Exploring the Biological Unknown

USC College geneticist Susan Forsburg studies yeast for insight into cell growth and cancer. In the long run, her research could yield new ways to treat the disease.
By Eva Emerson
Forsburg studies a key step in cell division, the beginning of the replication of DNA in the parent cell.

Photo/Philip Channing
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 do that 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, for example, heals as cells multiply to close the wound.

Figuring out exactly how cells make that decision drives the research of USC College of Letters, Arts and Sciences geneticist 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 USC 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.

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 oft-studied organisms in biology.

Key to the yeasts’ utility is the remarkable similarity between yeast genes that control cell growth in 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 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), or even the nature of scientific inquiry.

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,” Forsburg said.

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 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 since has 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 also has earned her recognition. As the author of a Web site that serves as a resource 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.

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.”