Forsburg studies a key step in cell division —
the beginning of the replication of DNA
in the parent cell.
Photo Credit: Phil Channing |
Exploring the Biological Unknown
College geneticist studies yeast for insight into cell growth and cancer
By Eva Emerson
November 2005
Like Hamlet, eventually all cells must make a fateful decision: To
divide or not to divide. And like the melancholy Prince of Denmark,
their choice to act, or in the cells’ case to grow and divide, may
expose them to grave dangers.
And yet, many human cells make that choice daily — skin cells divide
every 12 to 24 hours; bone marrow cells divide continuously to create
the millions of red blood cells needed in the body; a skinned knee
heals as cells multiply to close the wound.
Figuring out exactly how cells make that decision drives the research
of USC College geneticist (and theater aficionado) Susan Forsburg. So
does the question of how disruptions in the cell’s carefully
orchestrated cycle of growth can lead to cancer and birth defects.
Forsburg is one of a small cadre of College molecular biologists whose
basic research is shedding light on the underpinnings of cancer.
Ultimately, their work may lead to the development of new ways to
diagnose and treat malignant disease.
Cancer, scientists agree, is a disease of genetics, a catastrophic
accumulation of changes in the DNA that releases a cell from normal
growth restraints, allowing uncontrolled cell division and eventually
threatening the entire body.
Forsburg studies a key step in cell division — the beginning of the
replication of DNA in the parent cell and how it affects the packaging
and divvying up of the DNA, tightly packed into chromosomes, to the two
daughter cells. The cell’s survival depends on the successful
completion of both steps.
As a cell prepares to divide, it must copy all 3 billion chemical
“letters” of DNA in its genetic code. Danger comes from the very real
possibility of mistakes in the copying of DNA. In most cases, the
cell’s own surveillance system will find and fix mistakes or damage.
But the surveillance system is not perfect. If severe, changes in the
DNA code can lead to cell death, or set the stage for cancer.
“What we know happens in cancer is that cells have lost the ability to
not only maintain the integrity of their genome — the accuracy of the
genetic information — but also they’ve lost the ability to monitor
themselves and say, ‘Oh, I’ve got a problem,’ and then to fix the
problem or destroy the cell,” said Forsburg, an associate professor of
biological sciences who joined the College last year from the Salk
Institute of Biological Studies.
A Model Yeast
For her explorations of the biological unknown, Forsburg relies on the
fission yeast Schizosaccharomyces pombe — a simple, single-celled type
of fungus — to more easily probe what goes on in the more complex cells
of humans. For similar reasons, the baker’s yeast Saccharomyces
cerevisiae ranks as one of the most well studied organisms in biology.
Key to the yeasts’ utility is the remarkable similarity between yeast
genes that control cell growth their human counterparts. In fact, many
genes important in human cancers, which often encode the cell machinery
responsible for cell division and the repair of damaged DNA, were first
identified in yeast.
S. pombe long has been used by the people of east Africa to brew millet
beer. Thanks in part to her extensive, award-winning Web site,
Forsburg’s lab has become almost synonymous with S. pombe. She admits
to “relentless proselytizing” about the advantages of this yeast model,
particularly the ease of creating precise gene mutations that can
reveal a gene’s function. She is no less enthusiastic talking about her
research, issues facing women in science (about which she authored
another much-lauded Web site, the Women in Biology Internet Launch Pages), or even the nature of scientific
inquiry.
Risky Business
Forsburg sees science as a creative endeavor, fraught with risks. “You
can work five years on a project and have it go away. If there were
guarantees, it wouldn’t be science,” she said.
In her case, many of the risks have paid off. Forsburg made one of her
most important discoveries while studying a mutant strain of S. pombe,
in which the cells could grow but not divide. She cloned the damaged
gene and showed its product was part of the MCM family of proteins.
Scientists already knew that MCM proteins play an essential role in
normal DNA replication and cell division in a wide range of organisms,
from bacteria to mammalian cells.
She went on to reveal new details about how MCM proteins switch on DNA
replication. Called helicases for their ability to unzip and unwind the
double helix structure of a DNA molecule, MCM proteins go to work soon
after the cell makes its decision to divide. Her team’s work on the MCM
proteins and the molecules that regulate them expanded from there.
“We are interested in how the MCM helicase maintains genomic stability
and influences the structure of chromatin,” she said. In cells, DNA
wraps around proteins to form the condensed chromatin, which coils up
further to form chromosomes.
In the December 2003 Nature Cell Biology, Forsburg and colleagues
reported that an enzyme that controls MCM proteins also regulates the
separation and movement of chromosomes into the daughter cells. The
study was the first to link the two processes.
“Both these processes are important for normal cells, and both can go awry in cancer,” said Forsburg.
A Scientific Career
Forsburg is known for her passion for science, her ability to
articulate complex concepts and her infectious sense of wonder about
the natural world. Indeed, her captivation with biology is grounded in
her lifelong curiosity about how things work, which was stoked by an
early interest in birds.
As an undergraduate at UC Berkeley, Forsburg earned degrees in molecular biology
and English literature. She earned a Ph.D. in biology from the
Massachusetts Institute of Technology, where she specialized in
genetics, and learned to speak the language of the yeast S. cerevisiae.
She then completed a postdoctoral fellowship at Oxford University,
where she worked with Paul Nurse, then director of the Imperial Cancer
Research Fund.
It was Nurse, a leading biologist who went on to win the 2001 Nobel
Prize in Physiology or Medicine, who first introduced Forsburg to S.
pombe. Nurse, now the president of Rockefeller University, shared the
prize for his discovery of a gene (and its protein product) that
controls cell division. The discovery has since led to new treatments
and medicines for cancer.
Forsburg’s work has earned her a number of honors. Most recently, she
was elected as a 2005 Fellow of the American Association for the
Advancement of Science. In 2002, she received the Stohlman Scholar
Award from the Leukemia & Lymphoma Society. She has been a research
scholar both of the Leukemia & Lymphoma Society and the American
Cancer Society.
Her work to advance the careers of women in science has also earned her
recognition. For her Web site for
women scientists, in addition to her work in national and local
organizations to promote women in science, she received the 1996 Junior
Career Recognition Award from Women in Cell Biology of the American
Society of Cell Biologists.
“Susan is a dynamo,” said Myron Goodman, who leads the molecular and
computational biology program in the College and helped recruit
Forsburg as part of the College’s Senior Faculty Hiring Initiative.
Fundamental Approach
Forsburg notes that cancer research moves forward on two fronts.
“One is about how we take the knowledge we have now to make treatments
for the clinic. The other is recognizing that we still don’t know
enough. The cancer research we do is the ‘Let’s find out more, let’s
find out how the system works part.’ We are building knowledge for the
treatments that will come to fruition 10 to 20 years from now.”
She likens fundamental research to exploring an unmapped cave system with torches, searching for veins of rare minerals.
“We can say, ‘Look we found something,’ and the clinicians can come in
and set up the big arc lights and find ways to make use of [the
discovery], while we keep going ahead,” she said. “We’re the people
with the torches at the front of the cave. The people who will be
building on what we do and making it clinically relevant are the ones
stringing the bright lights behind us.”
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