Biotechnology at 25: Perspectives on History, Science, and Society Saturday, March 13, 1999


William Rutter, Ph.D.
Co-founder of Chiron Corp. and Professor of Biochemistry, Emeritus, University of California, San Francisco.

William Rutter: Hearing Jim's talk and seeing the painting of Dalí's Hommage to Watson and Crick reminds me of an incident. I don't think I've ever mentioned to Jim. One time, nearly twenty years ago, or there abouts, I was going into Chicago late at night and turned on the television to try to get some news and there was a talk show in Chicago called the Herb Cupsnit Show and it turned out that Herb Cupsnit, that night was interviewing Salvador Dalí and on the screen was Hommage to Watson and Crick. So Cupsnit said, "Well, Mr. Dalí, what is the motivation for this Hommage to Watson and Crick?" And Dalí said, "First, I love my wife, then I love money, then I love dioxyribonucleic acid."



[Rutter: laughs audience: laughs]



Now in the short time that I have up here I'd just like to record briefly the transition of myself from a confirmed academic to a confirmed commercially oriented scientist and executive in an attempt to essentially deliver products to human beings and in that course I've had the great good pleasure, of course, working with Ed Penhoet, my colleague for many years and also Pablo Vallenzuela and many, many people, some of whom are in this audience. But for today's discussion I just want to emphasize almost the explosive effect of the Cohen-Boyer experiment on people who are working in the field particularly those interested in expression of genes in higher organisms. And thus it was particularly pungent for the group at UCSF because that kind of orientation had been the direction in which we'd been recruiting people. Clearly, we wanted to work on higher organisms and we had an extremely close relationship with the clinical departments which supported our activities significantly. And in that sense, that particular department was a little bit different than many departments which existed in medical schools at the time.



So, in my own case, we were -- I was interested in expression of genes the development of the pancreas and one of those happened to be insulin and Howard Gooden and our groups got together and eventually cloned the insulin gene. And then after that cloning and actually during the process itself the whole department was alive with discussions about the utility and exactly the directions that cloning should take both from a scientific standpoint and from a non-scientific standpoint. During this time Herb and Bob Swanson were forming Genentech and for a while they had occupied some space in the department and so on, and so on. But the, sort of , the crowning event which began to transition my own point of view was a visit I was inclined to make in fact, invited to make to a committee of the Senate, chaired by Adelay Stevenson and Senator Schmitt to, in fact, investigate the dangers of recombinant DNA and alleged infringement which had occurred during the cloning and finally the benefits. I don't think they got to the last point. But in one of the major discussions that was associated with danger in walked Margaret Mead, a well known specialist in the field, and Margaret Mead had a long rope over her body and she had a large shepherd's staff and Adelay Stevenson gave her a great adulatory introduction and she came up to the podium and over the next quite a long period of time she emphasized that scientists after her would be proclaiming that this technology was safe. They are clearly wrong. And instead there was a huge danger behind this program. Later on, why, there was a tricky discussion which is, in fact, continued for nearly twenty years now. On the same subject and on the particular aspects of those early experiments, well, I became not only involved personally at that time but intellectually in the sense that I became then personally committed to looking at the danger risk of benefit issue. And in thinking about this I wasn't, at the time, convinced that insulin cloning would lead to the production of insulin for many obvious reasons. But I was looking for a strategy in which, first of all, acknowledging the coding itself but worrying a bit about the translation which would occur in a microorganism of a human gene. That is whether the fertility would be 100% when the tRNA populations were dramatically different. And also wanting to have a target which would have unassailable benefit, and gradually I became interested, very seriously interested, in hepatitis B. I became interested in that because of a consulting relationship I'd had for fifteen years with Abbot Laboratories, and they had developed a diagnostic business. One of their major diagnostics products was Hepatitis B, and of course the issue of Hepatitis B infection, especially in Asian countries was extraordinary. Literally a quarter of a billion people in Asia were carriers of this virus; women transmitting it to their children, and the children then being very highly susceptible to liver cancer. And this was, in fact, documented quite clearly via epidemiological studies by a man named Palmer Beasley (whose brother, by the way, lives in Berkeley). So this looked like a good target and Hepatitis B was, in fact, a very small virus. As it turned out, I had been discussing the issues associated with cloning and the vaccine itself with Roy Badgelos, who had just moved to Merk, Sharp and Done at the time. It turned out that they were working on the vaccine for Hepatitis B, and the virus particles or a fraction of the samples which they were producing from infected human sera were DNA rich. So there was available a source of the virus. Could we have the first slide?



So our attention was then drawn far away from Insulin itself to Hepatitis, and next slide. Could you dim the lights please. This is an electron micrograph of a concentrated population virus particles form a Hepatitis B infected individual, and you can see here that the virus itself are these large particles called dane particles: full viruses including the DNA. Where the smaller particles and, in fact, the filaments ostensibly didn't contain DNA. Next slide please. So the general idea in the Merck proposal was to isolate the particles, the small particle, which ostensibly didn't contain DNA, and use these as a vaccine. This was a tremendously difficult problem in itself, but the problem was contamination with the DNA itself. So that kind of a vaccine had within it both the problems of contamination with any other adventitious virus and the problems of contamination with the virus itself with small amounts of DNA containing virus. So potentially you have the same kind of situation which occurred with Polio. As you were to recall in the 1950s when several hundred cases of Polio were caused by the vaccine itself. This resulted in lawsuits which resulted in term and the closing of several companies, including Cutter Laboratories, which existed here in Berkeley. In fact that Polio consequence in the general industry was that all companies, there must have been at that time at least a half of a dozen companies that were producing vaccines, all left the field because of the risk and, in fact, the lack of commercial reward. Now you can see immediately in this schema the potential that recombinant DNA had to solve this issue. If it were possible using genetic procedures which nowhere included the entire viral DNA to produce this small particle, this would eliminate the chance of adventitious infection, and also simultaneously produce a marketing source which could potentially deal with the extraordinary needs that the world had that the world had for a vaccine for Hepatitis B. Next slide.



So after some discussions et cetera, Merk decided to support this program and UCSF, and Hablo Vallencuela, and a group of others and the laboratory began cloning experiments with the raw material provided by Merk. And it turned out that incidentally at UCSF in the laboratory Buras Vias there were a few snippets of amino acid sequence which were obtained by a man named Roger Peterson working in his group. And in blue here is shown the region of the virus which encodes a single protein, actually existing in three forms, that in large measure contributes to the envelope. In green are the genes associated with replication and in orange are the genes associated with the internal core. Next slide please.



So this then gave a simple picture of the virus since it was only 3,200 nucleotides long it was essentially technically possible to deal with this with the available technology which existed at that time. So the issue was how to express the surface. And during this time interval Hepatitis B became one of the targets that many individuals became interested in. So, during the cloning procedure and attempting onto expression it became obvious that one needed a quite disciplined approach to the expression problem; one that was not easily accomplished in the university laboratory with people trying to get degrees and post docs who were interested in getting jobs immediately, and so on and so on. Furthermore, it became obvious that the competition was extremely warm from other groups working on this area. And our own interests became crystallized when I attended a meeting on the East Coast, essentially organized by Patell, the Patell Group, on problems in this area. And I was surprised to see when I got there that the audience, at least half of them, were either venture capitalists, investment bankers, company representatives and pretty much the scientists were overcome with interest by this group. It became pretty obvious that my little lab was not going to be able to compete with the resources which were being placed on this and other problems. And so there were three alternatives, I think, to address this. One was to essentially work with the pharmaceutical house, and second to develop a technology lab within UCSF, and third was to try to do it ourselves. And we tried all of these alternatives, kicking a screaming, trying to start a company by ourselves. None of the pharmaceutical houses had technology in house, nor could they ramp up quickly. We tried significantly to do this through another biotechnology company and became a member of the scientific advisory board of AMGEN. But their program was so diverse that they really couldn't focus on these projects, the several projects which were sort of interesting to us. And finally, the idea of having a technology transfer lab associated with the school, although an interesting one, was totally impractical. There wasn't available capital; entrepreneurial capital is not usually available to universities in general. It would have been a controversial project, and frankly most of the people inside would have gone to other competitive activities.



So as a result of that we decide to form Chiron to be competitive and we moved a group of people, I know some of whom are in this audience today, to start Chiron and the issue on expression then became a very important issue: how to do it in bacteria. It turned out bacteria expressed in small quantities this surface antigen, but in fact never produced a particle. And so finally we decided that, well, a virus-like particle like this probably needed to be constituted within the context of eucaryotic membranes. And hence we shifted to yeast. Now in order to get the program going in yeast it was absolutely necessary to obtain a promoter, and at that time many people were working on promoters to drive these genes. Some of whom were my previous colleagues and even students. It was impossible to get a promoter. For many of these folks there was kind of, at this moment, a segregated competition until, sort of, the lay of the land was established. And finally we were able to establish a collaboration with an old colleague from Illinois, Ben Hall, who had moved to Washington. And we carried out these collaborations together. Next slide.



And to our great delight, in an appropriate system in yeast one could produce particles which were of the same size and character that those were present in human serum. We didn't see filaments and later on we understood the reason why we didn't see filaments. It’s the portion of the surface antigen gene that we used which forms these single particles. But these particles themselves had virtually all the same properties as a human virus particle. So at once we solved a major problem. We didn't know whether specific human genes were required for the production of these particles in human liver cells. We didn't know whether they needed other products to form the particles. So we were delighted that a particle like this could be formed in a totally different genetic system. And the next question is whether it would be utilized, and we found that, in fact, it had the same kind of imunigenicity as particles that could be isolated from human serum. And when the choice was made between having the particles from yeast and particles derived from, for example, tissue culture cells immediately we selected yeast because of the absence of any contaminating viruses. And of course that was a good choice because, defacto, under these circumstances we didn't run the risk of such a contamination, which would have been another issue. Incidentally, while this program was going on in yeast a program to isolate those particles in human blood was going on in a parallel fashion at Merk, and was, in fact, championed by the vaccine group at Merk. So there was a question after it was all finished whether it would ever see the light of day, and it did so in my view, or in our view, in large measure because of the threat of HIV. That is, in fact, one of the crazy benefits of such a plague on mankind. That it, in fact, contributed to the rapid development of this vaccine and subsequently its promulgation broadly. Now vaccines based on these particles are sold by Merk and SKB Worldwide to tens of millions of people, and now a program which would eventually protect all children from Hepatitis B. So having gone through this experience, this led to the full commitment of the few of us who were involved to focus on disease, itself, prevention by one way or another. And the next project was Hepatitis non A non B. I think I don't have time to go through that but I will just flash through the slides. Next slide please.



Of course that emphasized this program for diseases control by diagnosis prevention and therapy. [next slide] Non A non B was simply all the residual Hepatitis that was not know to be either A or B. It wasn't known whether one or two viruses were involved. [next slide] A group at Chiron headed by Michael Hotton and George Quo, and Qualim Chu finally sequenced this virus. It is about three times bigger than Hepatitis A and a totally different virus. [next slide] In fact related to Flavey viruses, viruses like for example, yellow fever but quite distinct from them. [next slide] Once having discovered the virus you could again determine its prevalence in its relationship to other disease. It then became obvious that this was a major major disease on a world-around basis. It became evident in subsequent months and years that it was a prime cause of liver cancer and cirrhosis, even a more aggressive cause than Hepatitis B itself. [next slide] And, lastly, just to emphasize the point that Ed made, the initial cloning that it made available, on the initial stage, the diagnostic tests which reduced the possibility of infection over a period of years from blood, from any use of human blood, to close to twenty five percent in the late 1970s when we started. And then through tests for Hepatitis B, HIV and Hepatitis C, in the end now in 1999 it is an infinitesimal amount of infection, about 1 in 100,000 that gets infection from any one of these agents. And so, in one sense, the immediate efforts through vaccination and through this kind of prevention through metric tests has demonstrated, I think, value over risk, and we are all happy to be part of that.



Thank you.

 


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