A notable exception to this pattern can be found at The Center for Genomic Sciences (CGS) within the halls of the University of Pittsburgh School of Medicine.

In January 1996, four researchers agreed to give up the stand-alone status of their individual labs to create a single, multidisciplinary gene discovery organization. The Center was funded by the summer of the same year.

"We have really merged things. We have joint meetings. We are all in all the labs. All of our grants support all the labs. It is very much a cooperative system," Dr. Garth D. Ehrlich, Executive Director of the Center, told HMS Beagle.

The CGS was formed, simply, to facilitate the discovery of genes for almost any disease. By pooling resources, CGS scientists bring together in one academic organization the four necessities for successful gene discovery: (1) well-characterized patient populations representing all medical disciplines; (2) state-of-the-art genotyping, sequencing, and gene expression laboratory facilities; (3) automated data processing and analysis systems; and (4) year round, ongoing cooperation among the principal scientists providing expertise in techniques of disease gene mapping, positional cloning and identification and characterization of previously unidentified genes through differential expression patterns.

"We have been quite successful," Ehrlich said. "We have mapped and cloned two genes since we formed and we have a number of other projects that are going along quite well."

Payoff: the gene for hereditary pancreatitis

Led by researchers from the CGS, collaborators from medical centers around the country identified the gene responsible for a painful condition known as hereditary pancreatitis (HP).

The team included fifteen scientists with expertise in subjects ranging from clinical care medicine to molecular biology to crystallography. Bringing people together is one of Ehrlich?s strengths; he realized early in his career that significant scientific advances often take place where disciplines meet. It took CGS less than three months to identify the gene after they had localized it to chromosome 7. Then it took approximately two days for them to work out a convincing model that explains the molecular basis of the condition.

The remarkably complete genetic and molecular explanation of the rare autosomal dominant disease was the subject of a Nature Genetics editorial that accompanied the report, "Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene," in the October 1996 issue of Nature Genetics. A brief summary of the genetics of this disease and future research directions is provided in our sidebar.

The discovery of the HP gene required two other factors, both involving cooperation, besides the expertise of the scientists at the CGS and their collaborators. The first was data already provided by the Human Genome Project. Because other genes on the long arm of chromosome 7 had been cataloged already by the Human Genome Project, the CGS workers were able to avoid false leads as they tracked the gene for HP. The second important factor was the help provided by all the families afflicted with HP. Such cooperation is invaluable to scientists searching for disease genes.

Lab heads become center directors

Each of the four scientists who contributed their lab space to the Center became CGS directors. Ehrlich, as Executive Director, supervises the Center?s operations on a day-to-day basis. A decade ago, he was one of the first researchers to apply the polymerase chain reaction to the detection of infectious disease agents. Trained as a a human retrovirologist, he now describes himself as a molecular biologist.

Ehrlich does not believe the cooperative example set by members of The Center for Genomic Sciences is part of a trend in academia. "The model we use is much more like an industrial model (than an academic model). Part of the it may come from the fact I worked in industry for several years before graduate work. Perhaps I am more comfortable with collaboration than a lot of academics," Ehrlich said. "One thing I realized very early on is that there are some things I am really good at and some things I am not. If you work with people who have complementary traits, you will be more successful."

This approach to research makes diplomatic skills as important as scientific skills, when the success depends on the cooperation of many accomplished, individual scientists and clinicians.

"You try to fairly divide up the credit. You try to decide who is going to be where on papers. It is never perfect. There will be times when there will be disagreements. But as long as everybody is reasonable, you try to work as best you can. So far there have not been any problems we have not been able to work through," Ehrlich said.

To lead the project to map the gene for hereditary pancreatitis, Ehrlich joined other directors of the Center, including Dr. David C. Whitcomb and Dr. J. Christopher Post. Dr. Whitcomb is the Chief of Gastroenterology at the Oakland Veterans Administration hospital in Pittsburgh. A Ph.D. in physiology, he is an expert on the control by the brainstem of pancreatic secretions. Dr. Post is a board-certified pediatric otolaryngologist and a Fellow of the American Academy of Surgeons. Post was instrumental in introducing molecular biology techniques into the field of otolaryngology. He maintains a large surgical practice at Children?s Hospital in Pittsburgh where he is also Co-Director of Pediatric Otolaryngology. Finally, the acquisition and intake of all patient specimens for genetic testing at the Center is the responsibility of CGS Director Dr. Richard Duerr. A practicing gastroenterologist, Duerr is an expert on inflammatory bowel diseases such as Crohn?s disease and ulcerative colitis.

Ongoing and future research projects

Many clinicians are providing patient populations for genetic studies at the CGS. These projects are exploring the potential molecular genetic basis of human craniofacial development, susceptibility to otitis media (a common childhood disease) and various forms of inflammatory bowel disease. Other disease gene targets include some that may contribute to diabetes and vesicoureteral reflux, which affects up to 3% of the population. The hereditary form of Dupuytren contracture (a hand-disabling condition), pre-eclampsia (a form of toximiaaffecting pregnant women), Towne Brock Syndrome (a disease displaying an autosomal dominant pattern of inheritance resulting in a variety of symptoms), ectrodactyly (a congenital absence of fingers, toes or parts of them), and psychiatric disorders are also targets for gene discovery projects at CGS.

"We are also working with a group in Audiology and Speech Communications trying to do segregation analysis on various types of language acquisition disorders and speech pathology," Ehrlich adds.

Half of the CGS projects employ familial linkage analysis, or affected pedigree member analysis. "The other half of the lab is doing gene discovery through differential display, an mRNA fingerprinting technique that permits comparison of tissues derived from various stages of development or environmental conditions," Ehrlich said. The CGS is now characterizing about a dozen different genes for the differential display studies.

"We are trying to clone out genes associated with those differences. And so we have a project looking at the issues of wound healing which could have enormous commercial implications," said Ehrlich. He predicts that as that system gets rolling, it will lead to the characterization of more genes than will familial linkage analysis.

To process the data generated by such a wide-ranging research program, CGS is developing software for the data they are generating now and for the samples they hope to handle in the future.

"We are trying to let clinicians know that if they have any disease or syndrome which they see more commonly in related individuals than among unrelated individuals, there is the possibility of doing genetic analysis to find the genes that are associated with a predisposition toward that disease. We are finding out that the most common maladies have genetic predispositions as well as environmental influences. They run in families," Ehrlich said.

Lingua franca

The decree that allows the collaborating scientists to make such an "open casting call" for potential disease genes is found in the CGS prospectus:

The founding premise of the CGS was that by pooling the varied expertise of the scientific and technical staffs of the member scientists and utilizing the combined laboratory resources, the CGS would achieve maximum efficiency. The developmental family of technologies based on the manipulation of nucleic acids has provided the biomedical sciences with a lingua franca for first time.

Endlinks

The Center for Genomic Studies does not have a website yet, but the research community it draws upon for collaborators, directors, students, and patients is well represented online. First, the University of Pittsburgh http://www.pitt.edu/~fasgrad/univ.html provides a complete site that lists most of the information which visitors and prospective students or employees might require concerning the academic community and the city.

Links to other important institutions in the area are included in the Pittsburgh education http://www.pitt.edu/ site. Many of these sites have ties with the Center for Genomic Studies.

An example of the quality of research being done at the CGS is illustrated by the successful identification of the gene for heritary pancreatitis. For a clinican?s eye view of this disease, check a clinical case of pancreatitis.

Rapid identification of the gene was greatly aided by the progress made in the Human Genome Project http://www.ornl.gov/TechResources/Human_Genome/project/, of course. The websites associated with the Project are impressively packed with information, well written, and thorough. Included is a useful brief tutorial on understanding the internet and WWW. Links to details of the Project?s history, goals, and budget are provided in an index http://www.ornl.gov/TechResources/Human_Genome/project/.

To understand the lab procedures used at the CGS and other genome research centers, try Genentech?s Access Excellence website http://www.gene.com/ae//. It covers procedures related to biotechnology and recombinant DNA protocols. Just type "familial" in the search window, for example, and all the right links to genomic information will fill your screen.

Dean A. Haycock is a journalist who writes science articles for many magazines and newspapers. He received his Ph.D. in Neuroscience from Brown University.