Paul Berg (Stanford): Recombinant DNA and Science Policy

I'm Larry Goldstein. I'm a professor of Cellular and Molecular Medicine at UC San Diego. And I have the great pleasure today to interview my friend, colleague, comrade-in-arms, Paul Berg, Nobel Prize winner, and also a recipient of the Public Policy Award from the American Society for Cell Biology. I'm going to ask Paul some questions about his life as a science policy advocate and public figure. So, Paul, thank you for taking the time to join me today. Thank you. Good. So, let's start at the beginning. You had a very illustrious career in science, but something made you decide to leave the lab at least part of the time and engage in policy debates. What was it that brought you out for the first time? Well, it certainly wasn't voluntary. It turned out that an experiment which we had planned and were in the midst of elicited a lot of concern amongst other scientists. The experiment we had in progress was to fuse a small mini-chromosome containing lambda genes and three genes of E. coli, the gal operon, and we fused that with SV40 to make a recombinant that contained. Now, this recombinant could propagate in E. coli, because it contained the parson in the mini-plasmid, which allowed it to propagate in coli, and it could also be propagated in transfect mammalian cells. So, it was kind of a dual-headed thing. And what we wanted to do is to be able to make mutations in the SV40 genome in coli and then test them in mammalian cells. And the other thing, we were going to test to see whether the gal genes could be expressed in mammalian cells. So, that was the idea of the experiment. The point was that we were going to be propagating SV40 genes in E. coli. So, the concern was, coli is a natural inhabitant in humans, and the concern was, inadvertently, could you infect humans with the E. coli you were propagating, and could that possibly lead to cancer? That was the concern. And, depending upon where you came down on the topic, you were either vociferous about it, or you were just saying, forget about it. It's not serious. But, soon after a lot of consultations, I became convinced that I could not dismiss the risk and make it zero likelihood. And so, I thought, well, we'll just put it on the shelf. And so, the whole thing died down. A year later, Janet Mertz, a graduate student in my lab, discovered that EcoRI made cohesive ends. And she discovered that she could take any two DNAs and join them together. And so, Stan Cohn and Herb Boyer then began to actually make a lot of recombinants using E. coli plasmids and checking drug resistance and showing that they can make chimeric DNA molecules. And they talked about it at a Gordon conference, and that elicited the same kind of response amongst a small minority of the audience, who said, oh my God, you guys can really make some dangerous things. So, what happens is, at that Gordon conference, they got Maxine Singer and Dieter Saul, who were the co-chairs, to draft a letter to the Academy and to publish that letter in Science, calling attention to the great promise of being able to make new kinds of DNA molecules, but also calling attention to possible dangers and risks. And when the president of the Academy got this letter, he said, what do I do with it? And Maxine said to him, call Paul Berg, because he's thought about this problem. And so, he asked me, would I put together a group of people that could advise the Academy on how to respond to the concerns that had been raised. And so I did. I put together a small group, and we met at MIT. Dave Baltimore, Dan Nathans, myself, Jim Watson, a few others, Norton Zinder, people who would understand the nature of the problem. We met for a whole day, this group, and in the end, there was no advice that we could provide. We didn't know what to do. So we said, literally, you could pick up the phone and call everybody of your scientific community who's likely to use the technology and say, hey, be careful. But we couldn't do that. So we said, well, the next best thing is, why don't we just publish a letter in Science, calling attention to the promise, to some of the potential risks that have been raised, and essentially asking the scientific community to put a short hold on three kinds of experiments. We didn't call for a moratorium on all this kind of work. It was three kinds of experiments that we specifically called attention to. And in the letter, we proposed having an international conference some six or eight months later to examine the risks in more detail and come forward with some recommendations. I think the scientific community got a lot of good kudos from the public, saying, here's a problem scientists call attention to. You actually got out in front of it. And they're proposing how to deal with this thing. So if you look back now, you say, I got into public policy through my own experiments and just being called on to say, what do we do when somebody raised the risk? So the initial so-called moratorium letter, which came out of the group, called for a meeting to deal with it. And so we convened. I was the chair of convening the Basilomar meeting, and the organizing committee was Maxine, Dave Baltimore, myself, Zinder, Sidney Brenner. We had a person from Europe. And we were going to organize a meeting of experts to try to assess, what was the magnitude of the risks, what was the likelihood of them coming true, and how could we proceed in any case. Okay, so the Basilomar meeting was a major event. 150 people, huge representation from the media, which was probably one of the best things we decided. There were 15 people from press and newspapers, magazines, and so on. And in those three days, we debated. What are the kinds of experiments you want to do? What are the possible risks? And we organized it very well so that the meeting was not all talking about risks. It was talking about science. And that was probably a saving grace to why the meeting succeeded, because people came prepared to talk about scientific experiments, and they were balanced by discussion. A lot of interesting science came out of the Basilomar meeting. One was the safe bug, the engineer microbe, which could not escape from the lab. Right, so the crippled host. The crippled host. And the second one was actually, so that was Sidney Brenner's idea. That's a good idea. He brought that to the meeting. And I think that turned people around a lot, because suddenly we could answer the question that you could devise the experiments in some way, which would markedly lessen the likelihood of escape. So this organism wouldn't be able to live outside the lab. So right in that meeting, you could see science taking over. People began, well, we could do this. Well, and I think you and I would agree. If you're going to have good science policy, it has to be driven by good science. Misunderstanding is not going to get the job done. Turning point of the meeting, frankly, was the last night when the lawyers had their session. And the ethicists. We'd invited a group of lawyers and ethicists. And did the lawyers and ethicists sit through the science as well? They participated in everything, as did the press. The press were free to ask questions, raise points, and in the evenings, they milled around and they were full members of the meeting. The lawyers pointed out the legal problems and challenged Jim Watson with the idea, because he had now turned and he was totally opposed to any kind of regulation, whereas he'd been a signer of the original letter. They said, people can close down Cold Spring Harbor if there's any danger or anything that happens. And then people's own personal risks were beginning to be played on. And eventually, I think everybody said, we cannot walk out of here tomorrow morning saying we don't have any advice. Well, especially with the press there, because they were going to cover it. And that night, I and Maxine and Dave and Sidney, we drafted a set of guidelines and recommended that the NIH use this as a sort of outline for a set of guidelines that would essentially determine the conditions under which this research could be done and the conditions under which it should not be done. And so the whole thing that came out was very positive. We debated it and voted on segment by segment until noon came and we had to leave. We had an approved list of regular... Was it unanimous or was it consensus? No, no. I would say it was 95% in favor going forward, even though the language was muddled and things like that. But we all agreed that we would smooth things out. So I worked on the language and Dave did and Maxine, and we finally got a document, which is now recorded as a famous document out of the Asilomar Conference. We look back on it and we say, you know, we're a bunch of amateurs. We mumbled through a bunch of stuff. We made some decisions that were smart in retrospect. For example, one of the things we did not do and did not include in any way of the agenda was the ethics. We didn't talk about genetic testing. We didn't talk about that. We talked about real experiments and what the impact of those experiments would be in the field. So there were agriculture, nitrogen fixation. You know, people had all kinds of ideas of what we call the low-hanging fruit. What were the things you were going to do right? The infamous low-hanging fruit, yes. Crohn insulin gene, Crohn growth hormone gene. All of those things were obvious. In retrospect, when you look back, you say most of what's happened, nobody even could conceive of it at the time. And so, you know, that's the way science goes. You make a slight breakthrough, you've got a lot of very smart people out there, very smart people figure out very quickly how to use this new notion, new tool, or whatever, and the field explodes, and that's what's happened. And why recombinant DNA has had the impact that it has. So when did the Congress get into the act? When did the politicians decide that this was something they should worry about? Okay, so the SOMAR meeting was held in February of 1975. The rest of that year, there were small groups that were meeting to devise the guidelines. The guidelines came out in the summer of 76, and that ruled the day. And then sniping occurred. And the sniping occurred from different people who said, well, these guidelines are not rigorous enough, or we don't trust the scientists to abide by them. Congress began to respond to these little barbs, and they set on a course that they were actually going to prohibit recombinant DNA research in the country. And I remember spending a lot of time in Congress, and I can remember vividly one senator from Arkansas, who was normally a liberal and was a pretty good guy, getting up and saying on the floor of the Senate, I never got through high school chemistry, and I don't profess to understand any of this science, but I believe this is the most dangerous work ever undertaken in this country, and I would recommend prohibiting it. There were a lot of people who shared that view, and I am cynical enough to now realize that what changed the whole picture and obliterated the concerns was the founding of Genentech and the first day's stock issue. Ah, money. Money. Suddenly it became clear that this was going to be a commercial entity and important, and to put any prohibitions on it was like shooting yourself in the foot, and the whole thing disappeared. So the promise of making insulin for kids was not the winning message, you think? It was a message, but when you actually saw something happen. Yes. It was no longer virtual. I believe that was the thing that actually was a switch. And the atmosphere changed completely as soon as it became companies starting up to take advantage of this technology to do this, that, and the other thing. So ultimately the resolution of this was, if I remember correctly, no law was ever passed in the Congress. No law was ever passed. And it was all done by scientists driving the development of good regulation through the funding bodies, which then spread. Exactly. Amazing. It's a fantastic example. Yeah.