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Indeed, perhaps one of Bissell's most spectacular results was described in a 1997 paper in the Journal of Cell Biology. When dosed with a certain antibody, breast tumor cells suspended in a 3-D culture reverted to their normal state, even though they still had gene mutations. In a 1999 paper she explored the opposite approach, creating spontaneous malignant and premalignant gene changes in previously normal mouse mammary cells by degrading the extracellular matrix, disrupting the interaction between the cells and their microenvironment.
The possibility that "disoriented" tumor cells can be made to behave normally suggests a revolutionary approach to treating cancer, one that starkly contrasts with current treatments that try to eradicate cancer cells with chemotherapy or surgery. Theoretically, Bissell says, one could develop drugs to restore the correct signaling between cells and the extracellular matrix — an analogous process sometimes naturally occurs in cancers that go dormant. "That dormant tumor cell finds a microenvironment that lets it just sit there and get the signal that you're not supposed to grow," she says. "And then ten years later or fifteen years later, sometime something happens and the signal in the microenvironment changes, now it is time to grow again."
If a chemically induced dormancy could make tumor cells quiet down, Werb says, it could be the key to solving breast cancer and possibly other cancers. "You don't have to cure the cancer, you don't have to kill every tumor cell, you just have to stop it from misbehaving," Werb says. "If you can turn it into a more or less normal cell, then you can live with that. It'll be like any other chronic disease."
And if that idea isn't big enough, consider that Bissell's main theory — that what's ouside the cell trumps what's inside — isn't really just about the breast, or even just about cancer. "The concept was that the three-dimensional organization of the organ or a tissue influences the way the genes behave," says Bissell firmly. "So that then is applicable to all cancers. That's applicable to all diseases."
Bissell became the director of Lawrence Berkeley National Laboratory's Cell and Molecular Biology division in 1988, and of its entire Life Sciences Division in 1992. And although she has always preached an outsider gospel, she won many converts who were awed by the scope of her vision.
Dr. Derek Radisky, now a research scientist at the Mayo Clinic and one of Bissell's postdoctoral fellows from 1998 to 2005, recalls that it took about nine months of working with Bissell before the implications of her theories really hit him. "I remember I had to sit down on my couch and think about it for about an hour, it's so different," he recalls. "She wasn't ten or twenty years ahead of her time, she is thirty or forty."
Boudreau puts it this way: "I went to Berkeley and had my mind blown, but it was in science and not drugs."
Yet Bissell's revolutionary ideas were not necessarily blowing minds outside of her own lab. "People who work in cancer therapy initially thought this was heresy, this was stupid," says Bissell.
Her frequent collaborator Zena Werb recalls that although they both started exploring similar ideas decades ago, Bissell's work received a much colder reception than her own. Werb's speciality is arthritis, a disease that doesn't involve malignancies. Bissell, on the other hand, "started to think about these things with respect to cancer, and that was like putting a red flag in front of a bull," says Werb. "Cancer became Mutation Central, and anyone who said, 'Wait, that's not all there is!' was really a wolf crying in the wilderness."
Indeed, Bissell felt that her ideas were often ignored. "It is worse than criticizing, they simply neglected and dismissed without even referring to the work," she recalls.
"For the longest time, nobody could figure out what she meant," Werb agrees. "We ignore things we don't understand, even if they're staring us in the face. We need context, too, just like the cells do."
When journals accepted Bissell's papers, Boudreau recalls, "Sometimes they would sort of keep raising the bar really high and asking for additional experiments."
At scientific conferences, Bissell was known for spiritedly questioning cancer experts, telling them that their ideas were too simple and didn't explain everything. "She could blow holes in people's story for being incomplete, but do it in a very pleasant way," recalls Boudreau. But even then, Boudreau felt Bissell was often disregarded. "In some ways it was like, 'Oh, it's cute, there is this little excitable Persian woman over there screaming about whatever,'" Boudreau says.
To a certain extent, Bissell says, this skepticism is healthy. Scientists are supposed to be a tough crowd. "If you are daring and you make a hypothesis that is very different, you get rejected for good reason. You should get rejected because, after all, people have spent years and years proving something, and if you are going to be saying, 'Here I am, I'd like to add something on the top of it,' you have to go and prove it," says Bissell. "That is why it takes a lot of perseverance, it takes a lot of self-confidence, it takes a lot of tenaciousness, and it takes a lot of optimism."
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