Massive new research effort will map inner workings of cells - San Francisco VA Medical Center chose

By Kevin Boyd

A new $50 million dollar research program launched this month will begin the
daunting task of mapping out the thousands of molecular interactions that cells
use in responding to their environment.  The San Francisco Veterans Affairs
Medical Center will host one of the five core research labs that will
collaborate on this project.

The Alliance For Cellular Signaling marks the first coordinated effort to
describe the hundreds of pathways used by cells to convert a message from
outside the cell into an appropriate response. This knowledge is essential to
more efficient discovery of new drug treatments, said Paul Simpson, MD,
co-director of the San Francisco core lab, staff cardiologist at the San
Francisco VA Medical Center, and UC San Francisco professor of medicine. 

“Usually, (in cell signaling) researchers have only one or a few receptors or
signaling molecules that they’re interested in.  This is going to look at the
whole picture,” he said.  “It’s like the human genome project of cell
signaling,” he said.

Last week, the National Institute for General Medical Sciences (NIGMS)
announced their decision to fund the project, and anticipates spending $25
million dollars over five years for the Alliance.  An equal sum will be
contributed by biotechnology and pharmaceutical companies, said Simpson.  At
the SF VAMC, the Alliance funds will be administered by the Northern California
Institute for Research and Education (NCIRE).

The payoffs for the project should be well worth the huge commitments of money
and research time, Simpson said.  “It should have tremendous therapeutic
implications. At the moment drug development is often a hit-or-miss
proposition, but if we understand how signaling works, we can design drugs that
will block harmful processes; we can turn a specific switch on or off to get a
specific result,” he said.

The NIGMS grant will help to establish and fund core laboratories at five
institutions: University of Texas Southwestern Medical Center in Dallas (the
headquarters campus); San Francisco VA Medical Center; University of
California, San Diego; Stanford University; and the California Institute of

The Alliance’s collaborative approach is an experiment in itself, said Bill
Seaman, MD, and co-director of the San Francisco core lab. “It’s an attempt to
change the way we do research.  By pulling together different groups with
different types of expertise, we can accomplish things that would be impossible
for even a very large single lab,” said Seaman, chief of immunology at the San
Francisco VA Medical Center and UCSF professor of medicine and microbiology.

And unlike most research projects, scientists in the Alliance will publish
their data on the Internet immediately after it has been analyzed, instead of
waiting to publish peer-reviewed papers.  Alliance researchers have also agreed
to give up intellectual property rights to the data.  According to Al Gilman,
director of the Alliance and a pharmacologist at University of Texas
Southwestern, any researcher who has a computer and Internet access will be
able to access the data freely, and combine it with their own research to
pursue new medical treatments more intelligently. 

The Alliance has assigned two key roles to the San Francisco VAMC core lab,
called the Laboratory for Development of Signaling Assays.  The researchers
will help to develop the experiments and methods that that other labs will use
to explore the cell signaling pathways, and they will try to confirm the
results of successful experiments performed in the Dallas core.

The Alliance will focus the project on two types of mouse cells: heart muscle
cells, and antibody-producing cells of the immune system known as B
lymphocytes, said Seaman.  The interactions among signaling proteins in mice
are often almost identical to those in humans.

Researchers in the Alliance first will attempt to understand signaling in
normal cells, Simpson said.  They will culture the cells and stimulate them
with various molecules that are known to activate cells. They will then observe
which among the thousands of signaling molecules are turned on or off over
time, and how these molecules interact.  They will compare these to more
general responses of the cells, such as the beating of heart muscle cells, and
migration of B lymphocytes towards a chemical signal.  Researchers will then
attempt to shut off, or knockout, certain key signaling genes, and observe the
effect on signaling patterns, and on the cellular responses.

The first major challenge for the VAMC lab, said Simpson, will be to figure out
how to make newly harvested cells grow in a culture dish.  Heart muscle cells
are especially problematic, he said, since it is difficult to keep them alive
and healthy in culture for longer than 24 hours. “We need to learn how to make
these cells happy long enough so that we can study their cell signaling
properties,” he said. 

According to Gilman, $25 million in funding for the Alliance will be provided
by several major pharmaceutical companies, including Eli Lilly and Company,
Johnson & Johnson, the Merck Genome Research Institute, Novartis
Pharmaceuticals, Chiron Corporation, Aventis Pharma, and the Agouron Research

Two biotechnology companies are also participating in the Alliance as
scientific partners.  Isis Pharmaceuticals of Carlsbad, Calif., and Myriad
Genetics, of Salt Lake City, will contribute custom-made reagents and relevant

NCIRE, which will administer Alliance funds at the SF VAMC, is one of the
fastest growing medical research groups in the nation.  Founded in 1988, NCIRE
now manages more than $20 million in funding from organizations such as the
National Institutes of Health, the National Aeronautics and Space
Administration, and the National Science Foundation.  Based at the San
Francisco VA Medical Center, NCIRE is the largest of the congressionally
authorized VA research corporations.