're also an incentive for academic

01:15:56 investigators. And to the extent that that incentive distorts the kind of research they

01:16:02 choose to do, one, well, the path that they take when they come to a fork in the road and a decision

01:16:07 has to be made whether you go this way or that way, and this way has a chance for patent, and

01:16:11 this one is pure research. The question is, to what extent will that choice be distorted to change

01:16:20 the vector of what I'll call curiosity-driven research exclusively? And even if the vector

01:16:26 change direction is small, over time it's magnified and will produce a big change in the way we do

01:16:33 science. Now, whether there will always be people who will say, I don't care about patents, but what

01:16:38 I find is that there are more and more people who do care about patents. And one of the consequences

01:16:45 are that when something is in the process of being produced as a patent, suddenly your

01:16:51 colleagues can't talk about something. They can't publish or they can't present it at a symposium

01:16:59 because the lawyers have told them that patent application would be null and void, at least in

01:17:06 certain circumstances, if there's any public disclosure. And so I think all of these things

01:17:11 we've not taken account of, and I personally believe that they are going to do us harm in

01:17:18 the long run. More and more emphasis, the more and more facing up to trying to generate income from

01:17:25 intellectual advances in the university. That's not to deny that the university is entitled in

01:17:32 some way to recompense for the discoveries that is generated, but the mechanism that's being used

01:17:40 is in fact, I think, better. I much prefer having industry essentially feed back support to the

01:17:47 basic science enterprise than it is by just applying for patents and then trying to recover

01:17:52 it from industry through royalties and licensing. Thank you very much. Yeah, yeah, I can imagine

01:17:58 that my colleagues over here. I don't disagree with her with all entirely. I mean, I think there

01:18:07 are some other thoughts that should come into this. I think there is potential for abuse,

01:18:13 and I'm concerned about that too, but everyone's guaranteed to the right to

01:18:20 have possession of their intellectual property, and whether they're scientists or not, they're

01:18:26 capable of generating intellectual property, and they have the right to protect that if it's

01:18:32 and what have you. But I think it's certainly the policies of most institutions

01:18:43 may or may not reward the inventor, but they certainly do always reward the institution,

01:18:48 and it can be a rather small but still effective way of helping to fund the activity of institutions.

01:18:58 But I don't think that there's much difference between a graduate student, if he does something

01:19:03 very important and significant, to have the right to that intellectual property. Now,

01:19:08 how it's distributed is one thing. Who gets the recognition? That is very much dependent on the

01:19:15 patent system and the patent law, and it's a reduction to practice, and it's an enablement,

01:19:22 which are the key terms. I don't understand what they mean, but that's what the lawyers

01:19:26 talk about all the time. But there are some very critical assessments of the patent application

01:19:33 process, but I mean, I can't see much difference between that and the numerous books that have

01:19:39 been copyrighted and come out of graduate PhD theses throughout the country and the world.

01:19:47 Yes, Stan, and then Charles.

01:19:49 Yeah. Actually, when the technology licensing department at Stanford first contacted me,

01:19:57 my reaction was very much that of Herb's, as that's, gee, this can't be patented. This is

01:20:04 basic research. How can you patent basic research? And besides, it's dependent on all of these

01:20:10 findings that have occurred in molecular biology for the past 15 to 20 years. And I was assured

01:20:17 that no invention is made in a vacuum. Every invention is dependent on something that preceded

01:20:24 it, that the key features required for patenting is that it has to be novel and not obvious,

01:20:33 to use the term, one skilled in the arc, and also enabling. And Stanford felt that it was,

01:20:41 and they convinced both Herb and me and the people at UC did also, that Stanford was entitled,

01:20:49 as Herb said, to recover something from this. Otherwise, industry using this technology would

01:20:56 really get greater profits on the industrial end. And Stanford was entitled to share some

01:21:03 of those profits, that this wouldn't inhibit any academic use of the intellectual property at all.

01:21:08 And on this basis, Herb and I decided to proceed on that. Now, some of the points that Paul raised

01:21:17 as areas of potential abuse, I think are areas of potential abuse, but whether or not they're

01:21:22 areas of actual abuse depends on how you run your lab. Since the initial patent that we've been

01:21:30 talking about, Stanford has applied for patents on a number of other things that I've found out,

01:21:37 and my colleagues and I have found out in my lab. And the processes that we've followed have been

01:21:44 that we don't delay the publication for one day in order for Stanford to apply for patents.

01:21:52 If they wish to apply for a patent, they've got to get their patent application in on a schedule

01:21:58 that allows them to meet whatever deadlines, or else it's too bad. Similarly, Paul talked about

01:22:04 the technology licensing office lawyers coming over and telling his graduate student what to do.

01:22:10 That's never happened to me, and I wouldn't permit it, because I certainly would not pursue any area

01:22:18 of investigation for the area of a patent, for gaining a patent. But if a patent comes

01:22:26 out of the work, I see nothing wrong with the university pursuing that patent application

01:22:33 and providing them with the information that allows them to do it. Now, similarly, I think that

01:22:40 there are various practices for intellectual property. I've always sent out my plasmids freely,

01:22:46 and with no requirement, in fact, Paul and others know that after the initial concerns were raised

01:22:55 about biohazards, there, in fact, even prior to that, there was only one restriction

01:23:01 on my sending out the PSC-101 plasmid, which at that time was the only plasmid suitable for

01:23:08 DNA cloning, or that anyone knew was suitable for DNA cloning, and that was that it not be used

01:23:15 to create new combinations of antibiotic resistances. And subsequently, after the

01:23:21 recommendations of the committee that Paul talked about, my restrictions extended to include the

01:23:31 other recommendations of the committee. But I think that, yes, a patent opportunity can be abused,

01:23:40 but that doesn't mean it necessarily has to be. One can conduct a patenting practice at a

01:23:46 university in a very straightforward way that doesn't allow abuse in a laboratory, and at the

01:23:53 same time allow the university to derive a fair share of income from that intellectual property.

01:24:00 Good. Thank you, Stan. Charles? I'd like to mention another problem that flows out of what every

01:24:06 patent attorney knows, and that is that a patent is only as good as your willingness and ability

01:24:12 to defend it in court, if necessary. When a university gets involved in a patent, if they're

01:24:19 serious about it, they must defend it, and then they run the risk of impairing their credibility

01:24:25 as an institution of learning and research publicly funded with a special status in society

01:24:31 because they act like a business organization in defending their property. This has come up

01:24:35 historically, and it came up, for example, when Cetus said around the mid-80s that they wouldn't

01:24:44 honor the Stanford recombinant DNA patent, even though, of course, you were involved with Cetus

01:24:51 as a consultant, that they wouldn't honor the patent. And there was a threat,

01:24:58 and the university countered and said, we put aside a war chest of a large sum of money

01:25:06 from the income that we've already derived from the patent, and we're prepared to fight it.

01:25:10 Unfortunately, it didn't happen. There was an amicable, I think, agreement, and the university

01:25:17 and Cetus wasn't put in that position. But that's another thing to take into account.

01:25:22 Things have changed a great deal, and I think the discussion is today about how much

01:25:30 they have changed and how to sort of minimize the frictions. But there really is a strong

01:25:36 change from the period prior to this work getting started. Charles, fine, thanks. A two-minute

01:25:43 clarification from Paul. Herb made the point that patenting in a commercial center entity

01:25:50 does not preclude the use of that invention for research. Point of fact, I always believed that,

01:25:56 and I think all of us in academia have always believed that. But I actually queried a lawyer

01:26:01 who was well-versed in this field and said, that's not true. There is nothing in the law that says

01:26:07 company cannot preclude your use of their intellectual property. And, in fact, Arthur's

01:26:13 been involved, Promega, who has tried to prohibit people from making an enzyme that they had...

01:26:20 Roche. Roche? I'm sorry, Promega is the target. Yes, exactly. But, Paul, that's a company, that what a company

01:26:26 does, the universities don't do that, because that's not their policy. No, no, I'm just...

01:26:31 No, I mean, make the point that patenting does, in fact, impact on the use of technology, methods,

01:26:38 tools, if they want to enforce it. You make a profit. I mean, unless the scientist who's

01:26:48 having problems is making a profit, he's not precluded. I mean, how else can you enforce it?

01:26:56 They can say that any discovery that you make may, in fact, be patented by your university. If it was

01:27:03 made using our patented reagent, it is now covered. Okay, so that now precludes you from actually

01:27:10 exploring any potential use. No, it only precludes you from taking a patent. No, no, no. They can

01:27:17 actually have an injunction that prevents you from using that technology. Arthur's been involved in

01:27:22 that discussion. A final word on patenting from Arthur. Well, it's not the final word, but...

01:27:27 This afternoon. There won't be a final word. And my comments are much more general,

01:27:35 and that is a couple of illusions may have been created, and I want to be sure I dispel them.

01:27:42 Number one, that justice will be served by the legal system, and that's nonsense.

01:27:48 I mean, the litigiousness of people at great expense and suicidal consequences come out of

01:27:56 prolonged adjudication, ultimately decided by a jury that's utterly incompetent to make that decision.

01:28:06 Does he want to throw it out? Now, there have been statements made, and I could almost quote each of

01:28:13 each of you, in which there could have been an interpretation that there are benign ways

01:28:20 in which the support of basic research can come out of one source or another.

01:28:27 Bill said that there are significant contributions of biotech and pharmaceutical industry to basic

01:28:35 research. I agree, but let's define significant in quantitative terms, and I'll state that in

01:28:43 the past and for the future, the amount of money for basic research deriving from industry, from

01:28:51 Howard Hughes Institute, from all sources, is less than 10 percent of what's furnished by the

01:28:58 of the total. That is more than 90 percent has been and must be furnished by federal government,

01:29:06 and Paul, as far as approaching biotech ventures or pharmaceutical companies to pay back, forget it.

01:29:11 Very few are profitable, and pharmaceutical companies will tell you we pay taxes, and so

01:29:18 if you want support, we're supporting it. So ultimately, the buck stops. The buck originates

01:29:28 in the federal treasury, and there's no question that as a nation,

01:29:33 we have to make that investment. It's not an expense, and so the catalytic and the

01:29:42 significant role that land-free industry plays is untested, but I'd like to be sure that one knows

01:29:50 that it's an illusion to think that these major advances will supplant the support that we have

01:29:56 to get from the federal treasury. Thank you. Thank you very much, Arthur. Let me pull this

01:30:01 piece to a close, because I've been around issues like this long enough to know that what we've got

01:30:07 now are fairly significantly different attitudes, and these different attitudes put a different

01:30:14 loss on what's out there. I think the points of view have been very well stated, and I think there

01:30:19 are some areas of real agreement. That is, real agreement that in the commercial sector, patenting

01:30:24 is absolutely essential as a mode of conducting business and getting work done, protecting the

01:30:30 rights gained through invention, discovery, etc. The crux comes in what happens in that relationship

01:30:37 within universities, universities to their students, to their faculty, and then the university-industry

01:30:45 relationship, and I think what we've watched in recent years in this area particularly,

01:30:50 biotechnology, have been some changing mores and practices, and these changing mores and practices

01:30:56 have brought forward a series of problems which for some remain unresolved. I'd say that

01:31:04 there are tensions and that they probably will continue for some time, and the question that

01:31:09 we'll want to watch carefully as we do contemporary history is how the pieces emerge. What are the

01:31:16 changes that occur? What are the boundaries that change? What's patentable and what's not? What

01:31:22 the usability will be across these borders? One thing was made clear by several people, and I

01:31:27 would just underline it, and this is the necessity of there being strong continued federal support

01:31:34 for research in the university sector from the NIH, from the NSF, whatever the agencies will be,

01:31:39 and I think there is total agreement. What I'd like to turn to now, because we've stayed away

01:31:43 from it so far and it's my fault as the moderator, is the question really of what we've learned.

01:31:52 What was it George Santayana said that those who forget the lessons of history are condemned to

01:31:56 repeat its mistakes, but the other end of it is when we've had a recent set of policy discussions

01:32:05 and debates in the area of recombinant DNA, and then we've watched the emergence of a policy in

01:32:12 the human genome discussions for supporting explicitly with three percent of allocated

01:32:19 money going to supporting ethical and social investigations into the implications of the

01:32:26 human genome. Have we learned things from the debate coming out of recombinant DNA

01:32:33 which provides something like a model for future discussions? For example, cloning of human beings.

01:32:42 And Maxine Singer, you've been in the middle of that debate. I wonder if you, not the cloning

01:32:47 debate, the earlier one, I wonder if you would like to look back at what you think we've learned

01:32:53 from the debate in the area of recombinant DNA and what implications you think it might have,

01:33:00 what it might serve to be into the future. Thank you. I would like to mention two things,

01:33:06 two quite different things. One very important thing that we learned was that things that we all

01:33:18 thought about as everyday knowledge was a complete mystery to most people in the country,

01:33:24 in our country. And we learned that the hard way, and I alluded to some of that this morning,

01:33:34 in that people who wanted to engage the issue very often did that by avoiding

01:33:42 what involves the science and technology and focusing on other kinds of things.

01:33:48 One thing that I remember is an example of that. At that director's advisory committee

01:33:53 in February of 1976, in Paul's presentation on the science, or perhaps later, he happened to mention

01:34:05 something about the fact that the experiments were actually quite easy to do and could be done by

01:34:10 high school students. And that was picked up and there was a long conversation taking up a very

01:34:17 significant part of the time available as to how dangerous it was, what you could do to stop it,

01:34:25 and so forth. And that was one of the first clues I had that people could focus in on the irrelevant

01:34:31 kinds of issues. And it was because they didn't understand a lot of the basic biology. In fact,

01:34:40 I think that's changing because in these last years there's been a big effort to try and improve

01:34:47 science education in the United States. And a lot of school students all over the country are

01:34:54 getting better basic scientific education. It's nowhere near what it ought to be, but at least

01:34:59 it's moving. And certainly it was my experience in the recombinant DNA debate that helped

01:35:07 make me decide that I was going to spend a lot of time on science education in more recent years.

01:35:13 So to me, that was a very big thing that we learned. And it was an important thing because

01:35:20 the public, after all, is holding all the strings. And if they don't understand what you're doing,

01:35:28 they will be frightened, and rightfully so. And therefore, it's our responsibility to be

01:35:36 sure that that improves. That's one thing. The second thing I wanted to mention is that

01:35:42 we didn't realize that when you start discussing a completely new topic in a public way,

01:35:48 you spawn industries. I mentioned it sort of obliquely in my talk when I mentioned the fact

01:35:54 that the people who wrote environmental impact statements were pros. I mean, they were contractors,

01:36:00 businesses set up to do this. And it turns out that every time there's a new issue abroad,

01:36:06 all kinds of opportunities arise for people in peripheral things to make little industries.

01:36:18 And so, for example, the whole field of bioethics, which practically didn't exist,

01:36:27 is now a substantive field in a lot of universities. And maybe that's a good

01:36:33 thing. I'm not saying good or bad, but you have to recognize that every time you raise something

01:36:37 like this, you do do that. On the other hand, there were some difficulties that arose because

01:36:44 people saw an opportunity in this debate to make a role for themselves. And perhaps the most famous

01:36:51 of those is Jeremy Rifkin, who really made a career on raising a variety of difficult issues

01:37:01 about recombinant DNA. Charlie mentioned before about the statements by religious leaders

01:37:08 opposing patenting, but we all know that to a very large extent that was orchestrated by Rifkin.

01:37:17 And so there's somebody who made a career, a reputation. He's famous. He's on TV all the time.

01:37:23 People write about him. His books sell better than mine do. And so that's another kind of thing

01:37:31 that arises, which I was totally ignorant of when we started discussing this, that you really spawn

01:37:37 all kinds of things. A nice summary of two key issues. Let me push a question for someone,

01:37:45 because you come right up to it. And that is, to what extent do you think scientists

01:37:50 should be the ones in control of the debate over the implications or potentials for what science

01:37:56 might do publicly? Well, if you're asking me, I will tell you I don't understand the question.

01:38:01 I don't understand what people mean when they talk about being in control.

01:38:06 To the extent that nobody else knows the science, certainly the scientists are in control in some

01:38:11 sense. But we learned in this debate that no single group in our country is in control of

01:38:19 anything, which is just as well, probably. So I'm always a little bit puzzled by that question and

01:38:27 exactly what's meant by it. So I think you need to be a little bit more explicit for me. I can

01:38:32 come back and be more explicit. What I was looking for here is, in a sense, the setting of the agenda

01:38:37 about what issues will be included in and which not. I think many people reacted with interest

01:38:44 when scientists seemed to say that the public was taking this debate away from us. And the question

01:38:50 was, where should a debate like this be held? Excuse me, who said that? Oh, they're funny

01:38:55 people. That said the public was taking the debate away from us? Scientists? What scientists? Who?

01:39:00 My colleague James Dewey Watson, sitting at Harvard. He said it loud and clear. He said the

01:39:04 public was... He wrote about it in the New Republic. I've never heard him make that particular statement.

01:39:10 I mean, I think my view of this is that there are societal issues, and my voice as a scientist

01:39:17 should be no louder than anyone else's voice about the societal issues. But there are also

01:39:26 issues relating to scientific expertise. And as Maxine, I think, quite correctly points out,

01:39:32 scientists have to provide a resource for that information to educate the public

01:39:37 so that the public can deal with societal issues. And so that I don't look at it as

01:39:44 taking any debate away from us. I think there are some issues that need to be

01:39:50 discussed at a public level, but I think scientists have a role, in fact, a duty to provide

01:39:58 information for and educate the public about issues. Yeah, Paul. Yeah, I want to return to

01:40:04 your first point, which is lessons learned, mechanisms put in place to deal with similar issues.

01:40:11 And I think for a long time, I think I was, in reflecting on the time and feeling a certain

01:40:18 bit of comfort with what we did, nevertheless, what I thought is we had not put anything in place

01:40:24 other than an experience. And you could go and read about the experience, but in fact,

01:40:29 nothing existed that could deal with a similar issue that might challenge

01:40:38 society. And one just has recently arisen. So here we are. We've got the DALI experience.

01:40:45 And what struck me right off was that the public did not know about all the work that was going on

01:40:54 doing the same thing until this sort of pronouncement that they'd cloned a sheep from an

01:41:03 adult differentiated cell. While, in fact, people had been doing it from embryo cells,

01:41:07 people had been doing it from fetal cells. And in fact, there was in the same paper,

01:41:12 he describes the experiments using other sources of nuclei and so on. So and in the recombinant DNA,

01:41:19 I think the public also was totally unaware of how close one was to actually being able

01:41:25 to do the kinds of things that were done. So it was a shock, a shock sort of thing.

01:41:30 So now let's look at how the DALI situation was handled. There was the instantaneous

01:41:39 hand-wringing. Oh, my God, what are we doing? What are we getting into? What are scientists

01:41:44 going to do? They're going to destroy the universe and the world and only the families.

01:41:52 And we had the president immediately call for a ban on this kind of research. Then, of course,

01:41:58 the politicians came out of the woodwork and immediately were proposing various kinds of

01:42:02 legislation. But we had this president's biomedical commission in place, interestingly enough.

01:42:09 And so the matter was referred to them. There wasn't any such commission existing at the time

01:42:15 of the recombinant DNA. And so in one sense, if it wasn't the scientists who were going to carry

01:42:20 the ball, it wasn't going to be carried. Here, the ball could be carried by this commission.

01:42:25 And I was struck by the fact that what the commission did, Maxine and I wrote an article

01:42:30 a couple of years ago now, published in Proceedings of National Academy of Science,

01:42:34 on sort of at least alluding to some of the lessons we learned. And one of the lessons we

01:42:39 learned was legislation was probably the worst kind of response that you could make to any of

01:42:46 these kinds of issues. And the second was to put in place a mechanism that allowed you to review

01:42:54 the issue that concerns you periodically so that you can reevaluate whether, in fact, it is as bad

01:43:01 as you thought it was when you first heard it. And two years down the line, you may, in fact,

01:43:05 conclude that there is no risk or else that there is some ethical benefit. In fact, when the report

01:43:12 was issued a few days ago, although I've read only parts of it, I did talk to one of the commission

01:43:18 members. And they did resort to legislation, not because they felt that a moratorium might not work

01:43:25 to the scientific community. They were more concerned about the public IVF in vitro fertilization

01:43:32 clinics and so on and so forth who were going to get involved in doing this. So the legislation

01:43:37 was an attempt to try to head that off. But they did put a sensate clause in, which at least says

01:43:42 we'll go back to look at it again in three to four years' time and see whether any new insights are

01:43:47 available. What destroyed the whole impact of that decision was the president saying in the Rose

01:43:54 Garden that he reviewed cloning of humans or attempts to clone humans as morally reprehensible.

01:44:03 Now, I don't know whether that term is going to come back to haunt him because in three or four

01:44:08 years, when people have come up with rational reasons for perhaps doing it on a limited scale,

01:44:17 this morally reprehensible tag will, I think, really have serious consequences. So

01:44:24 interestingly enough, and I want to draw one clear distinction between the recombinant DNA and this.

01:44:30 Recombinant DNA, we were concerned, as I said earlier, and Maxine has said, we were concerned

01:44:34 with safety and the health of the investigators and the public. We were not concerned and we

01:44:40 didn't pay attention to the ultimate long-term ethical and legal complications. This thing starts

01:44:47 with the assumption it's not so much a public safety issue, it's a moral issue. And in the

01:44:53 climate that we live today, the only thing that seemed feasible was to say no, don't do it. So it

01:45:00 was a little different, but the commission being in place and taking a tentative step, at least I

01:45:06 think, is maybe grew out a little bit of the recombinant DNA experiment. Certainly, I know that

01:45:12 one of the commissioners whom I talked with said, we read your stuff and we understood that there

01:45:18 were things the way we should proceed and not foreclose. And in fact, they left it possible to

01:45:23 do research using animals. And I think that could have been a disaster had they said ban all types

01:45:32 of research that lead to the cloning of any mammalian organism, in which case that would

01:45:38 have been a devastating effect, I think. Yeah, please, Charles. I have a couple of points about what we,

01:45:46 your original question about what has been learned from the early recombinant DNA discussions or the

01:45:54 deferral of the longer-term ethical issues which we're now faced with. One way to learn is to look

01:46:01 at the videotapes of the events that have been described here by many of the people, Maxine

01:46:06 Singer in particular, the Cambridge City Council hearings, the Director's Advisory Committee to the

01:46:11 NIH. Every moment of those things were videotaped. We went down with students at MIT to do it. It's

01:46:20 now part of a permanent record. 120 of the individuals who were involved in these controversies

01:46:26 at that time were interviewed, including five people on this panel, interviewed in 1975. And then

01:46:32 as their minds changed on some of the issues, a few, Paul and Maxine were interviewed again a few

01:46:39 years later. So there is a record if people want to take the trouble to probe into it and they can

01:46:45 get a flavor of the period and learn from it. I think something that wasn't learned was that

01:46:53 public concern shouldn't be treated as hysteria when there is serious scientific disagreement

01:47:00 and when there's uncertainty about the risks. That increases public concern with who's watching

01:47:07 the storm. And it came out in the early 80s, the period we're supposed to be stopping with on this

01:47:13 history today, in the work to release into agricultural production genetically modified

01:47:24 organisms. This was a deliberate and intentional release to make some changes that were seen to be

01:47:31 as beneficial by the company who was doing it compared to the accidental release that people

01:47:37 were worried about in the early recombinant DNA and the silomar discussions. There was enormous

01:47:42 community concern. People felt that they were the last to know. They didn't know whether they should

01:47:48 trust the company doing it because in fact it was a company and they saw it as profit and they

01:47:54 perceived that the regulators who they would like to have trust in and like to have confidence in

01:47:59 the project that the regulators just hadn't been there and hadn't established an appropriate

01:48:04 framework. That was a major crisis for the entire biotechnology industry because the credibility of

01:48:10 the industry was at stake. So that's a chapter that we haven't had time to explore but it did

01:48:14 come up again and I think people were not prepared for it. The things that are directly

01:48:21 concerning me about the lessons, when there was a change of heart and because of public concern and

01:48:29 what scientists felt was overreaction, many of the individuals who had originally called attention to

01:48:35 the recombinant DNA potential hazards, as I said earlier, recanted. They changed their minds and so

01:48:41 forth and some of them went to the point of belittling that early concern, ridiculing it,

01:48:49 saying that this was, you know, a really stupid thing. As Maxine Singer said she didn't feel that

01:48:56 way but some others referred to it that way. I believe that that sends the wrong message to the

01:49:02 next generations of scientists about responsibility. There was a slogan at MIT in 1976 when this

01:49:10 Cambridge City Council was looking into these issues and people were saying shut up or be shut

01:49:15 down. In other words, don't talk about any doubts that you might have about safety because this

01:49:19 enraged citizenry will shut you down. Now that's an extreme reaction but that was the message

01:49:25 I think that some people got and particularly a younger generation. So I was concerned that

01:49:29 the pendulum might swing the other way. The other issue that I think is of major importance is,

01:49:35 and the chickens are coming home to roost on it or the sheep are coming home to roost on it now,

01:49:41 is the deferral of the ethical concerns because scientists say it's too early, we can't do that

01:49:47 yet, so we have immediate problems to think about. And the longer term, more difficult problems

01:49:54 beyond the immediate laboratory safety issues or the agricultural environmental safety issues

01:50:00 are very difficult to deal with and perhaps it shouldn't be the realm of, certainly it shouldn't

01:50:04 be the realm of scientists alone, but those tend to get deferred until there's an immediate crisis

01:50:10 and I think that's a lesson to draw. We had an opportunity to look at these things

01:50:15 in the 1960s when they were first raised by scientists. I'm talking about the longer term

01:50:20 ethical issues of where do you draw the line in human genetic manipulation and we keep on

01:50:26 deferring those. We still don't have the mechanism. I think that the approach of the Human Genome

01:50:33 Project on it is to put those concerns into a compartment. It's over there, it's a

01:50:39 little compartment. The major part of the project works and producing really interesting results,

01:50:47 everyone acknowledging that those results will have important societal implications,

01:50:51 will raise questions of genetic discrimination and insurance employment and so forth.

01:50:56 These are readily acknowledged and the idea is, well, we're going to think about them while we're

01:50:59 doing the work here. We're going to think about them with the committee over in the corner.

01:51:03 That compartmentalization and that deferral, I think, is a continuing problem.

01:51:08 Yeah, Stan. I think there's another thing to point out here. One of the things we learned, in my view

01:51:16 at least, from the recombinant DNA policy experiences is not the issue which you've alluded

01:51:23 to of whether or not it was smart or stupid to have spoken out, but perhaps to have a firmer

01:51:33 ground for speaking out. I think that none of the people who signed the initial letter that Paul

01:51:40 talked about, myself included, would have made such bold statements and recommendations about

01:51:49 scientific aspects of our activities without more data and without some logical basis for

01:51:57 making recommendations, without some scientific basis. And here we were coming up with suggestions

01:52:04 and recommendations and raising concerns with notions that were coming out of thin air.

01:52:10 And as we began to talk more with epidemiologists and microbiologists, with experts,

01:52:17 with expertise in epidemiological spread of microorganisms, the folly of our act in having

01:52:30 spoken out with such little basic knowledge of scientific knowledge of the issues became clear,

01:52:37 at least to me, and I think to some of the others. And it was as a result of that that in the later

01:52:43 years, as those members of the committee know, there was an attempt to come up with a revision

01:52:51 of the Berg et al. letter that we all signed, and we ultimately couldn't agree on the wording

01:52:57 of that revision and it was never published. But from my perspective, one of the things

01:53:05 that I learned, at least, is to have a scientific basis for speaking out on issues

01:53:12 of interest to society. Can I ask, Stan, one question on that? Please.

01:53:19 The one group that prepared for Asilomar that did the most work, that's right, was very serious

01:53:25 scientific work, was the group on plasmids. They produced a beautiful, rich, technical document,

01:53:31 some of the best people, the best people in the field put their heads together on it. I thought,

01:53:37 and you can examine that document, it's part of the record, it's in the MIT archives and perhaps

01:53:41 elsewhere. I thought that was pretty hard work, scientifically, and that was pretty good research,

01:53:46 so I wouldn't belittle the hard effort that you folks put into that. It was the best you could do

01:53:51 at the time. That was something else. That was long after the initial letter. But on the other hand,

01:53:58 things that... Well, but let me make a point, just since you've raised that issue, I want to tell a

01:54:04 brief story which gives you some notion of what was going on at the time. For many years,

01:54:12 one of the restrictions in the recombinant DNA use was a 10-liter limit, okay? That there was

01:54:21 one set of rules if you were working with more than 10 liters and another set of rules if you're

01:54:28 working less than 10. And that came out of the plasmid group recommendations, and let me tell you

01:54:33 how we came to that conclusion. We sat around and discussed what's a reasonable amount that was a

01:54:39 break point, and we said, well, in a day, you can centrifuge down 10 liters in a sorval centrifuge

01:54:46 in big bottles, and therefore, you can have better containment. If you really want to do more than 10

01:54:54 liters, you'd probably need a sharpness continuous flow centrifuge, and it would be more risky,

01:54:59 and therefore, we suggested that 10 liter be the cutoff point. Now, that was adopted by the RAC,

01:55:07 and it was codified in law, not legislative law, but in the rules of the committee,

01:55:13 and it remained, in fact, for all I know, it's still on the books. But the point is,

01:55:20 it was this type of judgment that was made. Yes, we did the best that we could, and

01:55:27 we spent hours and hours haggling about these kinds of issues. That wasn't the issue that I was

01:55:34 referring to. What I was talking about was the initial letter that a number of us signed that

01:55:41 really, in my view at least, did not have the level of thinking that came later on.

01:55:49 Good. This may be a good place for us to begin to draw to a close rather than introduce still

01:55:55 another topic. I think what's come out of our discussion this afternoon has been an interesting

01:56:03 set of investigations about the nature of the research activities in universities as they

01:56:10 relate particularly to their commercial success in the industrial sector. And we've watched this,

01:56:16 and we recognize in the group here a host of people who've been directly involved, either by

01:56:23 moving back and forth between the university and the industrial sector or by being involved

01:56:29 in the processes that the commercial sector engages in, patenting and things of that sort.

01:56:35 What emerges, at least in my mind, from the discussions is that there are a series of issues

01:56:41 still unresolved. The practice is still in fairly fast motion. The differences in local,

01:56:50 across the United States, in national, across national boundaries, in industry expectations,

01:56:57 in university activities, in the nature of research that goes on in each, raises significant

01:57:02 questions about where we're headed and how the different activities of these organizations

01:57:08 will continue. The commercial sector in the biotechnology area is brand new by any long-term

01:57:17 historical standard and historical record. It's still in the process of evolving its forms and

01:57:23 evolving its social relations, relations with the other parts of this society, and with the

01:57:31 relations with longer-term public sanction, longer-term investment, longer-term confidence.

01:57:37 Universities are clearly undergoing enormous change in terms of their scientific sectors,

01:57:42 particularly those sectors which have utilizable products or utilizable intellectual properties

01:57:49 that are developed. And many of us still in universities watching this are aware of the

01:57:56 instability of the institutional forms we now have and aware of the fact that these are being

01:58:03 worked on, they're being experimented with, and we don't have a single national policy

01:58:08 on this at all. We have a host of ad hoc policies, some of which work, some of them don't.

01:58:15 Another area we looked at and began, not as successfully or fully as we might, although

01:58:22 it overlaps, and this is the relationship between scientific activity and public responses, and this

01:58:27 is in a sense where we were as we looked at policy. Policy in the public sector will always involve

01:58:36 segments of the public, whether it be through their elected representatives or whether it be

01:58:40 through single-issue lobbying organizations, the public will have its way in, and to expect

01:58:46 otherwise is to leave yourself open to disillusionment. The public will not necessarily

01:58:53 always be informed in the same way that the expert in whatever the field is will be informed,

01:58:58 and this creates the kind of tension which came out in our discussions this afternoon.

01:59:04 When one looks back at the debates over recombinant DNA and the excitement in those debates,

01:59:12 whether it be in the city council chambers or whether it be somewhere else, it obviously reflects

01:59:16 also a feeling at the time. Why did scientists step out front the way they did, beginning to

01:59:23 assert responsibility? Remember the years, 72, 73, 74, these were the years of the winding down of

01:59:30 Vietnam War when campuses expected intellectuals to take responsibility in ways which they haven't

01:59:38 since and certainly hadn't to anything like the same extent before, and I think the intensity

01:59:43 of that period led to at times extreme statements and led at times to extreme retreats. One looks

01:59:52 back at the history, and it's a fascinating history. I was interested to hear what my

01:59:57 colleagues here felt were the lessons learned, and some of them were right on target. Looking

02:00:02 back at something like the Cambridge Experiment Review Board, which I've looked at in detail,

02:00:07 it was not a bad bit of work. If the public had to get involved, it was an interesting way of

02:00:12 the public giving its sanction to a citizen's board, and when one looks at their very orderly

02:00:19 hearings, when one looks at the report they came out, it was a report which sanctioned and supported

02:00:24 research. Safeguards, yes, but supported research, so that as a model, it's not a bad one, with one

02:00:29 exception. You can't do this on the local level. This was a problem at least of national scope

02:00:35 or international, but in terms of watching and informed and learning citizenry get involved,

02:00:41 it had an interesting bit for us. One problem which hangs out there, the science we discuss

02:00:49 today, this period from the 1950s up to the early 1980s, in the area of molecular biology,

02:00:57 genetic engineering, or biotechnology, as it's become known, was a period of enormous excitement.

02:01:03 The technical successes were striking, and no history will be able to downgrade those

02:01:08 technical successes or take it away. The rapidity of commercial response to those successes

02:01:14 is fascinating when you look at it. The claims for what those successes might bring,

02:01:20 and they do it to this very day, the claims raise questions and leave people nervous. Will you

02:01:26 really be able to find the gene for alcoholism and somehow control it for that poor family

02:01:32 which is suffering from alcoholism, or what have you? The claims made often stimulate praise,

02:01:39 expectations, and at times fears. Part of what we're dealing with in the ensuing time

02:01:48 is the inability to begin to find a modus by which claims, realities, public reactions,

02:01:58 and experts' reactions get in harmony. I think it's the tension that emerges at times as a

02:02:06 scientific community feels under pressure from extravagant responses made to what are sometimes

02:02:13 extravagant claims. Not necessarily claims by all the official bodies, but claims by the scientists

02:02:19 who go before the press cameras or the television cameras to make a statement. What I hear as one

02:02:27 of the things coming out of these discussions, in a way, is addressed by the very thing we're

02:02:32 doing today, and that is put in the record those discussions by participants, by people who ask

02:02:39 questions of the participants, those discussions which invite segments of the public into the

02:02:45 discussion so that they too can learn from the history, in this case relatively recent history,

02:02:52 and begin to put that learning to work as they face the next level of problems, whether it be

02:02:57 the cloning issue which Alan raised or any number of the others which will be coming forward

02:03:06 in the near future. The fact that this science is still on a sharp upward trajectory and this

02:03:15 technology that goes with it leads us to believe that we're going to be back again in the future

02:03:22 to begin unpacking others of the issues which are going to come from this activity.

02:03:28 The answers are not in yet. I'm glad to see something like the Chemical Heritage Foundation

02:03:34 take on the responsibility of both preserving the records, but then also making the educational

02:03:40 materials available so that others can do some of the learning which we've been able to do.

02:03:46 Let me thank everyone on the panel for a really fascinating and remarkable set of discussions.

02:03:53 Let me thank all of you who've sat through these discussions, and particularly thank

02:03:57 Arnold Thackeray and his staff for a superbly organized session.

02:04:03 Thank you.

02:04:33 Thank you.