A Personal View of Genomics

It wasn't easy getting to the 4th International Meeting on Single Nucleotide Polymorphisms and Complex Genome Analysis held Oct. 10-15 at the Wenner-Gren Foundation in Stockholm. A week earlier, as flight cancellations continued in the wake of the Sept. 11 terrorist attacks, SwissAir had declared bankruptcy and an SAS jet had crashed in Milan, further disrupting schedules. So it was little surprise that several speakers had to phone in their talks. But not J. Craig Venter, president and chief sc

By | November 26, 2001

It wasn't easy getting to the 4th International Meeting on Single Nucleotide Polymorphisms and Complex Genome Analysis held Oct. 10-15 at the Wenner-Gren Foundation in Stockholm. A week earlier, as flight cancellations continued in the wake of the Sept. 11 terrorist attacks, SwissAir had declared bankruptcy and an SAS jet had crashed in Milan, further disrupting schedules. So it was little surprise that several speakers had to phone in their talks. But not J. Craig Venter, president and chief scientific officer of Celera Genomics Group in Rockville, Md., and the first keynote speaker.

"It is extremely important not to let the individuals who perpetrated these acts control our lives. I'm not controlled by them. We must all act in a normal fashion," he began, and then launched into an account of activities at Celera, past and future. But it was an unexpected musing about the uncertain present that explained his opening comments, and left the audience spellbound.

File Photo

Craig Venter

Venter began by speaking, like a father bragging about his firstborn, about Haemophilus influenzae, the organism that occupies a place in history as the first to have its genome sequenced.1 It is a bittersweet memory, marking one of several stops on Venter's career path where his ideas were dismissed as incredible. First came expressed sequence tag (EST) technology, over which he left the National Institutes of Health to found the not-for-profit The Institute for Genomic Research (TIGR) in Rockville in 1991. In 1994, TIGR sought NIH funding to sequence the genome of H. influenzae, using an assembly approach that skipped preliminary mapping stages. "NIH trashed the proposal. They thought it couldn't be done, that it was full of holes," recalled Claire M. Fraser, president of TIGR and Venter's spouse.2

Not only was it possible to sequence the microbial genome in under a year, but TIGR's success was the proof of principle that whole genome shotgunning could work-as it went on to do for Drosophila melanogaster3 and then the human genome.4

H. influenzae, a human pathogen, causes middle ear infections and meningitis, particularly in children. But its import isn't in medicine or as a trendsetter in genomic research; it is in evolution. And what the H. influenzae genome revealed in 1995 is especially chilling in light of recent events. "It illustrates Darwinian evolution in real time. Each one of us has a different variant. Rapid evolution in microbes has a big impact on human health, and Haemophilus influenzae was crucial in our understanding of that. DNA polymerase slips every 10,000 or so bases during replication, which leads to frame shift mutations which knock out some gene functions, causing changes in cell surface antigens that tremendously change the response of the human immune system," he explained.

Today, some 100 microbial genomes later, Venter remains critical of the focus of NIH funding, especially considering the deluge of genome data. "NIH grants have to be based on hypotheses. Well, my hypothesis is, we know 'diddly' about most genes. So why not, 'I want a grant to look at that gene and see what it does.' But we don't have the mechanism as a scientific society to deal with this. That's why I started TIGR. We deny that biology is descriptive, but it is," he told the Stockholm group. About half of the hundred sequenced microbial genomes involved TIGR. "We've seen an exponential growth in the pace of sequencing genomes," Venter added.

Contemplating the Human Genome

Celera's sequencing of the human genome derived from 39-fold coverage of the genomes of two males and three females, identity undisclosed, but chosen to show that race is literally only skin deep. "The Science cover showed six people, one a baby. I suggested to Science editor Don Kennedy that the baby was in honor of the nine months that it took to assemble the sequence," Venter joked.

At a recent speaking engagement at Harvard University, hecklers brought up the lack of medical miracle cures to have materialized from the human genome project. After mentioning this, with a "they just don't get it" look, Venter presented a brief, sweeping view of what the project did reveal about our genetic instructions. "There are regions with very high gene density, and also vast deserts of millions of base pairs with few or no genes. The early estimates of 50,000 to 100,000 genes were wrong. It was based on what I did at the NIH, when we predicted gene number from high density regions at the same time that we underestimated the deserts," he said.

As genomics has marched on, we are learning about the place of Homo sapiens in the living world. It may come as a shock to the many who see humans as special that at the DNA level, we are remarkably similar to other species, our differences dictated more by gene arrangement and number than by qualitative distinctions. "Humans have the same genetic complement as rat and mouse, dog and cat. But transcription factors turn different sets of genes on and off, in different combinations that give us our uniqueness. The genome is the recorded history of our species," Venter said. The extent of redundancy in the genome, from individual repeated genes to great chunks of chromosomes that have multiplied and moved through evolutionary time, surprised this man who is not surprised by much of anything. "Everyone ignored this aspect of our genome paper," he said, adding that the unexpected redundancy explains instances where research groups are certain that they have identified the gene behind an illness-only to find that there is more than one.

A project at Celera launched in July 2001, is documenting DNA differences among individuals via SNPs, or single nucleotide polymorphisms. These are sites in the genome that have an alternate base in 1 percent or more of a population. (Look for more on this in the upcoming Jan. 7 issue of The Scientist.) Neighboring SNPs that cover small portions of the genome can be used to construct haplotypes ("haploid genotypes"), which can be used to trace evolution (See "The Promise that Haplotypes Hold" on page 21). As a baseline for future research, Celera is compiling SNP maps and resequencing every human gene and exon in 40 to 50 individuals. At the meeting, Venter unveiled a twist to the research: "We are including a chimp to see if anyone can tell who he is!" So far, the Celera chimp genome database indicates that the human and chimp genomes differ in 1.27 percent of the sequence. "The chimp genome is the human genome with a slightly higher polymorphism rate," Venter said.

With the pace of genome sequencing accelerating daily, it's clear that the age of genomics is just dawning. "By the end of 2002, we will be able to take any genome and sequence all the genes in under a week, for under $1 million. We will have techniques to sequence the universe of human exons in under a week. First we thought it would take 15 years to sequence 3 billion bases, and got it down to 9 months. In a year, it will take a week, then two days, then two hours," Venter said. It was fairly typical hyperbole, yet people have learned by now not to doubt his claims. But what followed was most unexpected.

Venter, uncharacteristically silent, showed a series of photographs taken at "Ground Zero," where recovery work proceeded at the destroyed World Trade Center site in New York City. Head bowed, the silence grew uncomfortably long. Finally, in a barely perceptible voice, the man whom the press once compared to Darth Vader described the slides behind him that he would not face. "These are difficult slides for me to look at, and they should be for you, too. I was there last week. The forensics officials asked Celera to help with the sequencing, to use our high-throughput methods to help identify remains for the families. So I took these photos." Celera is sequencing mitochondrial DNA from tissues that have survived weeks of the persistent inferno, such as teeth and bone, to complement DNA typing being done on other tissues at Myriad Genetics Corp. in Salt Lake City. After more silence, Venter collected himself and said, "I never, ever thought we would have to do DNA forensics at this level, and for this reason."

It was a rare glimpse of humanity in the man who has sequenced the most genomes.

Ricki Lewis (rickilewis@nasw.org) is a contributing editor for The Scientist.
References
1. R.D. Fleischmann et al., "Whole-genome random sequencing and assembly of Haemophilus influenzae Rd," Science, 269:496-512, 1995.

2. R. Lewis, B.A. Palevitz. "Sequencing stakes: Celera Genomics carves its niche," The Scientist, 13[15]:1, 1999.

3. M.D. Adams et al., "The genome sequence of Drosophila melanogaster," Science, 287:2185-95, 2000.

4. J.C. Venter et al., "The sequence of the human genome," Science, 291:1304-51, 2001.
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