Genome Investigator Craig Venter Reflects On Turbulent Past And Future Ambitions

And Future Ambitions Editor's Note: For the past four years, former National Institutes of Health researcher J. Craig Venter has been a major figure in the turbulent debates and scientific discoveries surrounding the study of genes and genomes. Events heated up in 1991, when NIH attempted to patent gene fragments, which were isolated using Venter's expressed sequence tag (EST)/complementary DNA (cDNA) approach for discovering human genes (M.A. Adams et al., Science, 252:1651-6, 1991). NIH's move was widely criticized by the scientific community because, at the time, the function of genes associated with the partial sequences was unknown. Critics charged that patent protection for the gene segments would forstall future research on them. Despite NIH's reliance on the EST/cDNA technique, Venter could not obtain government funding to expand his research, prompting him to leave NIH in 1992. Since then he has been president and director of The Institute for Genomic Research (TIGR), a nonprofit research center based in Gaithersburg, Md. Last November, controversy surrounding Venter's research escalated. Access restrictions associated with a cDNA database developed by TIGR and its Rockville, Md.-based biotech associate, Human Genome Sciences (HGS) Inc. - including HGS's right to preview papers on resulting discoveries and for first options to license products - prompted Merck and Co. Inc. to fund a rival database project (F. Hoke, The Scientist, Dec. 12, 1994 page 1). In late May Venter announced that TIGR and collaborators had fully sequenced the first free- living organism - Haemophilus influenzae. And in September, TIGR researchers will be moving into a new facility, which, Venter says, will eventually double TIGR's sequencing capacity as well as its 80-member staff. Recently, associate editor Karen Young Kreeger met with Venter at the TIGR laboratory for a wide-ranging discussion, an edited presentation of which follows. IN DEVELOPMENT: Many advances in genomics will come from software engineers, contends TIGR president J. Craig Venter, shown here viewing part of a Haemophilis sequence. Q Do you feel that you were forced to enter a private venture to pursue your ideas; and would you have preferred to stay at NIH if officials there could have been convinced to back your work? A First, let me describe the situation at the time. I was at the National Institute of Neurological Disorders and Stroke [NINDS] from 1984 to 1992, and I had good funding for my program. I had a budget of somewhere, including salaries and staff, between $1 [million] to $2 million a year, with no absolute requirements on what I did. They were very nervous in NINDS about me going into the field of genomics, but they also liked the fact that I was one of the leaders of the field, and making new things happen. They were happy as long as I restricted my work to the human brain or to the nervous system. I could have stayed there, basically, forever. There was no mandatory retirement, and I had a very successful group, top publications, and was thriving. The limitations came from wanting to expand the work. I wanted to take the global overview of all of human-gene expression, not just what gene expression in the central nervous system was, even though that's highly important on its own. As I went on, I became more and more interested in the overall structure of genomes and genome evolution, then species evolution, by looking at whole genomes. All of this was much broader than the [mission of] NINDS. Bernadine Healy, then NIH director, was one of the few early on, at least in the administrative structure, who really saw the promise of my work. She became an instant fan and supporter, and all that got mixed up in the problems that she was having with [then head of the Human Genome Project] Jim Watson. At that time Jim Watson viewed me as competition because Bernadine appointed me head of the ad hoc committee to have an intramural genome program at NIH. To really answer your question, if I had a choice, I would definitely have stayed at NIH and done this at NIH. One of the most recent quotations that I found ultimately ironic was the one from the current NIH director [Harold Varmus] in Science [266:1800-2, 1994], in which he said he really wished NIH had pushed to do a similar database in the public domain. Oh? That's where the whole program started. Q Was the field of genomics born out of the Human Genome Project? A I think so. But it's more than what has come out of [Department of Energy] and NIH-funded programs - it's the development of a new, international field that is a collaboration between public and private efforts. Genomics has grown out of people beginning to think on a global level in biology, and being able to see and interpret the broad picture of genomes. This interpretation is somewhat like the difference between standing in the middle of New York and looking up at all the buildings and trying to sort out where you are, vs. being in a helicopter high above Manhattan, where you can see the whole picture. You get two different views, and both are important. Q You've described yourself as an impatient person. Do you still see yourself this way, and, if so, how has this helped or hindered you in science, a traditionally cautious profession? A I'm not sure that's an inaccurate description. I'm not afraid to take risks, which isn't necessarily a trait that's encouraged in science or in life. It's often penalized much more than it's rewarded. Some of my impatience comes from being [a hospital corpsman] in the middle of the war in Vietnam. And, feeling that I survived that year when a lot of people around me did not, I felt that I had nothing to lose by taking risks. I turned 21 in Vietnam. So, in that situation, I saw that there is too little time in life to waste on B.S. approaches. So, in that sense, I am impatient. I want to constantly be moving forward with the discovery of new things, and I'm frustrated with how long it takes new ideas to become part of the general thinking. Q Some of TIGR's critics have said that the information-sharing arrangement between TIGR and HGS and scientists wishing to access the EST/cDNA database stifles research. They basically claimed that you are holding valuable data too close to the chest. How do you respond to such claims? A The information has always been available to scientists pursuing noncommercial research. Any limitations have been in the commercialization of the data, not access to it by basic scientists for noncommercial purposes. It's been amazing to me - all of the concerns over commercialization issues vs. pursuing basic science. HGS's policies as a commercial organization are totally different than TIGR's policies as a nonprofit institute. It's always been my research group's philosophy and proven action that when we publish our papers in peer-reviewed journals, our data becomes available. For example, we're doing that with Haemophilis - it's going into the Genome Sequence Data Base [a Santa Fe, N.Mex.- based nonprofit organization]. And in September Nature will publish a special issue called the Genome Directory, which will describe partial sequences and assemblies of partial sequences of about 50,000 human genes in a 200-page article. To make this information available to the international scientific community, we're now in the midst of [a preliminary field test of] the TIGR database via E-mail interactions. This testing includes over 50 academic institutions worldwide, without intellectual property agreements. In conjunction with the publication of our Nature paper, we will be providing World Wide Web access [URL:http://www.tigr.org/] to the TIGR database covering over 45,000 of those genes. The remaining 5,000 will be available via the E-mail server. I don't think that's withholding data; I don't think that's keeping it too close to our chest. I think what we've done is unheard of, in terms of [the database's] quality and magnitude. I had to get money from the pharmaceutical industry [Philadelphia-based SmithKline Beecham] to fund [this work], and I don't think it's bad that they want to get some first advantage out of their now $85 million funding for this research. Q Concerning biomedical discoveries derived from human genomics research, is investment by private entrepreneurs necessary for the public to realize benefit from scientific innovation? A I think this data would not even exist if it was not for the pharmaceutical industry. Probably over 80 percent of all the human genes that are going to get discovered are going to because of the pharmaceutical industry. Despite what their political reasons and justifications are, they helped to prove that my approach was the most viable, productive approach. The level of research that the [pharmaceutical industry] is funding on human genes and human-gene discovery makes NIH programs pale by comparison. I mean, basically this data exists not just from here, but also from other sources, because the pharmaceutical industry came to fill in the gap where the government funding would not do it. Our society depends totally upon that effort, because the U.S. government does not develop new pharmaceuticals. If we would be reliant on the U.S. government to develop new drugs and therapies, we would all be paying 100 times as much in taxes as we pay now. I mean, I don't necessarily like to be classified as a defender of either the biotech or the pharmaceutical industry, but there are some really positive societal aspects to it. We have a situation where all these entrepreneurs are willing to run out and part with millions of dollars of their money to take a risk, and they hope that maybe they'll strike it rich, but, you know, most of them fail. I don't think there are many serious scientists who are aware of how drugs get developed that think patenting is not an important, essential aspect of it. Q Noting your continuing interest in ethics and policy, what are your thoughts on the relationship between scientific and bioethical concerns surrounding genomic research? A First, I think the worst thing for science and society is to leave the, quote, ethical issues up to the professional ethicist, because while there are some very good ones that have their feet on the ground and things based in reality, a lot of discussions that I've heard at ethical meetings are totally hypothetical situations that have nothing to do with facts or reality or even probability. I feel that the scientists doing the work - and I seem to have somewhat of a unique philosophy in this - and leading the discoveries should be some of the people most involved in the ethical discussions, not the ones sitting on the sideline, leaving it up to the professional ethicist. We're trying to build a research policy and ethics department here, recruiting additional people with expertise in the area. I think [ethical discussions] have to go hand in hand with this research. Most scientists rely on public funds, and I think with that comes an obligation to help educate the rest of society about these issues and about what the information means. Q Please discuss some of TIGR's international collaborations. A We're involved in a great number of them. The largest is a human gene-mapping project with investigators in France, England, and other institutes in the U.S. We're also starting an international effort to sequence the malarial genome. Another project is focused on trying to find new approaches to fight schistosomiasis. TIGR took some of its own research budget and sponsored a grant to help set up [molecular biologist] Sergio Pena's lab [at the Universidade Federal de Minas Gerais in Belo Horizonte, Brazil] and to train one of his graduate students here at TIGR. Pena's group has a number of candidate genes that look like they could be antigens for developing vaccines against schistosomiasis. It remains to be seen where this research will go, but I believe strongly in technology transfer. I don't believe that just the American public know and benefit from our research. Q Now, with the first sequence of a free-living organism about to be published in the July 28 issue of Science, what is on the horizon for genomic research? A Well, we're trying to start a new field of comparative genomics. Which genes do all species have in common? Which ones are totally unique to that species? Which genes are the essential set for life, the minimal set? That's why we took on sequencing [the bacterium] Mycoplasma genitalium. It's the smallest known genome of the free-living organisms. It's a developing field, because mathematically it's quite complex to compare the evolution of all the genes in an organism to all the genes in another organism. Advances in genomics are going to come, in part, from software engineers. As far as the near future is concerned, we will have three free- living organisms fully sequenced by the end of this year. Haemophilis and Mycoplasma are done. The third will be the hyperthermophilic Archea Methanococcus jannaschii [K.Y. Kreeger, The Scientist, Feb. 6, 1995, page 1]. And in the next few years we hope to fully sequence at least a dozen more microbial genomes. (The Scientist, Vol:9, #15, pg.1 , July 24, 1995) (Copyright © The Scientist, Inc.) garfield@aurora.cis.upenn.edu

Genome Investigator Craig Venter Reflects On Turbulent Past And Future Ambitions

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