“J. Craig Venter has never been a man to waste time,” noted Dr. Samuel Preston, dean of the School of Arts and Sciences, as he introduced the pioneering and often controversial genomics researcher to a packed Irvine Auditorium in February.
“By accelerating the sequencing of the human genome,” Preston added, “he has moved us closer to the enormous array of benefits that seem nearly certain to follow.”
The occasion was the 2002 Dean’s Forum, an annual event that showcases SAS’s most talented students while presenting a talk by one of the “academy’s leading public figures,” in Preston’s words. Earlier, he had presented awards to the 19 Dean’s Scholars for 2002.
If it weren’t for Venter, the world would probably still be waiting for the first map of the human genome. It was he who advocated using advanced computer technology to speed the work of DNA sequencing, and then—when the National Institutes of Health refused to fund the idea—organized a private effort to do the work instead. The ensuing competition between Venter’s company, Celera Genomics, and the federally funded Human Genome Project shaved years off the original timetable to produce a “working draft” of humans’ genetic makeup.
It also led to some harsh words between the two camps. In a story naming Venter “Scientist of the Year” in its “Person of the Year” issue, Time reported that he once referred to the directors of the public project as the “liars’ club”—after Dr. Francis Collins, leader of the public project, had predicted that Venter’s genome map would look like something in Mad magazine.
The race ended in a negotiated tie in June 2000, when Venter and Collins shared the stage with President Bill Clinton for a public announcement of both efforts’ success. The two groups’ independent drafts were published simultaneously the following February, Venter’s team’s in Science and the public project’s in Nature.
Venter was a scientist at NIH in 1990 when the Human Genome Project got under way. “I was actually one of the first biochemists that showed an interest in the project, which was driven by geneticists looking for ways to increase their funding,” he recalled.
In 1991, Venter developed a method called Expressed Sequence Tags (EST), able to single out DNA performing a function from the majority which does not, accelerating scientists’ ability to sequence single genes. “Within a three-month period, we doubled the number of human genes that had been sequenced,” he said.
“EST is the number-one method of gene discovery in the world, used with every major species to date,” said Venter. “But the huge discovery that came out of EST was a new mathematical approach.”
The challenge was how to connect multiple DNA fragments to sequence an entire genome, Venter said. A team of computer scientists working at the Institute for Genetic Research (TIGR), a nonprofit organization founded by Venter in 1992, developed “what became known as the ‘tiger’ assembler that allowed us to put these sequences together.”
This method involved “shotgun sequencing,” in which DNA was cut up into random fragments small enough to be sequenced by sequencing machines (500-600 letters is the limit) and then reassembled in the original, correct order using computers. In 1994 Venter—working with Dr. Hamilton O. Smith, the 1978 Nobel laureate in medicine—submitted a grant application to the NIH to support this new method of sequencing genomes. The NIH, Venter recalled, sent back a critique “telling us what we were doing was impossible and that they weren’t going to fund it.”
They went ahead anyway, and the technique proved successful. In 1995 they published a paper in Science that described the first genome of a living organism—haemophilus influenzae, which causes bacterial meningitis and ear infections in children. Since then, said Venter, there has been “exponential growth in the genomes completed because of this technique.” About 100 genomes have been sequenced, about half of them by Venter’s teams at TIGR and Celera. “These include pathogens that are major causes of human diseases,” he said. “And these are now driving new vaccines and therapeutic developments quite rapidly.”
Dissatisfied with the pace and quality of the work being done by the Human Genome Project—which, having initially rejected Venter’s computing-intensive approach, had divided up the work of sequencing into thousands of smaller projects in laboratories around the world—Venter founded Celera Genomics in 1998 as “the only way I could get $300 million to sequence the human genome.”
After successfully sequencing the Drosophila (fruit fly) genome as a test case, Celera began work on the human genome on September 8, 1999, using DNA from an ethnic and geographically diverse group of volunteer scientists that included Venter himself.
Assembling genomes is “very much like building a jigsaw puzzle,” noted Venter. The powerful algorithms developed by the Celera team, led by Dr. Eugene W. Myers, vice president of informatics research, did just that with the approximately 27 million pieces involved in shotgun-sequencing the human genome. They built a 11/2 teraquad computer to perform the calculations (a teraquad is 1 trillion calculations per second). “Even so it took months to assemble the human genome,” said Venter, who noted that humans were found to have a smaller number of genes than had been assumed—26,000 or so, roughly twice as many as fruit flies.
More significant than the number is the potential to track changes in our gene complement over the last 600 million years. Genes associated with the immune system are almost all new during that period, he said, with the most interesting category being an increase in transcription factors—protein molecules that regulate gene expression. “They turn on either single genes or whole sets of genes,” Venter explained, and are thus the “likely controllers of evolutionary events.”
Humans differ from each other “roughly one letter in 1,200 letters of the genetic code,” he said. As for our fellow mammals, there is about a 95 percent overlap between humans and mice, and the average difference between humans and chimps, genetically speaking, is 1.27 percent.
Discussing the effect of genes on disease and how that will play out in medicine, Venter noted: “We’re going to have the difficulty of knowing what a 30 percent increased risk of colon cancer means. But one thing it does for sure: If you know that you as an individual have an increased risk, it gives you power over your own life”—for example, by having colonoscopies more often and at a younger age. “Colon cancer is virtually wholly treatable by surgery if it’s caught early,” he added. “As we go to blood tests for these diseases, it will get even easier to move more into a preventative-medicine era.”
There are “multiple societal challenges involved” in integrating the new knowledge of genomics into people’s individual lives and public-policy decisions, Venter said, noting later that this would be a major future focus of his own work—such as in advocating passage of an anti-genetic discrimination bill in Congress to protect the public from misuse of genetic data.
“On the science side, we are dealing for the first time with the holistic nature of biology,” he concluded. “Using all this information to understand how it works together is a real challenge—and [we] will have to wait for new advances in computing for some of them.”
