SCIENCE & ENGINEERING NEWS

San Diego, CALIF. — The San Diego Supercomputer Center (SDSC) at the University of California, San Diego, will provide the bioinformatics infrastructure and information coordination environment for a novel scientific endeavor called the Alliance for Cellular Signaling (AFCS), a consortium of approximately 50 scientists at more than 20 academic institutions around the world. AFCS researchers will pursue unsolved biomedical problems, such as communication among types of heart muscle cells and immune system cells.

The National Institute of Gen eral Medical Sciences (NIGMS) announced September 5 that it will provide the AFCS with $5 million for its first year and anticipates spending a projected total of $25 million over the course of five years.

Central to maintaining close and regular contact among the AFCS scientists is keeping communication channels wide open, according to Alfred G. Gilman, a pharmacologist at the University of Texas Southwestern Medical Center at Dallas and leader of the AFCS effort. The communications “glue” for the consortium will be a sophisticated virtual conferencing system that can be operated using Internet2, a new university-based version of the Internet. High-capacity computing power will be necessary to house and organize the AFCS database of scientific results; SDSC expertise and resources will provide these capabilities.

“The amount of data generated by the Alliance will be enormous and require immense computational resources,” said AFCS participant Shankar Subramaniam, SDSC Fellow and professor in the Departm ent of Bioengineering and the Department of Chemistry and Biochemistry at UC San Diego. “The SDSC facilities will serve as a gateway for worldwide researchers to access and analyze AFCS data, as we conduct data mining and other bioinformatics tasks such a s database organization and maintenance.”

Subramaniam is serving as director for two AFCS core laboratories: the Bioinformatics Laboratory and the Information Dissemination and Data Coordination Laboratory. “The primary purpose of these two laboratories will be acquisition, management, storage, analysis, and distribution of information relevant to the Alliance activities,” said Subramaniam. “We will use a high-speed network of UNIX workstations at SDSC as database servers, and backup will be completed w ith our mass-storage system. Each of the Alliance laboratories will then house local computer facilities linked to the central repository at SDSC.”

The project will set out to study all aspects of cellula r communications in two cell types: cardiomyocytes (heart muscle cells that can beat in a dish) and B-cells (immune cells that are accustomed to roving around the bloodstream carrying out duties for the body). According to Gilman, a few characteristics he lped him and his colleagues to narrow the search to finding an “ideal cell” to study. The team sought “interesting” cells that could also live in a plastic lab dish long enough for scientists to study their features in great detail.

After much internal d ebate, the AFCS team chose to study cardiomyocytes and B-cells from the mouse, a mammalian model system that Gilman says is “extremely relevant to human health problems.”

A key goal of the effort is to map out in both cell varieties the vast number of s ignals that course through these cells, including – but not by any means limited to – those signals communicated through a class of specialized liaison molecules called G proteins. He and the late Martin Rodbell received the 1994 Nobel Prize in physiology o r medicine for discovering G protein signaling.

According to Gilman, studying mouse cells makes perfect sense since many of the molecules that scientists know are central to communication inside and between cells are nearly identical between the cells of mice and people. Within the next year or so, the complete genetic sequence of the mouse will be spelled out, Gilman predicts, enabling AFCS scientists to inventory the entire collection of genes involved in making mouse cardiomyocytes and B-cells do what they do.

“We hope to create a piece of a virtual cell,” said Gilman, adding that he anticipates drug developers will ultimately be able to test new compounds “in silico,” meaning that they will have the ability to search for new drugs using a computer a lone.

The AFCS project is a meaty effort because thousands of signaling molecules have been identified in cells, and assembling a catalog of all of the possible – and more importantly, authentic – interactions among them is a mind-boggling feat.

“Advances in genomics, proteomics, and informatics make the timing right for this bold experiment in how science is conducted,” said Rochelle Long, a pharmacologist at NIGMS. “Al Gilman’s vision is to transform the way cell signaling research is done, and he’s ded icating his career from this point forward to making this work,” she added.

Additional academic institutions participating in the Alliance include the University of Texas Southwestern Medical Center at Dallas, which serves are the AFCS lead site; the Ca lifornia Institute of Technology in Pasadena; the San Francisco Veterans Administration Medical Center; and Stanford University. The Alliance effort will also be partially funded with money from the pharmaceutical industry and several private donors.

In addition to the academic institutions involved, two biotechnology companies will participate directly in Alliance studies by providing custom-made materials such as antisense reagents (ISIS Pharmaceuticals of Carlsbad, Calif.) and a technology called two-hybrid analysis, a popular method scientists use to track encounters between proteins inside cells (Myriad Genetics, Inc. of Salt Lake City, Utah).

This innovative way to fund science grew out of NIGMS’ consultations with leaders in the scientific community who said repeatedly that the thorniest biological problems require the expertise and input of large, multifaceted groups of scientists.

Glue grants aim to do just that. “The purpose of the glue grant is to help address problems that are beyond the reach of individual investigators,” said Marvin Cassman, director of NIGMS. “The idea is to provide resources to a lot of people working together to collaboratively attack these problems.”

Impressive as it is, the AFCS effort stands out in another impor tant way. Alliance scientists working in the specially designed core laboratories have pledged to forgo two of the most coveted products of the biomedical science endeavor: intellectual property rights and first rights to publish in peer-reviewed journals, the respected anthology of scientific progress. Instead, all of the data produced in the core laboratories will be deposited immediately into the publicly accessible database.

Why would any right-minded scientist agree to such stipulations? Gilman is relying on the fact that many investigators will jump at the chance to participate in an interactive, collaborative science project they simply could not pull off in their own laboratories. And he would appear to be right, since to date, Gilman said, 250 scientists around the world have signed on as “Members,” hosting topic-specific Web sites called “Molecule Pages” that will be important auxiliary components of the Alliance public database.

This database will be freely accessible to any scientist with a computer and Internet access. Effectively, according to Gilman, thousands of scientists will be either participating in, or benefiting from, the Alliance. Gilman created these strict rules to encourage the free exchange of ideas and to foster other resea rchers’ efforts to translate research data into medically useful information. Once the data is posted publicly, any scientist – whether part of the Alliance or not – can pursue it via conventional strategies that may lead to publications and/or patents.

In addition to support from NIGMS, other funding for the AFCS project will be provided by several pharmaceutical companies and non-profit organizations, including Eli Lilly and Company, Johnson and Johnson, the Merck Genome Research Institute, Novartis Pha rmaceuticals Corporation, Chiron Therapeutics, Aventis, and the Agouron Institute.

NIGMS has reannounced the glue grant funding opportunity and hopes to lend a helping hand to researchers trying to solve other major biological mysteries.

A 20-second mu ltimedia presentation of a beating cardiomyocyte created by UCSD Professor of Chemistry and Biochemistry Roger Y. Tsien is posted at http://www.nigms.nih.gov/news/releases/images/cardiomyocyte.avi .

Additional information about the AFCS can be found at http://afcs.swmed.edu/ . More information on the NIGMS glue grant program can be found at http://www.nigms.nih.gov/funding/gluegrants.html .

SDSC is an organized research unit of the University of California, San Diego, and the leading-edge site of the NPA CI ( http://www.npaci.edu/ ). SDSC is funded by the National Science Foundation through NPACI and other federal agencies, the State and University of California, and private organizations. For additional information about SDSC and NPACI, see http://www.sdsc.edu/ .

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