J. Craig Venter on Whole Genome Shotgun Sequencing
  J. Craig Venter     Biography    
Recorded: 02 Mar 2006

Well, in fact, I was asked by the U.S. Surgeon General when I was still at NIH to sequence the smallpox genome. It was part of an international treaty between China, U.S. and Russia, that once we had sequenced the smallpox genome they were going to destroy all the remaining storage of smallpox and that became very controversial on its own. But I looked at the smallpox genome. It was roughly the size of the areas that we did our test sequence, you know, the human genome on. And I was frustrated at how slow those techniques were, that all the labs in the human genome lab were using. So that’s when I actually had the first idea to do a whole genome shotgun on the smallpox virus. But the security around it—they were worried about any one lab ever having the whole smallpox DNA in their lab. And so they set it up—we had to get one fragment at a time from the CDC. We would then sequence that. And so they didn’t want anybody to be able to put the DNA together to make smallpox. So we had to postpone the idea of doing the whole genome shotgun.

But when we talked about Haemophilus, Ham had trouble making libraries and he went back to his lab and he couldn’t interest anybody in his lab in doing this project either. It shows you even when you have these ideas, whether you are a Ham Smith or a Craig Venter, you know, you have to convince people on your teams that they have to take it on; and nobody wanted to do it. So he decided he would do it himself, working with me. We talked about various approaches we could take and I told him what we were thinking of doing with smallpox. He went and did a number of calculations and simulations and said he thought it was really possible and we decided to just try it.

It was a giant experiment. We didn’t set out to sequence the first genome in history. We thought it was going to be E. coli or yeast or something else. We set out just to try this new method based on these ideas, because if the ideas worked and the method worked, it would have a lot of implications of going forward and tackling things like Drosophila and humans. It was only when we were in the midst of it that we realized how powerful the technique was. It took only four months to sequence the genome instead of thirteen years for E. coli, ten years for yeast. So imagine, just four months later, we were finished and the mathematics were working. But key to that was the scientist that still works for me now, Granger Sutton, who developed the new algorithms that made it possible to assemble the DNA.

You know, a lot of people say that, Sanger developed whole genome shotgun sequencing. He certainly did fractionation of the viruses and he’s a hero to all of us in terms of what he did, and really a pioneer. And we are all using derivatives of his sequencing methods. But there’s nothing that was extrapolatable from sequencing phi-x174 lambda to doing a bacterial genome. We had to develop all new methods, all new mathematics, all new strategy to do it. And so, you know, we were obviously building on the work of Sanger, using his technique that in fact Mike Hunkapillar and Lee Hood converted into an automated sequencer. But the ideas were all totally new.

In fact, Ham and I wrote a grant and I wrote a grant and submitted to NIH to the genome center that we wanted to sequence as a test experiment Haemophilus influenzae using whole genome shotgun sequencing. We just wanted to try the experiment. And the grant got turned down, but it’s actually a very interesting history. Very rarely do grant committees have a big debate and so there was actually a group of scientists that filed a minority report. So, some of the scientists thought it was a brilliant idea and wanted to fund it immediately, but the majority said it wouldn’t work and it would be a waste of time and money. So Francis Collins refused to fund the grant and so we dipped into our endowment. So it’s the same story of ESTs. If I did not have independent money, I would not have been able to afford to do the experiment. So I actually used the money that was guaranteed to me for forming TIGR. I took a big risk. We took the money out of the bank to do the experiment. And it worked better than anybody ever imagined.

We all know brilliant scientists who have had great ideas that end up very frustrated in their careers because they can never have the resources to try their idea, to try their experiment. In fact, I can tell you another brief story. I’ve never met or interacted with Fred Sanger directly, but we exchanged correspondence. And when we published the Haemophilus genome, having it work with whole genome shotgun, he sent me a very lovely personal note saying he was always sure this approach would work, but he could never convince any of his colleague to try it. He said they all wanted to own their own piece of DNA. So I’m sure he thought of it before, but he had the same problem in his lab. He couldn’t convince anybody to try the experiment. So I thought that was just, you know a very touching note from him. Well, I think we convinced a lot of people. The field changed overnight. It was—we got so much correspondence. People said that all of a sudden they understood what genomics was about when they saw the complete genome and all the genes in Haemophilus. I think that was a turning point in the whole field of genomics

J. Craig Venter, biologist and genomic research pioneer, was born in Salt Lake City, Utah in 1946. Following military service in Vietnam, he studied biochemistry as an undergraduate at the University of California, San Diego, where he also received a Ph.D. in Physiology and Pharmacology in 1975. He joined the faculty of the Medical School of State University of New York at Buffalo in 1976, joining its affiliated Roswell Park Cancer Institute in 1982 as Professor and Associate Chief Cancer Research Scientist. Beginning in 1982, and for the next decade, Dr. Venter headed various sections of NIH's National Institute of Neurological Disorders and Stroke.

In 1992 he founded The Institute for Genomic Research (known as TIGR,) where he and colleagues became the first to successfully sequence the genome of an entire organism. Dr. Venter's Celera Genomics, founded in 1998, used a strategy known as the whole genome shotgun approach to compete with the publicly-funded Human Genome Project, which served to accelerate the mapping of the whole human genome by 2000. Dr. Venter's current venture, the J. Craig Venter Institute, was formed in 2006, from the merger of several predecessor enterprises. A leader in genomic research, the J. Craig Venter Institute announced in January 2008, the largest synthetically derived DNA structure, advancing it towards its goal of creating a living cell based on an entirely synthetic genome. In September 2007, the J. Craig Venter Institute announced the sequencing of Dr. Venter's genome, the first sequencing of an individual's genome.

Among Dr. Venter's numerous awards and honors are the American Academy of Microbiology Fellow (1997), the American Chemical Society, Division of Biochemical Technology David Perlman Memorial Lectureship Award (2000), and the U.S. State Department, Secretary's Open Forum Public Service Award (2001). Dr. Venter is a member of the American Society of Human Genetics, the American Association for the Advancement of Science, the American Society of Microbiology, and the American Academy of Arts and Sciences.