May 21, 1999

Robinson Lecture lures maverick genetics researcher

Robinson Lecture lures maverick genetics researcher


Dr. Roscoe Robinson, former vice chancellor for Health Affairs (center) chatted with Joel Hardman, Ph.D., former associate vice chancellor for Health Affairs (left), and guest lecturer J. Craig Venter, Ph.D. (photo by Donna Jones Bailey)

One of the most cited scientists in biology and medicine gave the first Roscoe R. Robinson Lecture at Vanderbilt University Medical Center last week.

J. Craig Venter, Ph.D., president and chief scientific officer of Celera Genomics Corp., breezed through a decade of genome research history during the lecture.

"It's really a tremendous basic science story about following leads from basic research and using advances in technology," Venter said.

The Human Genome Project was officially launched on October 1, 1990 as a 15-year program to map and sequence the complete set of human chromosomes and those of several model organisms. Discussions about it were already well under way by the mid 1980s, and Venter's laboratory at the NIH served as the test site for the first automated DNA sequencer in 1987.

Venter reasoned early on that genes could be identified more quickly by sequencing only pieces of DNA that were expressed – on the way to being translated into proteins – in cells. He named the partial DNA sequences from these pieces "expressed sequence tags," or ESTs.

"By the end of our trial effort, we had identified 337 new genes, all from the brain," Venter said. "At the time – the start of this decade – there were only 2000 genes identified, and only about two dozen of those were from the brain."

Venter left the NIH in 1992 to form The Institute for Genomic Research (TIGR), a not-for-profit research institute. Using the EST strategy, Venter and colleagues at TIGR have discovered and published more than half of the approximately 35,000 human genes that have been sequenced to date. In addition, about 73 percent of the DNA sequences (human and non-human) contained in the GenBank nucleic acid database are ESTs.

"We infer that some of the sequenced human genes are important based solely on comparisons to E. coli and yeast. This is one of the most important lessons of genome research – every piece of prior biological knowledge is absolutely crucial for understanding our own genes," Venter said.

TIGR subsequently developed the whole genome shotgun method for genome sequencing. The concept is simple: take the entire chromosomal content of a cell, use sound waves to blast it apart, sequence the ends of the pieces, and let a computer find the overlaps and fit the puzzle pieces back together. In fact, the concept is so simple that the NIH didn't believe it would work.

"We applied for an NIH grant to sequence the Haemophilus influenzae genome in one year, and by the time we got the pink sheet back saying that this was impossible to do – that the sequence would be full of holes – we were 90 percent done," Venter said.

TIGR published the sequence, the first complete genome from a self-replicating organism, in 1995. During the lecture, Venter described the genomes of ten different organisms that TIGR has successfully sequenced using the whole genome shotgun method.

"The universe in terms of gene content is growing rapidly," he said.

To apply the shotgun approach and advances in automated sequencing technology to the human genome, Venter and Perkin Elmer Corp. formed Celera Genomics Corporation in 1998. The company announced that it would sequence the human genome by 2001, four years earlier than the anticipated finish date for the federally funded Human Genome Project. Celera also plans to sequence the mouse, fruit fly, rice, and Arabidopsis genomes.

Celera will release its raw sequence data, and it intends to derive revenue from subscriptions to its powerful databases. Already, several large pharmaceutical companies have signed on.

The Human Genome Project responded to the unanticipated private sector competition by moving its completion target date forward to 2003. Recently it announced plans to produce a "working draft" containing at least 90 percent of the human genome sequence by the spring of 2000 and to finish the permanent, high-quality sequence by 2003 at the latest.

Whatever the outcome of this race, the complete sequencing of the human genome will revolutionize biology and medicine.

"Having the genome sequence will result in individualized and preventative medicine as we've never seen it," Venter said. "Having it will also pose the greatest threat to civil liberties ever. The biggest danger I see as we go forward is the misuse of new genetic information."

The Human Genome Project continues to support research on the ethical, legal, and social implications of genome analysis.

The Roscoe R. Robinson Lectureship was a gift by the faculty of Vanderbilt University School of Medicine to celebrate Dr. Roscoe R. Robinson's 16 years of vision and leadership as vice chancellor for Health Affairs. The lectureship was hosted this year by the Department of Medicine.