00:00:30 Good. Our plan for the afternoon is really straightforward, and that is to try to make sense of a number of the issues raised this morning and do it by taking questions which you raised in this array of papers that were handed in as a way into the question.

00:00:51 In some cases, I'll direct a question initially to one or another of the panelists, but I will invite all of them to come in at any point.

00:00:59 I would love to see the variety of interpretations where there is variety, or a consensus where there is a consensus on critical issues.

00:01:08 I'll move across the range from maybe back and forth between things which may be considered more technical to those which may be considered more social, which may have to do with industrial development, but try to deal with the richness of the issues that came out of the discussion this morning.

00:01:30 One of the first I want to turn to is a question submitted by an old friend and colleague in the history of science, and I won't read off the names in all cases, but he went right to the point that is obvious as you look at this group, and that is to ask the extent to which biotechnology is exclusively an American story, as this commentator says, looking at the panel.

00:01:56 Well, that is the question of choice of panelists who could get here, but there's more than that, and that is the extent to which there were patterns in the development of science in the United States in the post-World War II period which seemed to strengthen the American role.

00:02:15 We'd begun discussion of this last night informally around the supper table, and I'd love to move into it, and then I'm going to have a couple of hooks on it after the general American story is what about California?

00:02:28 And I don't mean the general California phenomenon, but links to phenomena like Silicon Valley, which several of you mentioned, the role of place.

00:02:40 Do you get a convergence in place that makes a difference?

00:02:44 I know, for example, that the first conference I ever ran as editor of the Journal of the History of Biology, when someone gave me a small amount of money to bring together both working scientists and historians, where did I head?

00:02:58 The conference site at Asilomar.

00:03:00 I'd never seen it, but I'd heard about it, and this was before the recombinant DNA discussions, but it had a lure.

00:03:09 So I want to ask then, and let me turn first if I can, Paul, to you, because you and I were discussing it last night, and perhaps to George, who was also in our last discussion.

00:03:19 To what extent is the emergence of biotechnology largely an American phenomenon?

00:03:26 And if it is, what were the characteristics that you see as being important?

00:03:32 Paul?

00:03:34 Well, I think if you dissociate different parts of the origin of biotechnology, you talk about the scientific base, I don't think it had a specific locale in California.

00:03:45 I think it was an international effort, and as I told you last night, I took great delight in pointing out to President Mitterrand on one occasion that, in fact, a large number of the American scientists who played a major role in the development of biotechnology

00:04:01 were, in fact, trained at the Pasteur Institute, and, in fact, they, in turn, trained the next generation of people.

00:04:08 So the Pasteur Institute in Paris and the MRC in Cambridge were major players in the development of the technology and the ideas.

00:04:18 The adoption of that technology or its implementation into the industry, I think, clearly is more of an American phenomenon.

00:04:28 And even to this day, 20 years later, the amount of biotechnology companies in France or England are infinitesimally small compared to what's happened in the U.S.

00:04:45 And Japan, which has certainly also been a major player in molecular biology, also has very little in the way of biotechnology.

00:04:54 So we have to ask, what are the characteristics of the American entrepreneurial system, if you will, which promoted it in this country?

00:05:06 And I think the fact that Silicon Valley already had been established as a center of innovation and venture capital and the whole idea of risk and starting new companies, particularly in the computer and electronics areas,

00:05:21 I think made starting biotech companies easier there than anywhere else.

00:05:28 And, in fact, I know from experience that the venture capitalists were on the prowl.

00:05:32 They were constantly prowling the corridors of the university, looking for ideas and tempting people to form companies.

00:05:42 And Bob Swanson, I think, Herb's recounting of Bob Swanson coming to him and saying, let's start a company.

00:05:51 Where did Bob Swanson come from? He was in the venture capital business.

00:05:54 And so he immediately was looking for entrepreneurial opportunities.

00:05:57 And so I thought, just as an aside, I had a trip to Japan some years ago.

00:06:06 I was asked to meet with a large group of business people on the southern island of Kyushu and wanted to know,

00:06:12 how is it that California became the center of development of biotechnology in this country and what was necessary?

00:06:19 And so I began to paint a picture that the funding of biotechnology was an enormous risk.

00:06:27 And, in fact, it was akin to gambling, is that venture capital people essentially accumulated other people's money and then bet on certain kinds of opportunities.

00:06:37 And they know they're going to lose on most of them. And as George pointed out, if they hit on one out of 10, they've done gangbusters.

00:06:46 So the question is, the rejoinder from the Japanese was, but what you describe is illegal in Japan.

00:06:56 In other words, somebody taking other people's money for investment purposes without promising them specific returns or dividends or interest,

00:07:07 but in fact, putting it at risk with the chance that they will lose it is just not acceptable.

00:07:13 And I think to the extent that I've talked to people in Europe, that same issue still pervades the financial markets in Europe,

00:07:25 is putting money at risk without getting some opportunities to call on it or recover it is something that is largely unacceptable.

00:07:33 The second thing is that investors in Europe, I am told, expect to be able to cash in at any time they want.

00:07:41 They want to be able to get at their funding. And, you know, investments in biotechnology companies are not going to bring that kind of an opportunity.

00:07:48 You're putting your money out there for long term with the likelihood that you're not going to get it back until maybe five or 10 years.

00:07:56 And again, the capital markets, as I understand it in Europe, don't accept that format.

00:08:01 So we've got we've acquired a culture. It has been probably more accentuated in California than it was.

00:08:10 But the area around Boston and Cambridge has certainly developed.

00:08:13 And now the East Coast certainly has an enormous number of biotech companies.

00:08:20 But as I understand it, I think two thirds of the American biotechnology companies are centered, in fact, in California, largely in the Bay Area.

00:08:28 George, do you want to add some? Well, Paul's stated it very well.

00:08:31 I think a couple of points at first is I think what is exclusively American, though it wasn't the science,

00:08:36 although it was performed extremely well and was very broad based here.

00:08:40 But what is exclusively American is the idea that the vehicle for doing great things with biotechnology is the small biotech company.

00:08:48 And that and that was not a given. As I pointed out, the small biotech company had to do a lot of things already in existence in larger companies.

00:08:55 So it's not surprising that what I think happened in Japan, for sure, in Europe, to a degree,

00:09:00 is the expectation would be that one of these big companies and they all got interested in biotech.

00:09:05 Japan, tobacco was interested in it. The food companies were interested in it.

00:09:09 The beer companies started quite independently. Then one of them tied in with Amgen and did very well.

00:09:13 But they didn't really believe that a small biotech company would be the vehicle for exploiting biotechnology.

00:09:20 And yet it turned out to be true. So that gave us an exclusive in that we were the country that had the small biotech companies and they were multiplying rapidly.

00:09:29 And if we then say that was essential to the success, as it turned out, we have to say that the venture capital availability was essential to that success.

00:09:37 I don't think that despite the fact that big companies have bought into pharmaceutical companies, I mean, to biotech companies, big pharmaceutical companies and others,

00:09:45 and even oil companies in the early days, the vehicle that really attracted that really got many companies started so they could prove they had an opportunity for public investment was venture capital,

00:09:55 many times in conjunction with big companies. And I think that the venture capital system, the risk capital system in general,

00:10:01 and I extend that all the way over to the public marketplace where there are many investors who are willing to take the risk that Paul just said is not willing to be taken in Japan and sometimes not in Europe.

00:10:11 I think those are the key points. So I think it's a marriage of wonderful science with this wonderful availability of risk capital.

00:10:18 Great. Bill, did you want to add a word? Just to comment on the science itself, whereas I fully agree with Paul that good science was being practiced in Europe and other places as well.

00:10:29 I think we had in the United States a system, an infrastructure which allowed explosive development after a finding was made of relevance.

00:10:43 The labs, big labs in Europe largely, I would say, clearly were up to date in the things that were going on.

00:10:51 But the ability to translate laterally across a large group of individuals was perhaps easier in the United States than elsewhere.

00:11:01 Then just a couple of points to amplify what George has said.

00:11:08 We've mentioned the availability of venture capital, perhaps as an as as a trailing effect of electrical engineering,

00:11:18 increases the semiconductor industry, and that was particularly vibrant in California.

00:11:24 But I think the other important component of that is the public market and NASDAQ.

00:11:32 That kind of public market for which you can essentially recover risk capital, venture capital to reinvest,

00:11:43 doesn't exist in any of the other countries in Europe, and especially this doesn't happen just now.

00:11:51 They're beginning to establish a small cap market in the public level.

00:11:58 And a couple of weeks ago, I was speaking with Robert Jennyard, who was one of the key financial investors in Credit Suisse First Boston.

00:12:10 I was talking with those folks, and I was asking him whether he thought there would be a viable public market in Europe that would be generated for technology-oriented efforts.

00:12:21 He said, not in our lifetime.

00:12:23 He still believes that that aspect, which is crucial, is absent from Europe, and most of the companies want to get on the NASDAQ or some other American exchange,

00:12:34 and as a result, why the drive is toward a relationship with America.

00:12:39 Let me fine-tune this one a little.

00:12:41 Please, Arthur.

00:12:42 This is for the sake of history, and that is that biotechnology was actually more advanced in Japan in the sense, not simply making beer,

00:12:54 but when I visited there in 1957, I was astonished at the kilogram quantities of vitamins, amino acids, nucleotides that we had only available in milligram quantities.

00:13:11 And so the capacity to engineer organisms in the ways available then was very advanced in Japan,

00:13:19 and so we might add that as a footnote, that that kind of science and technology was available years, years before here.

00:13:27 Look, they didn't capitalize on it.

00:13:31 This is one of those aspects that has come out neatly.

00:13:35 The science can be there, but unless something's done with it, and here, several of you pointed to what looked like particular characteristics of the American capital markets,

00:13:47 American financial system, which allowed it.

00:13:49 Let me push this a little bit further in terms of some fine structure.

00:13:53 A couple of people wanted to know whether a local place, San Francisco, University of California, San Francisco, Stanford,

00:14:03 is there something that you would look at, or is it largely individuals,

00:14:08 or was there something built which allowed these places to excel the way they did?

00:14:14 Herbert, you've crossed both parts of that line.

00:14:18 Well, stimulated by the discussion prior to this, I wanted to introduce the possibility that there is an additional factor involved here in terms of the science,

00:14:36 and that is a generational difference, and that rather than geography and nationalism,

00:14:44 although what I'm going to say does have a lot of nationalism involved in it,

00:14:47 but I was sort of trained around the time of the big push forward by the Sputnik and the competition between countries,

00:14:59 and put us in a position where we started to train large numbers of students in the basic sciences.

00:15:07 I came out of that period, and I'd say a lot of good talent came out of those days,

00:15:19 but our background was such that we were very much influenced by the academic environment of all of us,

00:15:29 which was, to a large extent, for good or bad, very negative towards business and capitalism, and so on and so forth.

00:15:39 So there was, in my generation, a lot of, or at least colleagues I happen to be associated with,

00:15:47 there was a lot of anti-government and anti-business sentiment, and our views could be, I suppose, described as very liberal.

00:15:58 And so I can remember around the time of trying to start Genentech that I was very much concerned with how to recruit scientists out of academia,

00:16:16 because I knew of this sentiment that many of my colleagues had.

00:16:24 But I was quite surprised by the people, the scientists we tried to hire at that time.

00:16:31 I remember being very much impressed by several scientists coming to me and said they would like to do something like this,

00:16:38 they'd like to get into business, they saw it as a very fruitful way of exercising their education and pursuing their scientific career.

00:16:49 And I think that this had a lot, I think they probably had a little better education in terms of a broader education than some of us were exposed to,

00:17:02 but that, I was very, I just happened to think of this while you were discussing this issue,

00:17:08 that there is a generational difference in the scientists of the period where I was trained and the ones that are being trained today.

00:17:17 Today, business and industry, biotech industry, whatever, is a very valuable option for many of these people,

00:17:26 as opposed to the day when I was a graduate student when we were very, we looked down our noses at the science being done in the pharmaceutical industries.

00:17:37 So I think there's a difference there. As far as geography is concerned, I don't know if one can really paint a valid picture for that.

00:17:49 I would like to think that the Bay Area was very important to the development of technology, not, I think it was an accident that the biotechnology industry started there.

00:18:00 There was certainly a big contribution from the venture capital atmosphere there, but just the right combination of people came together who did the work and went ahead with that.

00:18:18 But many of the people that we have attracted to Genentech, I think, and I think probably speak for other companies as well,

00:18:27 is that they come to the Bay Area not just because of the company, but because of the intellectual atmosphere provided by Berkeley and Stanford and UCSF.

00:18:37 So I think that's a big magnet and drawing point for many of these people.

00:18:42 Good, thank you. I think you've hit on a number of nice points. I particularly like the implications of the generational shift.

00:18:49 And we may come back to that in a couple of minutes. I want to give it to Charlie and then Stanley.

00:18:53 I want to throw something else into the mix. All of these biotech companies were university linked and based in terms of where the knowledge was coming from.

00:19:03 And the United States has a very large number of research universities over a vast territory.

00:19:10 I think if you take a look at the early companies in the field, you'll probably be surprised that they weren't just at the universities that happened to have been mentioned today,

00:19:20 east or west coast, but at places all over the country. And as the field developed, that's the way it has been.

00:19:27 In Europe, there are fewer research institutions and there are many more countries.

00:19:34 And these are investments that are made. Yes, there are multinational corporations investing, but it's generally there are different conditions,

00:19:43 different regulations in various countries so that it might account for the difference.

00:19:47 I think it's something that ought to be studied. I don't think we're going to thank you.

00:19:51 Yes, there's another issue ever to respond to your question about whether there was something special about the culture at Stanford and UCSF.

00:19:59 I think there was and that it's noteworthy that neither Herb nor I thought initially about patenting recombinant DNA, DNA cloning.

00:20:11 And we were approached by the Office of Technology Licensing at Stanford.

00:20:16 And the fact that Stanford at that time was one of the few universities that had an Office of Technology Licensing in place,

00:20:23 has something to do with the culture at Stanford, a legacy of its involvement in the electronics industry in Silicon Valley.

00:20:32 And UCSF also had a small Office of Technology Licensing in place at that time as well, which, of course, has expanded since.

00:20:44 And based on the models at those universities, analogous offices have been set up now at universities throughout the country.

00:20:52 So in addition to all of the things that have been already pointed out,

00:20:57 I think there was something special about the cultures at these specific universities that contributed to the early days of biotechnology.

00:21:06 That's a very nice point. I think the nature of the university's own approach to just these issues.

00:21:13 I mean, I can remember the discussion at Harvard, which grew out of our own banning any classified research on campus after the Second World War.

00:21:23 One of the things Conan brought back with him from Washington and the spillover from that was often, well, shouldn't we also therefore not get involved in commercial research?

00:21:32 It was fascinating. Now, other changes were made, but there is a and at times different university cultures.

00:21:38 I know a lot of our colleagues who wanted to do research which required defense classification left Harvard to do it because they couldn't.

00:21:47 They couldn't do it within the university, in their laboratories.

00:21:51 Yeah. I'm going to make just a little footnote to an event.

00:21:56 When the Asilomar conference was planned, you remember, I mentioned that it was initiated by a so-called moratorium request.

00:22:05 The people who signed that letter, three of us are up here.

00:22:11 The actual ones who drafted the letter were a group of seven, subsequently joined by Stan Cohen, Herb, David Hognes, and Ron Davis.

00:22:22 What we were asking for is everybody to put a hold on the experiments they were doing.

00:22:29 In contemplation of this meeting at which we would review whether there were risks or not.

00:22:34 A week or 10 days before the conference was to open, Stanford announced the patent claim for the Cohen-Boyer discovery.

00:22:46 You can imagine how I felt. I was the organizer of the or the chairman of the organizing committee.

00:22:53 And I know that I was inundated with telephone calls and outrage.

00:22:58 At what seemed to be to outsiders, a call for everybody to stop the work while Stanford proceeded to apply for the patent.

00:23:08 And I had quite a to do with the trustees and the president university about this issue.

00:23:15 I lost in the end because I felt the patent should not go forward.

00:23:19 And I and perhaps later in our discussion, I will tell you my own views on patenting in general.

00:23:24 But that's just a little footnote to that particular announcement,

00:23:29 which was really almost the first time that anybody who is doing basic research and contributing to the field,

00:23:37 that their university now took their thing and we're going to make a big claim on it.

00:23:42 And bear in mind that although Herb and Stan did the key experiments,

00:23:48 it was based on an enormous amount of information generated by a large number of people.

00:23:53 And and also a lot of input from people in my own department.

00:23:57 So there was a little bit of misunderstanding about why the patent claim should have emanated from Cohen and Boyer and Stanford.

00:24:06 When, in fact, this was had been a community effort in many respects.

00:24:10 Let me take this a couple of steps further, because many of you asked about the patent issue and related questions.

00:24:16 And rather than defer it, I'm quite willing to attempt to be flexible.

00:24:20 And I want to push it in two ways before before that.

00:24:23 You want to come in? Yeah, I think it's why has this emergence been an American phenomenon?

00:24:31 And I don't want it to be lost that the explosive growth of basic biomedical science is due to the NIH,

00:24:43 that these discoveries were made exclusively in academic laboratories.

00:24:48 As Bill has pointed out, they were not made in pharmaceutical companies.

00:24:52 They were not made by venture capitalists.

00:24:54 These were discoveries and academic laboratories supported almost entirely by the NIH.

00:25:00 That is an American phenomenon. Yeah, I wanted to pick this up.

00:25:04 And I was actually turning toward you, Maxine, knowing your role in the NIH and particularly what you see as the culture of the NIH,

00:25:13 both in terms of where it turned its grants, but then in terms of what its research scientists were doing in this aspect.

00:25:21 Actually, I was going to comment on something else, which is not totally unrelated to that.

00:25:28 I suppose it's very hard for all of you sitting out there listening to this to recognize that 25,

00:25:36 30 years ago when all of this was going on, we didn't have the gray heads that we have now.

00:25:43 And because of who we are sitting here now, it's hard to recognize that a very important component,

00:25:53 which Herb sort of talked about, but not really explicitly, is how young everybody was.

00:25:59 It wasn't just the scientists who were young. It was also the people who were starting, the scientists who were starting the companies.

00:26:06 It was the people who were bringing the money.

00:26:10 Bill mentioned how old Swanson was. I'm sorry, Herb mentioned how old Swanson was.

00:26:17 Twenty-nine, you said. And I think that adds, that's another reason why so much of this happened in the United States.

00:26:28 And that's because without any question, it is the country in the world where young people have always had the biggest opportunity.

00:26:38 People with money were willing to give money to young people to start things.

00:26:43 The NIH was always supporting young people.

00:26:47 Now, in part, it was a function of growth at the time.

00:26:51 And I think this played a role in the fact that things concentrated in California,

00:26:56 because it wasn't until after the Second World War that the population of California began to go up.

00:27:03 The universities grew enormously in size in the years so that the faculties at the universities were, on average,

00:27:11 somewhat younger than they were in the East.

00:27:16 And so it was a whole kind of concept of youth and trust of youth, which doesn't go on in European countries to this day or in Japan.

00:27:25 And I really think that that played a very critical role in the whole development.

00:27:32 And with respect to the NIH and the way things have developed, partly because of NIH policies and partly for other reasons,

00:27:45 it is becoming increasingly difficult in the United States for very young scientists to strike out on their own.

00:27:51 We find people with postdoctoral fellowships that keep them in multiple postdoctoral fellowships,

00:27:58 sometimes still in such positions when they're in their mid-30s, whereas most of the people sitting at this table had their own labs well before that.

00:28:09 And I think that's a very significant thing and something we ought to be worrying about, in fact.

00:28:15 That's a nice point also. Let me take this in one other direction.

00:28:20 There's been success now in terms of biotechnology in the United States,

00:28:24 and you've indicated reasons for it, and they ring true.

00:28:30 Surely there's then a feedback from this success as to what kinds of topics,

00:28:35 what kinds of research will be done in the United States as compared to Europe.

00:28:40 Is Europe now, or Japan now, out of some key areas because they've been usurped so completely by the success of biotechnology in the United States,

00:28:52 both at the industrial level and the support that gets into universities that way?

00:28:59 Paul?

00:29:00 Well, I think the name of the game today, at least in many people's minds, is the emergence of what people euphemistically call genomics.

00:29:12 And I think by far the largest number of biotech companies and even the large pharmaceutical companies

00:29:23 are betting on this enormous amount of information which will emerge from the solution of the sequence.

00:29:31 Somebody mentioned the necessity for doing the physiology, and I think it's through the genome sequence

00:29:37 and the recognition of the identification of genes that people will be able to explore the molecular basis of disease and physiology and so on.

00:29:48 And there, too, in this country, we've taken the lead.

00:29:50 We are far out in front of almost everywhere else.

00:29:54 And what I see is when I go around in Europe and Japan is all of them groping for how they can get into the game.

00:30:02 And the game today, at least as it's being funded in this country, is so far ahead of anywhere else that it's catch-up but not very efficient.

00:30:15 And so I see, as we move forward, that the U.S. is almost going to increase its lead in terms of the key discovery.

00:30:24 Now, an important point which I think has to be looked at is are we distorting the research enterprise in such a direction that is becoming more and more oriented to coming up with applicable solutions or discoveries

00:30:41 and ignoring the areas which we cannot yet discern the importance of but which may be the grounds for the next generation of advances?

00:30:52 And, Charles, I just want to remind you that there's a map that was once published of the U.S.

00:30:58 which shows by black dots the location of each biotech company in the United States.

00:31:04 And what you see is that the West Coast from virtually Seattle on down to San Diego is black and from Boston, Cambridge down to Washington, D.C. area is black.

00:31:15 And then you see occasional spots or clustering of spots at the research universities.

00:31:20 And the question you can ask yourself is where is the next massive development of black dots?

00:31:27 And it's going to come to places which are making some new breakthrough discovery.

00:31:30 And we don't know where they are and what field they're going to be.

00:31:33 And that's why I think the importance of having an agency that's still willing to fund pure, unadulterated, curiosity-driven research is so critical because it's from that direction that the next breakthrough will come.

00:31:48 Nobody predicted the recombinant DNA thing.

00:31:50 We were cooking along, doing interesting molecular biology, and then suddenly a technique gets developed that opens the world.

00:31:58 Where is the next technique going to come from, the next insight?

00:32:00 We don't know. But we need a system for funding that opportunity.

00:32:05 And I think the point was made, Europe and Asia and Japan certainly doesn't promote that,

00:32:12 either because they don't bet on young people or because they're not convinced yet that that's the way to develop neuroscience.

00:32:19 Almost CNRS, the Max Planck Institutes, the Pasteur, don't they compete in some way?

00:32:26 Pasteur now is much involved in biotechnology.

00:32:30 They've converted a large part of their activities to more applicable things.

00:32:34 So you think they're being distorted as they try to catch up?

00:32:36 As I think American universities are.

00:32:38 Yeah, Herbert.

00:32:40 I'd like to make a few comments with respect to what Paul has just said and Arthur as well.

00:32:48 And that has to do with what I may inappropriately interpret as an effort to delineate the contributions of NIH versus biotech and other components of the endeavor.

00:33:06 I don't think that the reason we're here today is because there are linear pathways for science, business and development.

00:33:17 I think they're all connected and it's actually a circular pathway.

00:33:22 I believe that NIH in-house and through its extramural grant program is largely responsible for training generations of scientists, which have been very contributory.

00:33:38 I have no doubt that NIH and academic institutions and universities, research institutions can develop the technology that's made available through basic scientific research.

00:33:53 I don't see a big difference actually between basic science and applied science.

00:33:57 I think it's muddled quite a bit and there's a lot of good science that goes on in industry, not in the basic science programs, but in developmental projects as well.

00:34:09 So it's a circular pathway, I think, which feeds on itself.

00:34:14 And I think the findings and contributions made in, for lack of a better term, the golden age of molecular biology were such that they provided a framework for the introduction of a new biotech industry.

00:34:33 That biotech industry in and of itself, whether or not it funds academic research, which it does, it pays its taxes, it returns money to its investors,

00:34:43 but it also provides new problems, provides new materials, research material, which can be used to stimulate thinking and academic research.

00:34:58 And I think hopefully this will continue to circulate.

00:35:01 This might be a naive way of looking thing, but I'm not particularly sure that one can make linear pathways for academic science and industry.

00:35:14 They have to be connected, in my mind.

00:35:17 And I think a lot of credit has to go to the system which allows for this, which is the system we have in the U.S.

00:35:29 And I don't want to be overly nationalistic, but I think that system was put in place by a number of wise people 40 years ago and it's paid off.

00:35:42 And I share the concerns that Arthur and Paul and the rest of us have that this system does need public support.

00:35:52 And in order for it to keep it going, we have to make sure that happens.

00:35:57 You know, you raise a number of interesting questions, some of them historical, which we may come back to,

00:36:02 remembering Vannevar Bush's projection that something like 5% of all R&D money ought to be put aside for things which were not explicitly a goal or mission directed.

00:36:14 The NIH had a more checkered history in terms of what its mission was, and a lot of it was seen as mission, but it was dealing with disease, which was a very broad category.

00:36:23 The question that emerges, though, is not only the money coming in, but also where is the prestige now for the younger investigators?

00:36:32 Where are they going to get the recognition?

00:36:34 Are many of the people who are coming through the departments of molecular biology now being siphoned off into the industrial sector?

00:36:42 Because that's where the fast action is and the remuneration.

00:36:45 You told us earlier today that you made it worthwhile in your recruiting, as well as giving a nice atmosphere.

00:36:51 What is the sense in terms of whether we're going to leave a population among the best and the brightest in the universities and the technical institutes as compared to the very active research sector?

00:37:04 Sam?

00:37:05 Well, that all depends on whether we're successful in providing the vehicle for funding young people that are starting out.

00:37:12 I mean, one of the problems for the past several years has been the inadequacy, particularly during the past several years, the inadequacy of federal funds.

00:37:20 And I know that many of the excellent laboratories at Stanford and other first-rate institutions are turning out people who cannot easily find positions and, in some instances, cannot find positions at all in academia.

00:37:37 And whether or not we are successful in attracting these people to academic positions, to answer your specific question, really depends on, in my view, how successful society is in recognizing the need to provide resources to attract these people and fund their grants

00:38:04 and perpetuate the educational system that has produced what we've been talking about today.

00:38:10 Yeah, we can leave some of these. I want to switch gears for a minute, just so that people in the audience who had other, more science-oriented historical questions in mind can get some of them brought forward.

00:38:22 A couple of questions came forward which had the intent of really asking the difference between the biochemical orientation, in part, I'd say, the kind of thing that Arthur Kornberg was alluding to in his opening remarks, as compared to the more focused molecular biological, molecular genetic orientation.

00:38:43 For example, what if, instead of the group we have today, the mix included Erwin Chargaff, Seymour Cohn, Khurana, Ochoa? Would the story of the development of molecular biology, biotechnology look different with that mix of people, or would it look the same?

00:39:00 You're smiling, Herbert.

00:39:03 I just want to recount something that was attributed to Chargaff, actually. He said that a molecular biologist was practicing biochemistry without a license.

00:39:14 Yes.

00:39:16 Yeah.

00:39:18 You go, Bill.

00:39:20 Well, in most cases, the translation of molecular biology to something useful in the commercial domain requires chemistry, ultimately requires chemistry, because a product has to be defined in chemical characteristics if the product is used as a single or a combined molecule.

00:39:42 And secondly, as targets become better developed, the structural information becomes an important aspect about the development of products which interact with those molecules.

00:39:54 So, more and more, this industry and the science itself is a coalescence of these several disciplines, going from physics, chemistry, and biology, because integrated, they form a whole.

00:40:10 Please, Arthur.

00:40:13 I guess the burden of what I had to say this morning was a reflection on the fact that science is driven by fashion, and it isn't to say it's not without purpose or intellect, not simply hemlines and that sort of thing.

00:40:33 And these fashions are overwhelming.

00:40:36 They have social, economic, and all kinds of personal components.

00:40:43 And so it's natural for a bright young person to go where the action is, where there are meetings, there are symposia, there are jobs, there are grants, etc.

00:40:54 And the consequence of this is that areas deemed unfashionable are neglected.

00:41:02 And I've realized that history isn't reversible, and the new wave of enzymology will take a different direction from the one that we took.

00:41:16 But ultimately, with all the genomics and all the enormous information that we get from gene sequences and arrangements and homologies and motifs and whatnot, we will, as F.G. Hopkins, my hero in science of the century, said, that chemistry or biochemistry won't explain life, but without its input, life will not be explained.

00:41:46 And so there's a plea that in one form or another that there be support.

00:41:53 And the support, Herb, has to come from the federal government.

00:41:58 With all due respect, the biotech venture is in business, and it's not in business to do research.

00:42:09 It's in research to do business and to be profitable.

00:42:13 And large companies may sustain some little alcoves or recesses where people can do what they wish, but largely that's not the case.

00:42:24 And so if we're to pursue knowledge for its own sake, just to understand nature, it's got to be in academic institutions by and large.

00:42:32 Thank you, Walter. Yes, Stan?

00:42:34 Yeah, I think, Everett, it's a little bit artificial to present this as a dichotomy between disciplines.

00:42:43 Clearly, biotechnology is an outgrowth of biochemistry and genetics and microbiology.

00:42:51 And all three components have an important role in what we've been talking about this morning.

00:42:56 I think that I would view it as not saying, well, there's a biochemical approach and there's a genetic approach,

00:43:03 or what we've been talking about really is an amalgam of multiple approaches and disciplines.

00:43:10 To pick up for a moment on what Arthur said about fashionable,

00:43:14 I agree strongly that unfortunately there is a tendency for students, especially young scientists, to pursue what they deem is fashionable.

00:43:28 On the other hand, I would point out to those of you in the audience who are young and trying to decide what you want to do,

00:43:36 that there's some merit in pursuing something unfashionable.

00:43:39 One of the reasons that I became interested in plasmid biology when, as Maxine pointed out,

00:43:45 we were all very young was because it was an area which was not very popular.

00:43:51 And when I was a postdoctoral fellow, I worked on bacteriophage lambda,

00:43:56 which at that time was one of the most competitive areas of molecular biology.

00:44:01 And I once did a calculation of the number of scientists working on lambda and the number of nucleotides in the lambda genome

00:44:10 and concluded that there was a scientist for every hundred or so nucleotides.

00:44:15 And I thought that was pretty crowded, but it was worse than that because scientists were interested in particular genes.

00:44:22 And in those genes, it was even more crowded.

00:44:27 I mean, a scientist was every 10 nucleotides or so, and it's pretty crowded to look 10 nucleotides away

00:44:34 and find that there's someone else working on exactly the same thing you are.

00:44:38 So I decided at that time, since very few people were interested in plasmids,

00:44:44 and plasmids were a very unfashionable area of molecular biology, that that was an opportunity.

00:44:51 And I think that that's often overlooked these days in terms of young people pursuing things that are fashionable.

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

00:45:03 what are those unfashionable areas which I ought to head to because they're going to be good in a few years?

00:45:11 Do you want the answer?

00:45:14 Well, I mean, in a sense, I've tried to do that in multiple aspects of my career.

00:45:21 I think that, as some of you may know, I currently work on RNA decay.

00:45:28 And that, until recently, has been not a very fashionable area of study.

00:45:35 People have been interested in the front end of gene expression,

00:45:38 things that control gene expression at the level of transcription and translation,

00:45:43 and they've considered RNA decay to be a kind of default mechanism.

00:45:47 On the other hand, there are very interesting mechanisms that are involved in this aspect of regulation of gene expression.

00:45:55 I don't know whether this is the place to go into other areas as well,

00:45:59 but there are many areas where there are interesting and important scientific questions to ask

00:46:04 that are not as crowded as the fashionable ones.

00:46:09 That's very helpful.

00:46:11 To follow up in a way, one question came, Herbert, directed exactly to you,

00:46:16 and it follows this in a way.

00:46:18 And the question was whether your initial interest in restriction enzymes

00:46:22 was generated by an anticipation of their potential for being able to purposefully modify DNA.

00:46:30 In other words, someone is trying to find out what the pathway of your thinking was

00:46:35 as you turned toward restriction enzymes.

00:46:42 It might be a little difficult to express it,

00:46:46 but I think you'd have to have gone through the experience of being a graduate student

00:46:52 to know that you were more or less relegated to what your advisor decided you were going to do in your thesis research.

00:47:03 And this observation that I had made as a graduate student was one that I made all by myself,

00:47:10 and this guy, my mentor, wasn't interested in it.

00:47:13 And on the side and in the evenings I tried to learn a little bit more about it.

00:47:20 And so I guess my initial interest was, one, it was a very self-fulfilling gratification

00:47:28 that this was something I had discovered.

00:47:32 I wanted to find out what it was.

00:47:34 So that was my initial interest.

00:47:36 And then as I progressed through postdoctoral fellowship and what have you,

00:47:45 it became clear, as I said through the work of Arbor and DeSwal,

00:47:50 that there was a lot of specificity involved at the DNA level.

00:47:54 And this presented the opportunity to look at a unique model for protein-DNA interaction.

00:48:01 And secondly, we didn't know in those days whether the breaks were, how specific they were,

00:48:11 what the recognition was, but I think there was some thinking at that time in my mind

00:48:23 about how it might be used to dissect small chromosomes.

00:48:28 But it was a very fleeting thought.

00:48:31 I think I may have put it in my original grant request, but I don't remember.

00:48:36 But I never thought about the commercial possibilities

00:48:41 until Stanley and I had done the initial experiments.

00:48:53 And as Bill, I think, said,

00:48:56 most of the large companies were not interested in the technology at that particular time.

00:49:01 I remember talking to at least one liaison person from a drug company

00:49:08 that used to come through the department every once in a while and talk to people,

00:49:11 and I tried to get him interested in this.

00:49:13 And he said, oh, it's very nice what you're doing.

00:49:15 It's interesting, but it's 10, 20 years away.

00:49:18 Just keep on doing what you're doing, and we'll check in with you now and then and see how it's going.

00:49:23 So it was at about that time that I started thinking about possible ways

00:49:30 to use the technology to make drugs.

00:49:36 I won't go into any little stories.

00:49:39 Very nice.

00:49:40 Thank you.

00:49:41 Yeah, Paul, you wanted to come in.

00:49:42 Yeah, I want to comment a little bit on a thing that Stan put up and one that offered.

00:49:49 I got my early training in enzymology.

00:49:51 In fact, I was a postdoctoral fellow with Arthur for several years.

00:49:56 And at one point, I guess I did what we all said, maybe one of us has to branch off completely

00:50:04 to go into a different field.

00:50:06 And I chose to go off on sabbatical and work on tumor viruses.

00:50:12 And I recall, I hope Arthur won't mind if I recall, that he told me I was wasting my talent

00:50:20 by leaving enzymology and the tried and true path of E. coli enzymology.

00:50:26 That's true.

00:50:27 It's still true.

00:50:28 It's still true.

00:50:31 And that I was really jeopardizing a career by making this transition to a Murphy system

00:50:38 that was going to have to work with cells and not purified enzymes and so on and so forth.

00:50:45 But I guess like, as he said, I was young and brash and I was ambitious

00:50:49 and I wanted to do something different.

00:50:52 And I frankly thought that the route to doing something different was to move to animal cells

00:50:58 and ask whether the themes and paradigms that had been developed with E. coli

00:51:02 were also true of higher organisms.

00:51:04 And working through viruses was a procedure that had worked with the phages

00:51:09 in understanding E. coli and certainly would do that.

00:51:14 Now, SV40, which is a virus I work on, is a circular DNA.

00:51:21 And one of the things that I had learned from my colleague Gail Kaiser

00:51:26 was that the lambda chromosome is a linear molecule and therefore has defined ends

00:51:32 and you can map things along relative to those ends, relative to their distance.

00:51:37 But if you have a circular molecule, you have no reference point.

00:51:42 And so in 1968, when I came back from the Salk Institute sabbatical,

00:51:48 I heard about restriction enzymes.

00:51:50 And I thought, well, maybe restriction enzymes actually might cut the DNA

00:51:54 and provide us with a reference point.

00:51:57 And so I called Herb and asked him if he could, actually I think it was not Herb,

00:52:03 not Herb, but Matt Messelson, who sent us two of the enzymes that Herb said

00:52:09 don't make specific cuts.

00:52:14 And then we heard about EcoR1.

00:52:16 I called Herb.

00:52:18 He didn't give us buckets, but he gave us some enzyme.

00:52:22 And John Morrow, a graduate student in my lab, showed that EcoR1 did in fact

00:52:27 cut the DNA once and did in fact open it at a unique site.

00:52:31 And for the first time, we had a reference point to which we can map both physical features

00:52:37 and genetic markers and genes.

00:52:41 And so in terms of using restriction enzyme, not to paste things together,

00:52:47 but in fact to just do a job of cutting the DNA and opening it up.

00:52:54 And I'll just tell one other little footnote because it relates to what Herb also mentioned,

00:52:58 and that is one of my students, Janet Mertz,

00:53:03 and one of my colleagues on the department, Ron Davis,

00:53:06 actually began to explore this cut SV40 and found that it cyclized.

00:53:13 It formed circular molecules under certain conditions,

00:53:16 but these could be melted out as you raise the temperature.

00:53:20 So if you raise and lower the temperature, the molecule goes from a circle to a linear molecule.

00:53:25 And the deduction was quite clear on the experience with Lambda that it must have cohesive ends.

00:53:31 And we called Herb, who was then working with Howard Goodman, and told them of our result.

00:53:37 They dashed down to Stanford and we discussed the thing and divided up the problems in two ways.

00:53:43 One was to explore the implications of the so-called cohesive end,

00:53:47 and the San Francisco group determined the sequence at the cleavage site.

00:53:52 Somebody earlier mentioned the place.

00:53:57 And it's very clear that the fact that we could communicate so easily,

00:54:01 we had met at many seminars, we had gone from Stanford to UCSF and back,

00:54:06 that the proximity, the friendship, the relationship,

00:54:10 made it easy to do things not in a collaborative sense necessarily,

00:54:14 but helping each other and doing that.

00:54:16 And I would venture to ask whether you two guys, Stan and Herb, would have actually collaborated

00:54:22 or even sort of sat down and had your pastrami sandwich in Hawaii,

00:54:28 over which you cooked up this experiment and then made the collaboration easier.

00:54:34 Now if you'd been on the East Coast and Herb on the West Coast,

00:54:38 it's a real question about whether this collaboration would have matured in the same way.

00:54:44 I think it's a very good point.

00:54:46 I think it is a good point, too.

00:54:48 And I'd just point out that at this conference, prior to my discussions with Stanley Cohen,

00:54:54 I had talked to Stanley Falco, who was also a plasmodologist.

00:54:59 And Stanley, I think, was in Washington at that time.

00:55:02 And Stanley said, we're too far apart.

00:55:04 He says, Stan Cohen's very close by and he's interested in doing this.

00:55:09 And he's much smarter than I am.

00:55:13 I was happy that Stan was agreeable we could do that.

00:55:17 So I think it's a good point.

00:55:21 Thank you.

00:55:22 I'd like to shift gears again for a minute, if I may,

00:55:26 and turn back to a question which we'd begun addressing but hadn't gone into directly.

00:55:32 And that is the question of patenting, what it is and what the differing views are.

00:55:38 And here I'd like to begin by turning to Charles Weiner, who has been engaged in this discussion at one level,

00:55:45 and to George Raftman, who obviously is right smack in the middle of it,

00:55:49 in his leadership in the industrial sector.

00:55:54 What about the implications for the way in which science is done for university-industry relations

00:56:03 if patents are granted for whole genomes, for DNA sequences,

00:56:09 even without knowing their function, or for organisms themselves?

00:56:13 We've now had, what is it, 1980, we said the first patent was given for an organism.

00:56:18 We've now had 17 years of experience.

00:56:22 What are the implications now, particularly as we watch in those 17 years

00:56:27 this enormous burst of energy in the biotechnology field?

00:56:31 Charlie, why don't you start?

00:56:33 Originally, there was a great deal of resistance to patenting in the academic world,

00:56:39 in particular in biomedicine.

00:56:41 And of all fields, this was felt that if any patenting was allowed in other fields,

00:56:47 that you'd have to be very careful in biomedicine.

00:56:50 This goes throughout the 20th century, and there was certainly the position in the U.K.

00:56:56 And in the U.S., there were statements by medical people, by university researchers,

00:57:01 said we should not profit from the public's ills.

00:57:04 Where there was patenting, there wasn't an aggressive approach,

00:57:09 and there were considerable controversies in universities

00:57:12 over a number of medical devices and pharmaceuticals as well.

00:57:18 It doesn't mean that university professors didn't consult for companies,

00:57:24 but there was strong resistance to it.

00:57:27 So when the Supreme Court decision came down in 1980,

00:57:34 it opened up a very large discussion, not only for the leaders of major religious groups,

00:57:42 wrote a letter to the President of the United States saying that this raises very serious implications

00:57:47 because not only is it in the field of biomedicine,

00:57:49 but specifically it has to do with genetic manipulation and tinkering with life.

00:57:53 And it raised for them the deeper moral issues,

00:57:56 and a presidential commission was appointed to consider those issues

00:58:01 on the basis of the patenting decision.

00:58:04 At universities, there was a very great amount of confusion

00:58:09 over the effect of this on the informal communication, as I mentioned this morning,

00:58:15 and the free flow of information, the free flow of cell lines and bacterial strains and plasmids.

00:58:22 And pretty soon people were signing agreements and specifying that if I give this material to you,

00:58:29 which I've always done, now you'll have to sign a form on it,

00:58:34 so that I know that you won't, as the President of Stanford said at the time,

00:58:38 that you won't clone it and patent it.

00:58:41 So you found a great deal of resistance to it and a great deal of confusion.

00:58:46 Coming back from that older tradition about is it appropriate for a university professor

00:58:52 to engage in commerce and to profit from federally funded research,

00:58:57 university professors traditionally, even though there had been involvement,

00:59:01 on the whole they had said over the years that we want special privileges as academics,

00:59:06 we have a special ethic, we like to be left alone,

00:59:10 to choose our own research problems so that we can be protected from the,

00:59:14 and we are protected from the marketplace so you can trust us.

00:59:18 Now there's a rich tradition and history of science showing where that changed,

00:59:22 but this was the overall ethos.

00:59:25 Jumping from there to the more recent period, patenting is the norm.

00:59:30 There's a new status quo.

00:59:32 Universities have aggressively set up technology licensing offices.

00:59:37 They encourage and in some cases pressure their faculty to patent

00:59:42 and then approach them about starting companies where the university would,

00:59:48 as the owner of the patent, if you work for a university,

00:59:51 the university can't apply for the patent, but they encourage you to

00:59:55 and then you assign the rights to the university.

00:59:58 You may get a percentage, a small percentage usually, of the royalties should any be forthcoming

01:00:04 if the university was able to license that patent.

01:00:07 Universities now are saying we will provide the patent to you

01:00:12 and we'll help you raise venture capital to set up a company

01:00:16 and what we want out of it is some return.

01:00:18 So their venture capital that they're bringing to it very often is the patent itself.

01:00:23 It's a very large change.

01:00:26 It sets up questions about do you hire faculty because of their ability to bring in patents,

01:00:33 because of their entrepreneurial nature, who makes those decisions,

01:00:39 what about the effects on young scientists, and so forth.

01:00:42 So there's been a real shift in the status quo and the issues are not settled.

01:00:49 The same issues persist.

01:00:51 Thank you, Charles.

01:00:53 Yeah, George, you must look at this from a very different direction,

01:00:56 so I'd be interested in your own take on the subject.

01:00:59 Well, first of all, there are much better qualified people here to comment on the pros and cons

01:01:03 of the attitudes about professors if they're being stimulated to do patents,

01:01:07 how they're going to be recruited, how they're going to be rewarded,

01:01:10 and I really don't think I can look into that carefully enough,

01:01:13 but I can tell you what the impact on a biotechnology company is,

01:01:17 and that is we're forced to think about how we can get a return

01:01:24 on the investments that are being made.

01:01:26 Our investors are risking their money.

01:01:28 They're looking for a better-than-average return, so that guides us in certain ways.

01:01:32 One is that if we're going to have a success, we'd better be able to protect it,

01:01:35 because we certainly aren't one of the bigger companies around,

01:01:38 and that goes even for Amgen.

01:01:40 That certainly goes for the new company I'm associated with, Icos.

01:01:43 If we don't have something that gives us an extra shield,

01:01:46 we will not be able to return a profit from even good ideas.

01:01:50 If you look also at the enormous amount of money and the connection with the exact place

01:01:54 where people may think patents have some ethical overtones that are negative,

01:01:59 it's exactly that place where you're going to spend $400 million or $500 million

01:02:02 to get a product approved, and if someone can cherry-pick afterwards

01:02:05 which ones were successful and which ones were not,

01:02:09 they would have very little trouble, even if you didn't disclose the nature

01:02:12 of what you're doing, to retro-engineer, take a piece of the material,

01:02:16 clone it, express it without much time.

01:02:19 So you wouldn't really be able to protect anything in the face of much stronger companies.

01:02:23 So it's absolutely essential.

01:02:25 It also induces us to do hard things and new things, which I think is very productive,

01:02:30 because obviously if patents aren't going to be important,

01:02:34 then maybe you're much better off to copy somebody else instead of doing something new.

01:02:39 And lastly, the patent system, as a lot of people understand,

01:02:42 and I certainly understand it, is an astonishingly good communicator

01:02:46 of implementable facts concerning every invention.

01:02:51 And these days the situation is that if you want to have worldwide protection,

01:02:56 and you certainly want that because you'd hate to encourage a big competitor

01:03:00 coming out in Europe or Japan, so you look for worldwide protection,

01:03:04 within 18 months, at the outside 20 months from the time you filed your U.S. case,

01:03:09 if you filed overseas in a timely way, it will be published overseas.

01:03:13 And eventually it will be published in the United States,

01:03:15 as we now know that there are some changes underway.

01:03:17 So the idea that enormous delays in communicating from scientist to scientist are occurring is not true.

01:03:24 Now that's not quite the same as Herb and Stan talking to each other about their latest result,

01:03:30 which does happen when there is academic collaboration.

01:03:35 It does not always happen when there isn't academic collaboration.

01:03:38 There's not a huge incentive for a scientist to tip off a fellow scientist

01:03:42 as to what might be the next most fruitful experiment to run,

01:03:45 and I don't think it necessarily happens in real time.

01:03:48 But it could happen in less than 18 months.

01:03:50 On the other hand, those disclosures that go into the patent office by law

01:03:54 and for a valid patent have to be total and implementable and enabling,

01:03:59 and that's a pretty fine disclosure, sometimes better even than what's in a publication.

01:04:03 So the enormous downside that's seen by some doesn't seem near as significant

01:04:10 as the downside of just, frankly, leaving a biotechnology company

01:04:14 with wondering what the heck they would work on

01:04:16 if they didn't hope to be able to protect something with a patent system.

01:04:20 Yeah, let's get Bill, and then I'll come back to you, Paul.

01:04:23 As I mentioned this morning, I think that in the early 1980s,

01:04:29 personnel moved primarily from universities into small or large companies, not vice versa.

01:04:35 I think there's a fair degree of movement now backwards,

01:04:38 and that fact isn't necessarily to prosecute research for which patents of value are developed.

01:04:47 It's because of an intrinsic interest in the science that goes on in universities,

01:04:51 and there's a vibrant interaction now.

01:04:54 I also would make the point to sort of supplement the other comments that have been made.

01:05:00 I believe nowadays that research, though dominantly supported by the NIH,

01:05:05 is substantially and significantly supported by complementary research in companies.

01:05:12 Certainly, for example, the discovery of hepatitis C, which happened to occur with us,

01:05:18 would have been quite difficult in a singular laboratory in the university,

01:05:23 although it would have happened at some time.

01:05:26 Other kinds of things that are going on, the development of a facility to measure

01:05:32 a single or small number of molecules of nucleic acid,

01:05:36 the development in companies like Affymetrix to do matrix displays,

01:05:42 which are going to be important for research in general as well as commercial research,

01:05:47 all those kinds of activities indicate a kind of complementarity which exists between those two organizations.

01:05:54 Finally, I'd say that if you took a look at the research which is going on in universities,

01:05:59 do we have a real distortion that is aimed at providing patentable materials

01:06:07 and therefore commercial rewards?

01:06:10 Well, perhaps to some degree, but I would posit to a very small degree.

01:06:15 We have a vibrant, interesting group of young people who are interested in science per se,

01:06:22 in systems which are unlikely to give a patent per se,

01:06:26 but really understanding biology itself and human biology is a commanding interest

01:06:32 by a majority, I think, of people in science.

01:06:36 Yes, please, sir.

01:06:39 Just to give you a few personal anecdotes,

01:06:43 I can remember when Stan called me with a request from their patent and licensing office

01:06:50 that they wanted to patent this technology,

01:06:53 and my first words to Stanley were, that's illegal.

01:06:57 And even though I had signed a piece of paper when I joined the faculty at UC

01:07:04 dealing with patent issues, I don't think I even read it.

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

01:07:11 And so I'd been totally unaware of what patents were, had no idea they played a role.

01:07:17 I'd heard about them, I'd heard about Thomas Edison and whatever,

01:07:20 but I hadn't really paid much attention to it or the particular role it played in commerce.

01:07:25 And when Stan and I got involved with the patent process, I learned a little bit about it,

01:07:32 but I couldn't stand all the little details that had to go into writing a patent,

01:07:39 and fortunately Stanley was very good at that, and he gives us the credit for putting that effort into it.

01:07:45 But, you know, patents have a history from the 15th century,

01:07:53 and I think they serve a very valuable and commercially valuable mechanism for industry.

01:08:05 They were introduced to Venice by the Doges, primarily in the glassware business,

01:08:11 as a way of attracting talent and in turn jobs and commerce to Venice,

01:08:18 and they had to do so by providing an incentive,

01:08:21 and that incentive dealt with providing them with some form of payment if they would divulge their information.

01:08:29 This system spread throughout Europe and impressed such people as Thomas Jefferson,

01:08:35 who incorporated in the Constitution right here in this city as one of the features of the Constitution

01:08:41 that patents are a viable system of our country.

01:08:47 And I had myself, and I think many scientists of that generation,

01:08:54 were totally ignorant of exactly what a patent was,

01:08:57 and it took a long while, and we had to put up with a lot of criticisms from various individuals

01:09:04 about how we were going to destroy science and communication and so on and so forth,

01:09:09 and many of them thought that they would not be able to use this technology in their laboratory

01:09:16 unless they paid a royalty to UC and Stanford, and there was a great deal of misinformation.

01:09:23 Fortunately, I think that has been taken care of today.

01:09:28 But I think patents do encourage innovation and risk-taking.

01:09:35 There are some examples.

01:09:37 There was a family of Dutch physicians that were actually obstetricians,

01:09:44 and one of them invented the forcep method of delivering babies,

01:09:49 and this was a closely guarded secret which they kept in the family for many years

01:09:54 and therefore was only used by royal households because they could afford to put forth

01:09:59 all of the appropriate monies to satisfy these individuals.

01:10:03 So if they had had a way of patenting this, they might have been able to have been more widespread.

01:10:11 But I just close by saying that our patent attorney said that,

01:10:19 which I think is a true statement, a patent is nothing more than a key to the courthouse door,

01:10:25 and the fact that you have a patent doesn't mean that it is actually valid or enforceable.

01:10:30 It will be challenged, and the more broad it is, the more impact it has,

01:10:35 the more challenged it will be by your competitors.

01:10:39 And I might say that a lot of the issues that we originally started out with

01:10:42 I think are going to be dealt with and adjudicated and dealt with in the courts,

01:10:50 and I think there has been some recent decisions which are taking a much more narrow focus

01:10:57 towards the patents in the biotech industry.

01:11:00 Yeah, Herb, you've left us at a very good point.

01:11:03 My managers tell me that it's important for us to take a brief break now, so let me thank you.

01:11:10 We can pick this up because I think there are elements of patents

01:11:13 and what has got to be the two-way relationship between industry and university

01:11:18 which are worth further exploration.

01:11:20 But thanks a lot for this start.

01:11:22 We're going to take a 15-minute break and then be called back.

01:11:26 All right, let's come back to the second half of our discussion.

01:11:30 As we broke, you remember, we were right smack in the middle

01:11:33 of what I thought was a fruitful, if somewhat hot, exchange on patenting and what it means.

01:11:41 There was the question, in a sense, of patenting from the industrial side.

01:11:45 Charlie raised the point of patenting from the university side,

01:11:49 and I felt around me some urgency to get some things out.

01:11:54 Paul Berg, you were about to speak.

01:11:56 I think it's terribly important to understand the distinction

01:12:00 between the legitimacy or value of applying for patents from the industrial side.

01:12:07 That's the intellectual capital.

01:12:09 They have to protect that.

01:12:10 There's no argument.

01:12:11 Nobody's ever raised any question about whether a new company

01:12:16 that makes some discovery that they think has value of patenting.

01:12:19 They're doing it aggressively.

01:12:21 God bless.

01:12:23 The question, I think, that was raised is what's the consequence

01:12:28 of an aggressive patenting policy on the part of research institutions

01:12:33 like academic or even the NIH, let's put it.

01:12:39 There I think I do have some real concerns.

01:12:43 Let me start off by saying that I think the Stanford-Cone-Boyer patent set us on a bad course.

01:12:52 So I'm going to say that right off.

01:12:54 Because I think the reaction on the part of many scientists was,

01:13:00 hey, wait a minute, where does Stanford and UC get the entitlement to this whole thing?

01:13:06 Because the broadness of the patent that was actually approved

01:13:10 essentially preempted almost any kind of cloning operation.

01:13:15 It said, in all possible hosts, in all possible vectors,

01:13:19 joined in all possible ways with all possible DNAs.

01:13:23 And that left nothing for anybody to explore.

01:13:27 So there was a certain amount, I certainly heard it, resentment.

01:13:32 One reaction to that resentment was a tit-for-tat one.

01:13:36 So Columbia then applied for a patent for being able to introduce DNA into mammalian cells.

01:13:45 Something that we were all doing and had been relatively routine.

01:13:50 So now Columbia had preempted.

01:13:52 So anybody who wants to now introduce DNA into a mammalian cell,

01:13:56 any commercial or for-profit thing, has to now pay Columbia royalties.

01:14:03 And I think both of those have set in train a whole attraction.

01:14:08 It's not difficult to see that an enormous income flow can be generated from a successful patent,

01:14:15 especially if you can make it broad enough to include everybody having to pay your royalties.

01:14:21 It's become very, licensing offices and universities, I think,

01:14:26 have become more and more aggressive in pursuing patent opportunities.

01:14:30 So, in fact, they are having a hand in directing some of the kind of research that goes on.

01:14:37 Because, as I was recounting earlier, my own experience is I had a student who made a discovery

01:14:42 which he thought had commercial value and he called up the licensing office on his own.

01:14:47 They sent over a battery of lawyers and they sat with them for a week

01:14:51 figuring out how to capture this mythical invention.

01:14:57 And, in the end, he had to do experiments to satisfy their needs

01:15:02 to validate the claims that they were putting forward.

01:15:06 And I was astonished because that was not his role.

01:15:09 He was there as a PhD student and it wasn't his job to try and figure out

01:15:13 how to make some future income from his discovery.

01:15:16 He was there to explore, I thought, the relevance and physiological significance

01:15:22 of this protein that he had discovered.

01:15:25 More and more, what I find is, as Herb alluded to, patents are an incentive.

01:15:31 Well, they're also an incentive for academic investigators.

01:15:35 And to the extent that that incentive distorts the kind of research they choose to do.

01:15:40 One, the path that they take when they come to a fork in the road

01:15:44 and a decision has to be made whether you go this way or that way

01:15:47 and this way has a chance for a patent and this one is pure research.

01:15:51 The question is, to what extent will that choice be distorted

01:15:57 to change the vector of what I'll call curiosity-driven research exclusively.

01:16:02 And even if the vector change direction is small, over time it's magnified

01:16:08 and will produce a big change in the way we do science.

01:16:11 Now, whether there will always be people who will say, I don't care about patents,

01:16:16 but what I find is that there are more and more people who do care about patents.

01:16:21 And one of the consequences are that when something is in the process of being

01:16:27 produced as a patent, suddenly your colleagues can't talk about something.

01:16:32 They can't publish or they can't present it at a symposium

01:16:37 because the lawyers have told them that patent application would be null and void,

01:16:43 at least in certain circumstances, if there's any public disclosure.

01:16:47 And so I think all of these things we've not taken account of

01:16:51 and I personally believe that they are going to do us harm in the long run.

01:16:56 More and more emphasis, the more and more facing up to trying to generate income

01:17:01 from intellectual advances in the university.

01:17:05 That's not to deny that the university is entitled in some way

01:17:10 to recompense for the discoveries that is generated.

01:17:15 But the mechanism that's being used is in fact, I think, that one.

01:17:19 I much prefer having industry essentially feedback support to the basic science enterprise

01:17:26 than it is by just applying for patents and then trying to recover it from industry

01:17:30 through royalties and licensing.

01:17:33 Thank you very much.

01:17:35 I can imagine that my colleagues over here...

01:17:39 I don't disagree with Paul entirely.

01:17:44 I think there are some other thoughts that should come into this.

01:17:48 I think there is potential for abuse and I'm concerned about that too.

01:17:53 But everyone's guaranteed to the right to have possession of their intellectual property

01:18:00 and whether they're scientists or not, they're capable of generating intellectual property

01:18:06 and they have the right to protect that if it's innovative and what have you.

01:18:11 I think it's certainly the policies of most institutions may or may not reward the inventor

01:18:22 but they certainly do always reward the institution.

01:18:26 It can be a rather small but still effective way of helping to fund the activity of institutions.

01:18:35 But I don't think that there's much difference between a graduate student

01:18:40 who does something very important and significant to have the right to that intellectual property.

01:18:45 Now how it's distributed is one thing.

01:18:47 Who gets the recognition?

01:18:50 That is very much dependent on the patent system and the patent law.

01:18:55 And it's a reduction to practice and it's an enablement,

01:19:00 which are the key terms and I don't understand what they mean

01:19:02 but that's what the lawyers talk about all the time.

01:19:05 There are some very critical assessments of the patent application process.

01:19:10 But I mean I can't see much difference between that and numerous books that have been copyrighted

01:19:18 and come out of graduate PhD theses throughout the country and the world.

01:19:24 Yes, Stan and then Charles.

01:19:26 Yes, actually when the technology licensing department at Stanford first contacted me,

01:19:34 my reaction was very much that of Herb's.

01:19:38 Gee, this can't be patented. This is basic research.

01:19:42 How can you patent basic research?

01:19:44 And besides, it's dependent on all of these findings that have occurred in molecular biology for the past 15 to 20 years.

01:19:53 And I was assured that no invention is made in a vacuum.

01:19:58 Every invention is dependent on something that preceded it.

01:20:02 That the key features required for patenting is that it has to be novel

01:20:08 and not obvious to use the term one skilled in the art and also enabling.

01:20:15 And Stanford felt that it was and they convinced both Herb and me

01:20:21 and the people at UC did also that Stanford was entitled, as Herb said, to recover something from this.

01:20:29 Otherwise, industry using this technology would really get greater profits on the industrial end.

01:20:38 And Stanford was entitled to share some of those profits that this wouldn't inhibit any academic use of the intellectual property at all.

01:20:46 And on this basis, Herb and I decided to proceed on that.

01:20:50 Now, some of the points that Paul raised as areas of potential abuse, I think, are areas of potential abuse.

01:20:58 But whether or not they're areas of actual abuse depends on how you run your lab.

01:21:03 Since the initial patent that we've been talking about, Stanford has applied for patents on a number of other things that I found out

01:21:14 and my colleagues and I have found out in my lab.

01:21:17 And the processes that we followed have been that we don't delay the publication for one day in order for Stanford to apply for patents.

01:21:29 If they wish to apply for a patent, they've got to get their patent application in on a schedule that allows them to meet whatever deadlines or else it's too bad.

01:21:40 Similarly, Paul talked about the technology licensing office lawyers coming over and telling his graduate student what to do.

01:21:48 That's never happened to me and I wouldn't permit it because I certainly would not pursue any area of investigation for the area of a patent, for gaining a patent.

01:22:02 But if a patent comes out of the work, I see nothing wrong with the university pursuing that patent application and providing them with the information that allows them to do it.

01:22:14 Now, similarly, I think that there are various practices for intellectual property.

01:22:21 I've always sent out my plasmids freely and with no requirement.

01:22:26 In fact, Paul and others know that after the initial concerns were raised about biohazards, in fact, even prior to that,

01:22:36 there was only one restriction on my sending out the PSC-101 plasmid,

01:22:42 which at that time was the only plasmid suitable for DNA cloning or that anyone knew was suitable for DNA cloning.

01:22:50 And that was that it not be used to create new combinations of antibiotic resistances.

01:22:57 And subsequently, after the recommendations of the committee that Paul talked about,

01:23:03 my restrictions extended to include the other recommendations of the committee.

01:23:11 But I think that, yes, a patent opportunity can be abused, but that doesn't mean it necessarily has to be.

01:23:20 One can conduct a patenting practice at a university in a very straightforward way that doesn't allow abuse in a laboratory

01:23:29 and at the same time allow the university to derive a fair share of income from that intellectual property.

01:23:37 Good. Thank you, Stan. Charles?

01:23:39 I'd like to mention another problem that flows out of what every patent attorney knows,

01:23:45 and that is that a patent is only as good as your willingness and ability to defend it in court if necessary.

01:23:53 When a university gets involved in a patent, if they're serious about it, they must defend it.

01:23:59 And then they run the risk of impairing their credibility as an institution of learning and research

01:24:05 publicly funded with a special status in society because they act like a business organization in defending their property.

01:24:12 This has come up historically, and it came up, for example,

01:24:16 when Cetus said around the mid-'80s that they wouldn't honor the Stanford recombinant DNA patent,

01:24:25 even though, of course, you were involved with Cetus as a consultant,

01:24:31 that they wouldn't honor the patent.

01:24:33 And there was a threat, and the university countered and said,

01:24:38 we put aside a war chest of a large sum of money from the income that we've already derived from the patent,

01:24:46 and we're prepared to fight it.

01:24:47 Unfortunately, it didn't happen.

01:24:49 There was an amicable, I think, agreement, and the university and Cetus wasn't put in that position.

01:24:56 But that's another thing to take into account.

01:25:00 Things have changed a great deal, and I think the discussion is today about how much they have changed

01:25:09 and how to sort of minimize the frictions.

01:25:12 But there really is a strong change from the period prior to this work getting started.

01:25:19 Charles, fine, thanks.

01:25:20 A two-minute clarification from Paul.

01:25:22 Herb made the point that patenting in a commercial entity does not preclude the use of that invention for research.

01:25:31 Point of fact, I always believed that, and I think all of us in academia have always believed that.

01:25:36 But I actually queried a lawyer who is well-versed in this field and said that's not true.

01:25:41 There is nothing in the law that says a company cannot preclude your use of their intellectual property.

01:25:49 And, in fact, Arthur's been involved, Promega, who has tried to prohibit people from making an enzyme that they had—

01:25:57 Roche.

01:25:58 Roche? I'm sorry, Promega is the target of—

01:26:01 Yes, exactly.

01:26:02 But, Paul, that's a company that what a company does is the universities don't do that because that's not their policy.

01:26:07 No, no, I'm just—

01:26:08 No, I mean—

01:26:09 Make the point that patenting does, in fact, impact on the use of technology, methods, tools, if they want to enforce it.

01:26:18 To make a profit. I mean, unless—

01:26:21 Only to make a profit.

01:26:22 Unless the scientist who's having problems is making a profit, he's not precluded. I mean, how else can you enforce it?

01:26:31 If I can just add to that.

01:26:33 Okay.

01:26:34 They can say that any discovery that you make may, in fact, be patented by your university.

01:26:40 If it was made using our patented reagent, it is now covered.

01:26:45 Okay, so that now precludes you from actually exploring any potential use.

01:26:50 No, it only precludes you from taking a patent.

01:26:52 No, no, no. They can actually have an injunction that prevents you from using that technology.

01:26:59 Arthur's been involved in that discussion.

01:27:01 A final word on patenting from Arthur.

01:27:03 Well, it's not the final word, but—

01:27:06 This afternoon.

01:27:07 There won't be a final word.

01:27:10 My comments are much more general.

01:27:13 And that is, a couple of illusions may have been created, and I want to be sure I dispel them.

01:27:19 Number one, that justice will be served by the legal system.

01:27:24 And that's nonsense.

01:27:28 The litigiousness of people at great expense and suicidal consequences come out of prolonged adjudication,

01:27:38 ultimately decided by a jury that's utterly incompetent to make that decision.

01:27:45 Does he want to throw it out?

01:27:47 There have been statements made, and I could almost quote each of you,

01:27:52 in which there could have been an interpretation that there are benign ways

01:27:58 in which the support of basic research can come out of one source or another.

01:28:05 Bill said that there are significant contributions of biotech and pharmaceutical industry to basic research.

01:28:14 I agree.

01:28:15 But let's define significant in quantitative terms.

01:28:20 I'll state that in the past and for the future,

01:28:24 the amount of money for basic research deriving from industry, from Howard Hughes Institute, from all sources,

01:28:31 is less than 10% of what's furnished by the total.

01:28:37 That is, more than 90% has been and must be furnished by federal government.

01:28:43 And Paul, as far as approaching biotech ventures or pharmaceutical companies to pay back, forget it.

01:28:49 Very few are profitable.

01:28:51 And pharmaceutical companies will tell you, we pay taxes.

01:28:55 And so if you want support, we're supporting it.

01:28:59 So ultimately, the buck stops.

01:29:03 The buck originates in the federal treasury.

01:29:08 And there's no question that as a nation, we have to make that investment.

01:29:12 It's not an expense.

01:29:14 And so the catalytic and the significant role that the land-free industry plays is untested.

01:29:26 But I'd like to be sure that one knows that it's an illusion to think that these major advances will supplant the support that we have to get from the federal treasury.

01:29:36 Thank you. Thank you very much, Arthur.

01:29:37 Let me pull this piece to a close, because I've been around issues like this long enough to know that what we've got now are fairly significantly different attitudes.

01:29:49 And these different attitudes put a different gloss on what's out there.

01:29:53 I think the points of view have been very well stated.

01:29:56 And I think there are some areas of real agreement.

01:29:59 That is real agreement that in the commercial sector, patenting is absolutely essential as a mode of conducting business and getting work done, protecting the rights gained through invention, discovery, etc.

01:30:11 The crux comes in what happens in that relationship within universities, universities to their students, to their faculty, and then the university-industry relationship.

01:30:23 And I think what we've watched in recent years in this area particularly, biotechnology, have been some changing mores and practices.

01:30:31 And these changing mores and practices have brought forward a series of problems which for some remain unresolved.

01:30:39 I'd say that there are tensions and that they probably will continue for some time.

01:30:46 And the question that we'll want to watch carefully as we do contemporary history is how the pieces emerge.

01:30:53 What are the changes that occur? What are the boundaries that change?

01:30:57 What's patentable and what's not? What the usability will be across these borders?

01:31:03 One thing was made clear by several people, and I would just underline it.

01:31:06 And this is the necessity of there being strong, continued federal support for research in the university sector, from the NIH, from the NSF, whatever the agencies will be.

01:31:16 And I think they're this total agreement.

01:31:18 What I'd like to turn to now, because we've stayed away from it so far and it's my fault as the moderator, is the question really of what we've learned.

01:31:28 What was it George Santayana said that those who forget the lessons of history are condemned to repeat its mistakes?

01:31:35 But the other end of it is, when we've had a recent set of policy discussions and debates in the area of recombinant DNA,

01:31:46 and then we've watched the emergence of a policy in the human genome discussions for supporting explicitly,

01:31:54 with 3% of allocated money going to supporting ethical and social investigations into the implications of the human genome.

01:32:04 Have we learned things from the debate coming out of recombinant DNA which provides something like a model for future discussions?

01:32:17 For example, cloning of human beings.

01:32:20 And Maxine Singer, you've been in the middle of that debate.

01:32:22 I wonder if you, not the cloning debate, the earlier one, I wonder if you would like to look back at what you think we've learned from the debate

01:32:33 in the area of recombinant DNA and what implications you think it might have, what it might serve to be into the future.

01:32:41 Thank you. I would like to mention two things, two quite different things.

01:32:46 One very important thing that we learned was that things that we all thought about as everyday knowledge was a complete mystery to most people in the country, in our country.

01:33:03 And we learned that the hard way, and I alluded to some of that this morning, in that people who wanted to engage the issue very often did that by avoiding what involves the science and technology and focusing on other kinds of things.

01:33:25 One thing that I remember as an example of that, at that Director's Advisory Committee in February of 1976, in Paul's presentation on the science, or perhaps later,

01:33:40 he happened to mention something about the fact that the experiments were actually quite easy to do and could be done by high school students.

01:33:49 And that was picked up, and there was a long conversation taking up a very significant part of the time available as to how dangerous it was, what you could do to stop it, and so forth.

01:34:02 And that was one of the first clues I had, that people could focus in on the irrelevant kinds of issues, and it was because they didn't understand a lot of the basic biology.

01:34:17 In fact, I think that's changing, because in these last years there's been a big effort to try and improve science education in the United States.

01:34:27 And a lot of school students all over the country are getting better basic scientific education. It's nowhere near what it ought to be, but at least it's moving.

01:34:38 And certainly it was my experience in the recombinant DNA debate that helped make me decide that I was going to spend a lot of time on science education in more recent years.

01:34:50 So to me that was a very big thing that we learned. And it was an important thing, because the public, after all, is holding all the strings.

01:35:01 And if they don't understand what you're doing, they will be frightened, and rightfully so, and therefore it's our responsibility to be sure that that improves. That's one thing.

01:35:15 The second thing I wanted to mention is that we didn't realize that when you start discussing a completely new topic in a public way, you spawn industries.

01:35:28 I mentioned it sort of obliquely in my talk when I mentioned the fact that the people who wrote environmental impact statements were pros.

01:35:36 I mean, they were contractors, businesses set up to do this. And it turns out that every time there's a new issue abroad, all kinds of opportunities arise for people in peripheral things to make little industries.

01:35:55 And so, for example, the whole field of bioethics, which practically didn't exist, is now a substantive field in a lot of universities.

01:36:08 And maybe that's a good thing. I'm not saying good or bad, but you have to recognize that every time you raise something like this, you do do that.

01:36:17 On the other hand, there were some difficulties that arose because people saw an opportunity in this debate to make a role for themselves.

01:36:27 And perhaps the most famous of those is Jeremy Rifkin, who really made a career on raising a variety of difficult issues about recombinant DNA.

01:36:41 Charlie mentioned before about the statements by religious leaders opposing patenting, but we all know that to a very large extent that was orchestrated by Rifkin.

01:36:54 And so there's somebody who made a career, a reputation. He's famous. He's on TV all the time. People write about him. His books sell better than mine do.

01:37:05 And so that's another kind of thing that arises, which I was totally ignorant of when we started discussing this, that you really spawn all kinds of things.

01:37:15 A nice summary of two key issues. Let me push a question for someone, because you come right up to it.

01:37:24 And that is, to what extent do you think scientists should be the ones in control of the debate over the implications or potentials for what science might do publicly?

01:37:35 Well, if you're asking me, I will tell you I don't understand the question. I don't understand what people mean when they talk about being in control.

01:37:43 To the extent that nobody else knows the science, certainly the scientists are in control in some sense.

01:37:49 But we learned in this debate that no single group in our country is in control of anything, which is just as well, probably.

01:37:59 So I'm always a little bit puzzled by that question and exactly what's meant by it. So I think you need to be a little bit more explicit for me.

01:38:08 I can come back and be more explicit. What I was looking for here is, in a sense, the setting of the agenda about what issues will be included in and which not.

01:38:17 I mean, I think many people reacted with interest when scientists seemed to say that the public was taking this debate away from us.

01:38:25 And the question was, where should a debate like this be held?

01:38:30 Excuse me, who said that?

01:38:32 That said the public was taking the debate away from us?

01:38:35 Scientists? What scientists?

01:38:37 My colleague James Dewey Watson, sitting at Harvard, said it loud and clear.

01:38:41 He said the public was...

01:38:43 He wrote about it in the New Republic.

01:38:45 I've never heard him make that particular statement. I mean, I think my view of this is that there are societal issues.

01:38:52 And my voice as a scientist should be no louder than anyone else's voice about the societal issues.

01:39:01 But there are also issues relating to scientific expertise.

01:39:05 And as Maxine, I think, quite correctly points out, scientists have to provide a resource for that information to educate the public so that the public can deal with societal issues.

01:39:17 And so that I don't look at it as taking any debate away from us.

01:39:25 I think there are some issues that need to be discussed at a public level.

01:39:29 But I think scientists have a role, in fact a duty, to provide information for and educate the public about issues.

01:39:39 Yeah, Paul.

01:39:40 Yeah, I want to return to your first point, which is lessons learned, mechanisms put in place to deal with similar issues.

01:39:48 And I think for a long time, I think I was reflecting on the time and feeling a certain bit of comfort with what we did.

01:39:57 Nevertheless, what I thought is we had not put anything in place other than an experience.

01:40:04 And you could go and read about the experience, but in fact nothing existed that could deal with a similar issue that might challenge society.

01:40:16 And one just has recently arisen.

01:40:18 So here we are.

01:40:19 We've got the Dolly experience.

01:40:22 And what struck me right off was that the public did not know about all the work that was going on doing the same thing until this sort of pronouncement that they cloned a sheep from an adult differentiated cell.

01:40:43 Well, in fact, people had been doing it from embryo cells.

01:40:45 People had been doing it from fetal cells.

01:40:47 And in fact, in the same paper, he describes the experiments using other sources of nuclei and so on.

01:40:54 And in the recombinant DNA, I think the public also was totally unaware of how close one was to actually being able to do the kinds of things that were done.

01:41:05 So it was a shock, a shock sort of thing.

01:41:08 So now let's look at how the Dolly situation was handled.

01:41:12 There was the instantaneous hand-wringing.

01:41:17 Oh, my God, what are we getting into?

01:41:20 What are scientists going to do?

01:41:22 They're going to destroy the universe and the world.

01:41:26 Only the family is what they're doing.

01:41:29 And we had the president immediately call for a ban on this kind of research.

01:41:35 Then, of course, the politicians came out of the woodwork and immediately were proposing various kinds of legislation.

01:41:41 But we had this president's biomedical commission in place, interestingly enough.

01:41:47 And so the matter was referred to them.

01:41:49 There wasn't any such commission existing at the time of the recombinant DNA.

01:41:55 And so in one sense, if it wasn't the scientists who were going to carry the ball, it wasn't going to be carried.

01:42:00 Here, the ball could be carried by this commission.

01:42:03 And I was struck by the fact that what the commission did, Maxine and I wrote an article a couple of years ago now.

01:42:10 It's published in Proceedings of the National Academy of Science on sort of at least alluding to some of the lessons we learned.

01:42:16 And one of the lessons we learned was legislation was probably the worst kind of response that you could make to any of these kinds of issues.

01:42:26 And the second was to put in place a mechanism that allowed you to review the issue that concerns you periodically

01:42:35 so that you can reevaluate whether, in fact, it is as bad as you thought it was when you first heard it.

01:42:40 And two years down the line, you may, in fact, conclude that there is no risk or else that there is some ethical benefit.

01:42:48 In fact, when the report was issued a few days ago, although I've read only parts of it, I did talk to one of the commission members

01:42:57 and they did resort to legislation, not because they felt that a moratorium might not work to the scientific community.

01:43:04 They were more concerned about the public IVF in vitro fertilization clinics and so on and so forth who were going to get involved in doing this.

01:43:13 So the legislation was an attempt to try to head that off.

01:43:16 But they did put a sensate clause in which at least says we'll go back to look at it again in three to four years time

01:43:22 and see whether any new insights are available.

01:43:25 What destroyed the whole impact of that decision was the president saying in the Rose Garden

01:43:32 that he viewed cloning of humans or attempts to clone humans as morally reprehensible.

01:43:41 Now, I don't know whether that term is going to come back to haunt him because in three or four years

01:43:46 when people have come up with rational reasons for perhaps doing it on a limited scale,

01:43:54 this morally reprehensible tag will, I think, really have serious consequences.

01:44:00 So, interestingly enough, and I want to draw one clear distinction between the recombinant DNA and this.

01:44:08 Recombinant DNA, we were concerned, as I said earlier and Maxine has said,

01:44:11 we were concerned with safety and the health of the investigators and the public.

01:44:16 We were not concerned and we didn't pay attention to the ultimate long-term ethical and legal complications.

01:44:23 This thing starts with the assumption it's not so much a public safety issue, it's a moral issue.

01:44:30 And in the climate that we live today, the only thing that seemed feasible was to say, no, don't do it.

01:44:37 So, it was a little different, but the commission being in place and taking a tentative step,

01:44:43 at least I think maybe grew out a little bit of the recombinant DNA experiment.

01:44:49 Certainly, I know that one of the commissioners whom I talked with said,

01:44:52 we read your stuff and we understood that there were things the way we should proceed and not foreclose.

01:44:59 And in fact, they left it possible to do research using animals.

01:45:04 And I think that could have been a disaster had they said,

01:45:08 ban all types of research that lead to the cloning of any mammalian organism.

01:45:14 In which case, that would have been a devastating effect, don't you think?

01:45:20 Yeah, please, Charles.

01:45:22 I have a couple of points about what we, your original question about what has been learned

01:45:28 from the early recombinant DNA discussions or the deferral of the longer-term ethical issues which we're now faced with.

01:45:36 One way to learn is to look at the videotapes of the events that have been described here by many of the people,

01:45:43 Maxine Singer in particular.

01:45:45 The Cambridge City Council hearings, the Director's Advisory Committee to the NIH.

01:45:50 Every moment of those things were videotaped.

01:45:54 We went down with students at MIT to do it.

01:45:57 It's now part of a permanent record.

01:45:59 120 of the individuals who were involved in these controversies at that time were interviewed,

01:46:05 including five people on this panel, interviewed in 1975.

01:46:09 And then as their minds changed on some of the issues, a few, Paul and Maxine, were interviewed again a few years later.

01:46:18 So there is a record if people want to take the trouble to probe into it

01:46:22 and they can get a flavor of the period and learn from it.

01:46:26 I think something that wasn't learned was that public concern shouldn't be treated as hysteria.

01:46:35 When there is serious scientific disagreement and when there's uncertainty about the risks,

01:46:41 that increases public concern with who's watching the store.

01:46:46 It came out in the early 80s, the period we're supposed to be stopping with on this history today,

01:46:53 in the work to release into agricultural production genetically modified organisms.

01:47:03 This was a deliberate and intentional release to make some changes

01:47:08 that were seen to be as beneficial by the company who was doing it

01:47:12 compared to the accidental release that people were worried about

01:47:15 in the early recombinant DNA and the silomar discussions.

01:47:19 There was enormous community concern.

01:47:21 People felt that they were the last to know.

01:47:24 They didn't know whether they should trust the company doing it

01:47:28 because in fact it was a company and they saw it as profit.

01:47:31 And they perceived that the regulators, who they would like to have trust in

01:47:35 and like to have confidence in the project,

01:47:38 that the regulators just hadn't been there and hadn't established an appropriate framework.

01:47:42 That was a major crisis for the entire biotechnology industry

01:47:46 because the credibility of the industry was at stake.

01:47:49 So that's a chapter that we haven't had time to explore.

01:47:52 But it did come up again and I think people were not prepared for it.

01:47:55 The things that are directly concerning me about the lessons,

01:48:01 when there was a change of heart

01:48:05 and because of public concern and what scientists felt was overreaction,

01:48:09 many of the individuals who had originally called attention to the recombinant DNA potential hazards,

01:48:15 as I said earlier, recanted, they changed their minds and so forth.

01:48:19 And some of them went to the point of belittling that early concern,

01:48:24 ridiculing it, saying that this was a really stupid thing.

01:48:30 As Maxine Singer said, she didn't feel that way.

01:48:34 But some others referred to it that way.

01:48:37 I believe that that sends the wrong message to the next generations of scientists about responsibility.

01:48:43 There was a slogan at MIT in 1976,

01:48:47 when this Cambridge City Council was looking into these issues

01:48:50 and people were saying, shut up or be shut down.

01:48:53 In other words, don't talk about any doubts that you might have about safety

01:48:56 because this enraged citizenry will shut you down.

01:48:59 And that's an extreme reaction.

01:49:01 But that was the message I think that some people got,

01:49:04 and particularly a younger generation.

01:49:06 So I was concerned that the pendulum might swing the other way.

01:49:09 The other issue that I think is of major importance is,

01:49:13 and the chickens are coming home to roost on it,

01:49:15 or the sheep are coming home to roost on it now,

01:49:19 is the deferral of the ethical concerns.

01:49:21 Because scientists say, it's too early.

01:49:24 We can't do that yet.

01:49:26 So we have immediate problems to think about.

01:49:28 And the longer term, more difficult problems,

01:49:31 beyond the immediate laboratory safety issues

01:49:34 or the agricultural environmental safety issues,

01:49:37 are very difficult to deal with.

01:49:39 And perhaps it shouldn't be the realm of,

01:49:41 certainly it shouldn't be the realm of scientists alone.

01:49:43 But those tend to get deferred until there's an immediate crisis.

01:49:47 And I think that's a lesson to draw.

01:49:50 We had an opportunity to look at these things in the 1960s

01:49:54 when they were first raised by scientists.

01:49:56 I'm talking about the longer term ethical issues

01:49:58 of where do you draw the line in human genetic manipulation.

01:50:02 And we keep on deferring those.

01:50:04 We still don't have a mechanism.

01:50:06 I think that the approach of the Human Genome Project on it

01:50:12 is to put those concerns into a compartment.

01:50:15 It's over there. It's a little compartment.

01:50:18 The major part of the project works

01:50:21 and producing really interesting results,

01:50:24 everyone acknowledging that those results

01:50:26 will have important societal implications,

01:50:29 will raise questions of genetic discrimination

01:50:31 in insurance, employment, and so forth.

01:50:33 These are readily acknowledged.

01:50:35 And the idea is, well, we're going to think about them

01:50:37 while we're doing the work here.

01:50:38 We're going to think about them

01:50:39 with the committee over in the corner.

01:50:41 That compartmentalization and that deferral,

01:50:43 I think, is a continuing problem.

01:50:46 Yeah, Stan.

01:50:47 I think there's another thing to point out here.

01:50:52 One of the things we learned, in my view at least,

01:50:55 from the recombinant DNA policy experiences

01:50:59 is not the issue which you've alluded to

01:51:02 of whether or not it was smart or stupid to have spoken out,

01:51:05 but perhaps to have a firmer ground for speaking out.

01:51:15 I think that none of the people who signed the initial letter

01:51:19 myself included, would have made such bold statements

01:51:25 and recommendations about scientific aspects

01:51:28 of our activities without more data

01:51:32 and without some logical basis for making recommendations,

01:51:36 without some scientific basis.

01:51:38 And here we were coming up with suggestions

01:51:41 and recommendations and raising concerns

01:51:44 with notions that were coming out of thin air.

01:51:47 And as we began to talk more with epidemiologists

01:51:52 and microbiologists with expertise

01:51:55 in epidemiological spread of microorganisms,

01:52:00 the folly of our act in having spoken out

01:52:08 with such little basic knowledge of scientific knowledge

01:52:12 of the issues became clear, at least to me

01:52:15 and I think to some of the others.

01:52:17 And it was as a result of that that in the later years,

01:52:21 as those members of the committee know,

01:52:25 there was an attempt to come up with a revision

01:52:28 of the Berg et al. letter that we all signed

01:52:32 and we ultimately couldn't agree on the wording of that revision

01:52:35 and it was never published.

01:52:37 But from my perspective, one of the things that I learned,

01:52:43 at least, is to have a scientific basis

01:52:47 for speaking out on issues of interest to society.

01:52:51 Can I ask, Stan, one question on that?

01:52:54 Please.

01:52:56 The one group that prepared for Asilomar

01:52:59 that did the most work...

01:53:00 Was our plasmid group.

01:53:01 That's right. It was very serious scientific work

01:53:03 was the group on plasmids.

01:53:05 They produced a beautiful, rich, technical document.

01:53:08 Some of the best people, the best people in the field

01:53:11 put their heads together on it.

01:53:13 I thought, and you can examine that document.

01:53:15 It's part of the record.

01:53:16 It's in the MIT archives and perhaps elsewhere.

01:53:19 I thought that was pretty hard work scientifically

01:53:22 and that was pretty good research.

01:53:24 So I wouldn't belittle the hard effort

01:53:26 that you folks put into that.

01:53:28 It was the best you could do at the time.

01:53:30 That was something else.

01:53:31 That was long after the initial letter.

01:53:34 But on the other hand, things that...

01:53:36 Six months.

01:53:37 But let me make a point.

01:53:39 Just since you've raised that issue,

01:53:41 I want to tell a brief story

01:53:43 which gives you some notion

01:53:45 of what was going on at the time.

01:53:48 For many years, one of the restrictions

01:53:52 in the recombinant DNA use

01:53:54 was a 10 liter limit.

01:53:57 There was one set of rules

01:53:59 if you were working with more than 10 liters

01:54:04 and another set of rules

01:54:05 if you were working less than 10 liters.

01:54:07 That came out of the plasmid group recommendations.

01:54:10 Let me tell you how we came to that conclusion.

01:54:12 We sat around and discussed

01:54:14 what's a reasonable amount that was a break point.

01:54:17 We said, well, in a day,

01:54:19 you can centrifuge down 10 liters

01:54:22 in a sore of all centrifuge in big bottles

01:54:25 and therefore you can have better containment.

01:54:29 If you really want to do more than 10 liters,

01:54:32 you'd probably need a sharpness

01:54:33 continuous flow centrifuge

01:54:35 and it would be more risky.

01:54:37 Therefore, we suggested that 10 liter

01:54:40 be the cutoff point.

01:54:42 Now, that was adopted by the RAC

01:54:44 and it was codified in law,

01:54:48 not legislative law,

01:54:50 but in the rules of the committee.

01:54:51 It remained.

01:54:52 In fact, for all I know,

01:54:53 it's still on the books.

01:54:56 The point is,

01:54:58 it was this type of judgment that was made.

01:55:03 Yes, we did the best that we could

01:55:05 and we spent hours and hours

01:55:07 haggling about these kinds of issues.

01:55:10 That wasn't the issue that I was referring to.

01:55:13 What I was talking about

01:55:14 was the initial letter that a number of us signed

01:55:18 that really, in my view at least,

01:55:20 did not have the level of thinking

01:55:23 that came later on.

01:55:26 Good.

01:55:27 This may be a good place for us

01:55:29 to begin to draw to a close

01:55:30 rather than introduce still another topic.

01:55:34 I think what's come out of our discussion

01:55:36 this afternoon

01:55:38 has been an interesting set of investigations

01:55:42 about the nature of the research activities

01:55:45 in universities

01:55:47 as they relate particularly

01:55:48 to their commercial success

01:55:50 in the industrial sector.

01:55:52 We've watched this

01:55:53 and we recognize in the group here

01:55:56 a host of people

01:55:58 who've been directly involved

01:56:00 either by moving back and forth

01:56:02 between the university

01:56:03 and the industrial sector

01:56:05 or by being involved in the processes

01:56:07 that the commercial sector engages in

01:56:09 patenting and things of that sort.

01:56:12 What emerges at least in my mind

01:56:14 from the discussions

01:56:16 is that there are a series of issues

01:56:18 still unresolved.

01:56:20 The practice is still in fairly fast motion.

01:56:24 The differences in local,

01:56:27 across the United States,

01:56:29 in national,

01:56:30 across national boundaries,

01:56:32 in industry expectations,

01:56:34 in university activities,

01:56:36 in the nature of research

01:56:37 that goes on in each

01:56:38 raises significant questions

01:56:40 about where we're headed

01:56:42 and how the different activities

01:56:44 of these organizations will continue.

01:56:49 The commercial sector

01:56:50 in the biotechnology area

01:56:52 is brand new

01:56:53 by any long-term historical standard

01:56:56 and historical record.

01:56:58 It's still in a process

01:56:59 of evolving its forms

01:57:01 and evolving its social relations,

01:57:04 relations with the other parts

01:57:06 of this society

01:57:08 and with the relations

01:57:09 with longer-term public sanction,

01:57:12 longer-term investment,

01:57:13 longer-term confidence.

01:57:15 Universities are clearly

01:57:16 undergoing enormous change

01:57:18 in terms of their scientific sectors,

01:57:20 particularly those sectors

01:57:21 which have

01:57:23 utilizable products

01:57:24 or utilizable intellectual properties

01:57:27 that are developed.

01:57:28 And many of us still

01:57:30 in universities watching this

01:57:32 are aware of the instability

01:57:35 of the institutional forms we now have

01:57:37 and aware of the fact

01:57:39 that these are being worked on,

01:57:41 they're being experimented with,

01:57:43 and we don't have

01:57:44 a single national policy

01:57:45 on this at all.

01:57:46 We have a host

01:57:47 of ad-hoc policies,

01:57:50 some of which work,

01:57:51 some of them don't.

01:57:53 Another area we looked at

01:57:54 and began,

01:57:56 not as successfully

01:57:57 or fully as we might,

01:57:59 although it overlaps,

01:58:00 and this is the relationship

01:58:01 between scientific activity

01:58:03 and public responses.

01:58:04 And this is, in a sense,

01:58:05 where we were

01:58:06 as we looked at policy.

01:58:09 Policy in the public sector

01:58:12 will always involve

01:58:13 segments of the public,

01:58:14 whether it be through

01:58:15 their elected representatives

01:58:16 or whether it be through

01:58:18 single-issue lobbying organizations,

01:58:20 the public will have its way in.

01:58:22 And to expect otherwise

01:58:24 is to leave yourself open

01:58:27 to disillusionment.

01:58:29 The public will not necessarily

01:58:31 always be informed

01:58:32 in the same way

01:58:33 that the expert

01:58:34 in whatever the field is

01:58:35 will be informed.

01:58:36 And this creates the kind of tension

01:58:37 which came out

01:58:38 in our discussions

01:58:39 this afternoon.

01:58:41 When one looks back

01:58:42 at the debates

01:58:43 over recombinant DNA

01:58:45 and the excitement

01:58:47 in those debates,

01:58:49 whether it be

01:58:50 in the city council chambers

01:58:51 or whether it be somewhere else,

01:58:52 it obviously reflects also

01:58:54 a feeling at the time.

01:58:56 Why did scientists

01:58:57 step out front

01:58:59 the way they did,

01:59:00 beginning to assert responsibility?

01:59:02 Remember the years,

01:59:03 72, 73, 74.

01:59:05 These were the years

01:59:06 of the winding down

01:59:07 of the Vietnam War

01:59:08 when campuses expected

01:59:10 intellectuals

01:59:11 to take responsibility

01:59:13 in ways which

01:59:14 they haven't since

01:59:15 and certainly hadn't

01:59:16 to anything like

01:59:17 the same extent before.

01:59:19 And I think the intensity

01:59:20 of that period

01:59:22 led to

01:59:24 at times extreme statements

01:59:26 and led at times

01:59:27 to extreme retreats.

01:59:29 One looks back

01:59:30 at the history

01:59:31 and it's a fascinating history.

01:59:32 I was interested to hear

01:59:34 what my colleagues here

01:59:35 felt were the lessons learned

01:59:36 and some of them

01:59:37 were right on target.

01:59:38 Looking back

01:59:39 at something like

01:59:40 the Cambridge Experiment

01:59:41 Review Board,

01:59:42 which I've looked at

01:59:43 in detail,

01:59:44 it was not a bad

01:59:45 bit of work.

01:59:46 If the public

01:59:47 had to get involved,

01:59:48 it was an interesting way

01:59:49 of the public

01:59:50 giving its sanction

01:59:52 to a citizen's board

01:59:53 and when one looks

01:59:54 at their

01:59:55 very orderly hearings,

01:59:57 when one looks

01:59:58 at the report

01:59:59 they came out,

02:00:00 it was a report

02:00:01 which sanctioned

02:00:02 and supported research.

02:00:03 Safeguards, yes,

02:00:04 but supported research

02:00:05 so that as a model

02:00:06 it's not a bad one

02:00:07 with one exception.

02:00:08 You can't do this

02:00:09 on the local level.

02:00:10 This was a problem

02:00:11 that at least

02:00:12 at national scope

02:00:13 or international,

02:00:14 but in terms of

02:00:15 watching and informed

02:00:16 and learning citizenry

02:00:18 get involved,

02:00:19 it had an interesting

02:00:20 bit for us.

02:00:22 One problem

02:00:24 which hangs out there,

02:00:25 the science we discussed today,

02:00:27 this period from the 1950s

02:00:29 up to the early 1980s,

02:00:31 in the area

02:00:33 of molecular biology,

02:00:35 genetic engineering

02:00:36 or biotechnology

02:00:37 as it has become known,

02:00:38 was a period

02:00:39 of enormous excitement.

02:00:40 The technical successes

02:00:42 were striking

02:00:43 and no history

02:00:44 will be able

02:00:45 to downgrade

02:00:46 those technical successes

02:00:47 or take it away.

02:00:48 The rapidity

02:00:49 of commercial response

02:00:50 to those successes

02:00:51 is fascinating

02:00:52 when you look at it.

02:00:54 The claims

02:00:55 for what those successes

02:00:56 might bring,

02:00:57 and they do it

02:00:58 to this very day,

02:00:59 the claims raise questions

02:01:01 and leave people nervous.

02:01:03 Will you really be able

02:01:04 to find the gene

02:01:05 for alcoholism

02:01:06 and somehow control it

02:01:08 for that poor family

02:01:09 which is suffering

02:01:10 from alcoholism

02:01:11 or what have you?

02:01:12 The claims made

02:01:14 often simulate praise,

02:01:16 expectations,

02:01:18 and at times fears.

02:01:19 And part of what

02:01:20 we're dealing with

02:01:21 in the ensuing time

02:01:25 is the inability

02:01:28 to begin to find

02:01:29 a modus

02:01:30 by which claims,

02:01:32 realities,

02:01:33 public reactions

02:01:35 and experts' reactions

02:01:37 get in harmony.

02:01:39 And I think

02:01:40 it's the tension

02:01:41 that emerges at times

02:01:42 as a scientific community

02:01:44 feels under pressure

02:01:45 from extravagant responses

02:01:49 made to what are

02:01:50 sometimes extravagant claims.

02:01:52 Not necessarily claims

02:01:53 by all the official bodies,

02:01:55 but claims by the scientists

02:01:56 who go before

02:01:57 the press cameras

02:01:58 or the television cameras

02:01:59 to make a statement.

02:02:01 What I hear

02:02:03 as one of the things

02:02:05 coming out of these discussions

02:02:07 in a way is addressed

02:02:08 by the very thing

02:02:09 we're doing today.

02:02:10 And that is put in the record

02:02:12 those discussions

02:02:14 by participants,

02:02:16 by people who ask questions

02:02:17 of the participants,

02:02:18 those discussions

02:02:19 which invite

02:02:20 segments of the public

02:02:22 into the discussion

02:02:23 so that they too can learn

02:02:25 from the history,

02:02:27 in this case

02:02:28 relatively recent history,

02:02:29 and begin to put

02:02:31 that learning to work

02:02:32 as they face

02:02:33 the next level of problems,

02:02:34 whether it be

02:02:35 the cloning issue

02:02:36 which Alan raised

02:02:40 or any number of the others

02:02:42 which will be coming forward

02:02:43 in the near future.

02:02:45 The fact

02:02:47 that this science

02:02:49 is still on a sharp

02:02:50 upward trajectory

02:02:52 and this technology

02:02:53 that goes with it

02:02:55 leads us to believe

02:02:56 that we're going to be back

02:02:57 again in the future

02:02:59 to begin unpacking

02:03:01 others of the issues

02:03:02 which are going to come

02:03:03 from this activity.

02:03:05 The answers are not in yet.

02:03:07 I'm glad to see

02:03:08 something like

02:03:09 the Chemical Heritage Foundation

02:03:11 take on the responsibility

02:03:13 of both preserving the records

02:03:15 but then also making

02:03:16 the educational materials

02:03:18 available so that others

02:03:20 can do some of the learning

02:03:22 which we've been able to do.

02:03:23 Let me thank everyone

02:03:25 on the panel

02:03:26 for a really fascinating

02:03:28 and remarkable set

02:03:29 of discussions.

02:03:30 Let me thank all of you

02:03:31 who've sat through

02:03:32 these discussions

02:03:33 and particularly thank

02:03:34 Arnold Thackeray

02:03:35 and his staff

02:03:36 for a superbly

02:03:38 organized session.

02:03:40 Thank you.

02:04:10 End