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It didn't help that she was out of step with the hot molecular biology topics of the '80s and '90s: mutations, oncogenes, and the Human Genome Project, which it was hoped would shed light on how medicine could target these cancer-causing genes. "When people were sequencing the human genome, everybody was promising, 'Oh, we'll know everything,' she recalls. "Here I was at a national lab and I was a director and the genome center was under me and I used to say, 'This is nonsense!' We will know the sequence of all the genes, but we still have to understand why is the nose a nose?"
While Bissell and her collaborators agree that cancer wouldn't happen without mutation, they felt mutation was only half the story. To understand cancer, you needed to see the tumor cell within the broader context of tissue organization, not just this or that bit of DNA. "The sum is not simply the addition of the parts," Bissell says. "There is something bigger, larger, more integrated."
Radisky recalls that Bissell would often quote Jules Henri Poincare to drive this point home to her postdocs: "Science is built up of facts, as a house is with stones. But a collection of facts is no more a science than a heap of stones is a house."
However, Radisky notes that it isn't easy for scientists to chase a broader vision. "The way that virtually all biological science is done is that everyone decides they're going to study one molecule and all the things that are touching it and that it touches, and the philosophy is that when I know everything about my molecule, and some guy in Utah knows about all his molecule, and some woman somewhere else knows all about hers, we're all going to get together in one room and we'll know everything," Radisky says. "It's imposed on us by the way articles are structured, because they have to be about one thing, and the way grants are given, because there has to be a consistent body of research. But the truth is, part of a toilet or a pipe or a stove can't be studied in isolation. A brick outside of the house doesn't work the same way as a brick inside a house."
Bissell's early supporters knew it would take years of buttressing her theories with scientific papers before her ideas would win any mainstream acceptance. "Conceptually, it was something that was going to take ten or fifteen years' worth of putting little pieces together for it to make sense for most people," says Boudreau. But by now, many of those pieces are in place. Bissell herself has published nearly 300 scientific papers on the microenvironment, and her former postdocs and colleagues have expanded her ideas to new areas outside of breast cancer.
Boudreau, for example, studies angiogenesis, or the creation of blood vessels — a process tumors manipulate to grow blood vessels to feed themselves. Her work is aimed at finding ways to control the vessel-forming factors that tumors produce, so that the malignancies will essentially starve and not be able to grow.
Radisky specializes in matrix metalloproteinases, which are responsible for normal breakdown, repair, and growth functions within the extracellular matrix, but are also thought to play a role in allowing cancers to invade neighboring cells and metastasize. Since they're necessary for normal body function, you can't just wipe them out to treat cancer, but it would be beneficial to know more about which of their processes are tumor-related. Radisky's work focuses on both breast and lung cancers. Other former postdocs, Bissell says, are working on ovarian cancer and viral oncogenes.
Perhaps one of the more surprising connections to Bissell's work is being made by one of her Lawrence Berkeley colleagues, Dr. Judith Campisi. Bissell recruited Campisi to the lab in 1991, where the two worked on breast and prostate cancer, but Campisi began to make some links between cancer — a disease of too much cell proliferation — and aging, a problem of not enough proliferation.
"Normal human cells have intricate mechanisms that stop them from growing very effectively when they are faced with potentially cancer-causing stimuli, for example radiation, chemicals, or mistakes in DNA or even certain oncogenes," Campisi explains. "Cells are hardwired to protect themselves from cancer — they will shut themselves down and not proliferate. If a cell doesn't divide, it will never form a tumor."
However, she says, "You can clearly see how a long time of calling on this mechanism will also cause symptoms that we recognize as aging, a slowdown of repair" — and essentially a pileup of nondividing, senescent cells. So, the cost of not getting cancer all the time is that we get old. "Evolution has had to make some bargains with the devil," Campisi says.
Like cancer cells, these senescent cells interact with their microenvironment — and in this case, Campisi found, they actually secrete chemicals into it. "When the cells stop dividing they act as though they're responding to a wound," she says. "We began to look at what cells were pouring outside and showed that they are changing the tissue microenvironment, and it's causing normal cells to not function properly because of all these secretions. It also stimulates any nearby precancerous cells to become more aggressive.
"The tissue is changing and becoming more permissive," Campisi says, "and one thing Mina has said for a long time is you need a permissive tissue for cancer to grow."
It's a fascinating example of how Bissell's work sheds light on other health questions, and there are likely to be many more as Bissell's theories gain attention. As Campisi puts it, "Right now, the microenvironment is hot." In 2004, the National Cancer Institute earmarked $40 million annually to study the cancer cell microenvironment. Pharmaceutical companies like Merck, GlaxoSmithKline, and Genentech have asked Bissell to lecture to their scientists. She has won a host of honors and prizes, including election to the Institute of Medicine of the National Academies and the American Academy of Arts and Sciences, becoming president of the American Society of Cell Biology, and most recently receiving the Pezcoller-AACR International Award for cancer research. "I couldn't get any money for fifteen years," Bissell says. "Now, they're all funding me."
Still, there are reminders that hers has long been an outsider point of view. A sore point with Bissell is that, to this day, her ideas are mentioned in only one med school textbook. But as someone who has embraced her role as a rabble-rouser, Bissell has tried to pass on that spirit to the young researchers on her lab team. "I try to teach them to have courage," she says. "I try to teach them also how to work hard and yet think of research as a pleasure, even though it can be very, very frustrating." She encourages them to take on big, difficult questions, and to challenge the wisdom of the establishment — which, she'll admit wryly, she is perhaps becoming. "There is a lot to learn, and there is a lot to do, and the big message that I like to give is that scientists should not be arrogant," she says.
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