ROCKVILLE, Md.--A mural-sized illustration of the first-ever sequenced bacterial genome, Haemophilus influenzae, decorates the lobby at The Institute for Genomic Research (TIGR) here, home to the team of scientists that made history with its completion in 1995. Hidden within one of the tiny color-coded purple genes is a barely decipherable message: "Elvis lives."
The prank is telltale of the informal culture at the nonprofit institute, where, on a recent Friday afternoon, shorts, golf shirts, and sneakers were the work-wear of choice among molecular biologists engaged in groundbreaking research. The institute's laid-back style says something, too, about the personality of its president and director, biochemist J. Craig Venter--a personality that clashed strongly enough with that of the CEO of his commercial sponsor to bring an early end to genomics' most famous, if not most successful, partnership.
In late June, in a deal that cost TIGR $38.2 million in funding, Venter cut short a contract with Human Genome Sciences Inc. (HGS), TIGR's private backer and nearby neighbor in a sprawling science park along what is known as Maryland's technology corridor. According to Venter, the breakup was largely attributable to a personality conflict between himself and William Haseltine, the HGS CEO.
Success at Warp Speed
Founded in 1992 with a 10-year, $70 million grant from HGS, TIGR quickly made its mark on the genomics field using Venter's revolutionary strategy for rapid gene data identification through express sequence tags. In their first two years, TIGR scientists claimed to have tagged more than half the 60,000-80,000 genes that their research estimates are in the human genome. In 1995, TIGR published the world's first sequenced bacterial genomes: H. influenzae, a bacterium that causes invasive childhood infections, and Mycoplasma genitalium, which has the smallest genome of any free-living organism.
For the past year, TIGR's H. influenza research has been the most frequently cited paper--and its authors among the 20 most cited scientists--in biology, according to the Institute for Scientific Information's Science Watch, which tracks the impact of scientific publications.
In a phone interview from his Cape Cod vacation home, Venter said the HGS divorce has freed him and his staff to expand into new areas. Venter and Anthony Kerlavage, director of the TIGR database and Department of Bioinformatics, listed some new priorities: ramping up TIGR's gene array project in a soon-to-be-announced consortium with three key gene chip companies; licensing TIGR databases to private firms; and negotiating two upstart businesses--one in antimicrobials development, the other a bioinformatics venture with an existing software company and several large pharmaceutical and biotech firms.
To be sure, the HGS divorce did not leave the institute unscathed. "We walked away from $38 million," Venter acknowledged. "Research grants don't pay all the bills. We cut back on a couple of new ideas we were trying." But he expects to recover quickly. With $30 million in committed grants from the National Institutes of Health (NIH), the National Science Foundation, and the US Departments of Energy and Defense; income from some contract sequencing projects for the pharmaceuticals industry; and an endowment bolstered by the sale of its HGS stock, the institute is still in a rapid growth phase, Venter claimed.
Already one of the world's largest sequencing facilities, with over 60 automated sequencers and several on order, TIGR continues to expand. After nearly doubling its staff from 85 to 150 between 1995 and 1997, it outgrew a two-year-old, 50,000-square-foot facility and erected trailers on its 12-acre campus. According to Venter, new hires are joining TIGR at a rate of 10-20 per month.
Venter told BioInform that he is currently engaged in "serious discussions" with several pharmaceutical and biotech firms that could expand TIGR's walls beyond the Rockville campus. Within the next month, he expects to announce a joint venture with several private companies that would focus on developing bioinformatics software tools for managing the vast quantities of genomic data now available. "The biggest problem biotech and pharmaceutical companies are facing right now is that they're overloaded with information," he observed.
To illustrate the exponential rate at which data are being produced, Venter pointed out that in 1995 TIGR published the first two genomes ever completed; in 1996 four more were published. He predicted another eight will be published this year (four by TIGR alone), and eight to 10 next year. In addition, the day following TIGR's split from HGS, Venter released 40 million base pairs of data and more than 20,000 new genes into the public domain over the Internet. In August, Nature published TIGR's completed sequence for Helicobacter pylori, an ulcer-causing bacterium.
Stanford University School of Medicine Professor of Develop mental Biology and Professor of Genetics Lucy Shapiro told BioInform that such data have huge consequences for the science community. TIGR's H. pylori data were so important to her lab that when they were released one student spent four days and four nights annotating the raw sequence. "If you're working on a given bacterial cell, unless you get the genome sequence you'll be left in the dust," she commented.
"The challenge is using the data in an intelligent fashion to innovate new drugs and therapeutics, finding the one or two genes that are important for antibiotic development," Venter explained. "We think that by virtue of doing this longer than anybody else, we can lead the way to figuring out how to use all this information intelligently."
TIGR's upcoming joint venture would also handle the business of licensing the institute's dozen-plus databases, including custom human, plant, mouse, rat, microbial, and vaccine inventories. In particular, the databases' relational construction makes them highly valuable. "Users can search for complex information in the relational database, instead of just being able to seek a sequence match," Kerlavage noted.
For instance, Venter explained, "if you're looking for a receptor and want to know where it's expressed, you can get a list of all brain receptors that also occur in the heart and kidney but not the liver, or in any similar combination. Licensing the databases privately would allow companies to combine TIGR data with their own data in-house to develop a customized maximum set of data, he added.
As for its in-house research, TIGR's efforts are divided between two key scientific areas: the human genome project and plant and bacteria research. TIGR is one of six NIH-funded pilot centers for the human genome project. With a chance to be scaled-up by NIH later this year, TIGR is exploring robotics inventions that could increase its output. TIGR now analyzes 4,000 DNA fragments a day, four times its 1994 rate. "We hope to increase output by 10, but costs by only two," said Kerlavage.
Major pathogens being researched by the TIGR team include malaria--a project funded by the Department of Defense, NIH, and the Burroughs Wellcome Fund--and organisms that cause tuberculosis, syphilis, Lyme disease, cholera, diarrhea, pneumonia, meningitis, and skin infections.
A third scientific area into which TIGR is expanding is gene array research, a method by which gene expression is derived. "We can put all the different genes from a genome on a glass slide and get expressive information and gene content information from a whole variety of sources," Venter said. "These gene chips allow biology to be studied at the genome scale."
Ultimately, the research will lead to advances in microbial diagnostics. "You will go into a doctor's office with an infection and get a readout of what it is and what antibiotic it will be sensitive to within an hour," Venter explained. TIGR's will be the nation's largest gene array facility, he contended.
As more expression data are discovered, the TIGR database will grow exponentially, increasing commercial demand. But while he welcomes, and is currently negotiating, new commercial relationships, Venter said he does not intend to relinquish TIGR's nonprofit status, nor does he intend to establish another exclusive relationship like the one with HGS.
"I'm someone who learns from mistakes; I try not to make the same ones twice," Venter concluded. "Hopefully we will not get tied up in an exclusive deal again."
--Adrienne J. Burke