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Thinking Outside the Cell

For decades, the scientific establishment ignored Mina Bissell. Now her insights could revolutionize how cancer is understood and treated.

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During her first year of her Ph.D program, Bissell became pregnant with her daughter Yalda. People assumed she would drop out — it was the '60s, she was a young woman, and her family was on the other side of the globe. But Bissell ardently believes that women can simultaneously pursue career and motherhood, and often cites her own biography as proof for her young female colleagues. She has no patience for women who feel guilty over wanting to work instead of staying home with the kids because, as she says, "Everybody owes themselves the dignity of work."

At a recent meeting of the East Bay Association for Women in Science, Bissell recalled the consternation inspired by her pregnancy. "I walked into my professor's office and he said, 'Of course you are quitting! What is your mother going to say?'" she recalled. "And my mom called from Iran and said, "You are not quitting!" Instead, her mother came to help out for several months. Bissell shot her audience a knowing look. "Microenvironment," she said slyly, to roars of laughter.

Bissell completed her Harvard program in six years — during that time, her first marriage ended, and she met Dr. Montgomery Bissell over a centrifuge. The couple married in Boston, then moved to Berkeley in 1970, when Mina Bissell was awarded an American Cancer Society postdoctoral fellowship at UC Berkeley in the Molecular Biology Department, and her husband began a distinguished career at UC San Francisco, where he is now Chief of Gastroenterology in the Department of Medicine. Their son, Ahrash, was born a few years later.

In the late '70s, Bissell happened to attend a talk given by Dr. Beatrice Mintz of the Fox Chase Cancer Center, who had done an extraordinary experiment, transplanting stem cells from a tumor into an embryonic mouse. Mintz was able to show that even though the tumor cells' genetic code integrated into the mouse's genes, the resulting baby mouse was normal with no tumors. "The tumor stem cell had become stably normalized by integration into the normal microenvironment of the developing embryo," Mintz wrote. In other words, even stem cells from a tumor could give rise to normal tissue, if kept in check by the environment.

The lecture changed Bissell's outlook. "I just was floored with how exciting this was," Bissell remembers. Mintz herself recalls: "Mina has told me that she was electrified at hearing about this work."

But Mintz and others had concluded that the tumor-derived mouse had to have no mutations, because it appeared normal. "At that time, everybody was discovering exciting oncogenic mutations, and they assumed that once genes get mutated they have to give rise to cancer," Bissell recalls. But she set out to prove an entirely different hypothesis: that normal-looking tissues could indeed have tumorous mutations that are suppressed by the cell's environment.

Once Bissell had her own lab, she explored this idea with her postdoctoral fellow, David Dolberg. They used the Rous sarcoma virus, which contains a cancer gene, to infect chicken cells in a Petri dish. When the virus was injected into a chicken's wing, it would cause a tumor. Yet if the virus was injected into chicken embryos, no tumors. If the embryo was disassociated and put into a dish, the cells became cancerous again.

"The virus causes that ugly tumor in the chicken; in the embryo it doesn't," says Bissell. "So this meant that context — the microenvironment, which is what is outside the cell — determines even when a potent oncogene can cause cancer."

Becoming increasingly interested in how tissue architecture might influence the genesis of cancer, Bissell chose to study the mammary gland, one of the few tissues that completely remodels itself over a woman's lifetime. In studies of both mouse and human mammary cells, Bissell saw something extraordinary: If the cells were placed on the flat surface of a tissue culture dish, they would lose their polarity, stop producing milk, and "forget" the form and function they had when they were in an animal. Yet if the cells were put in material that simulated the 3-D environment of real tissue, they would reorganize and look normal again.

Dr. Nancy Boudreau, who was one of Bissell's postdoctoral fellows in the early '90s and who now directs the surgical research laboratory at UC San Francisco, recalls how different Bissell's approach to studying this extracellular matrix was. She explored its overall function at a time when other researchers were individually scrutinizing its proteins. "The way scientists do things is they go, 'What's in the matrix?' and take one thing out at a time," recalls Boudreau. "But Mina's whole thing was, 'Let's take the whole thing together.'"

For example, Boudreau recalls an experiment she performed in Bissell's lab that dramatically illustrated how crucial the extracellular matrix is to the cells' well-being: when she destroyed the matrix around mammary cells, the cells essentially committed suicide.

One way to think of this relationship between cells and their surroundings, says Boudreau, is that the cells fit into a communication "network" provided by the matrix. When the cell and the matrix are both communicating with each other correctly, Bissell believes, each cell knows where it is in the system and what it is supposed to do, and malignancies can be kept in check.

But this balance can falter, she believes. Normal wear and tear caused by aging, the sun's radiation, oxidation, and inflammation change the microenvironment. If the cell and its surroundings stop being able to signal each other, Boudreau says, the cell has no social context. "It's kind of like mental illness," she says. "People know where they are in society and within groups, but crazy people are not aware of social boundaries. The tumor cell is like the nutjob on the street that says, 'I don't care.'"

Can these prodigal cells be brought back into the fold? Bissell and her collaborators think so, and their argument reads almost like a "nature vs. nurture" debate for the cell. Zena Werb, vice-chair of the anatomy department at UCSF, and one of Bissell's longtime friends, compares the cell's relationship to its microenvironment to the way a kid relates to his neighborhood. Take a smart kid and raise him on a crummy block where drug-dealing is the only way to get ahead, and he'll excel at criminality. Change that kid's environment to one that rewards scholarship, she says, and maybe he'll grow up to be a concert pianist. And if you drop a cell gone bad back into a healthy environment? "That's one of the major observations that Dr. Bissell has made," Werb says. "If you can change the cells so that they perceive that they have a normal environment, then they're going to behave normally enough."

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