“My task this morning is to summarize 35 years of work in less than 17 minutes,” says Mina Bissell. She is a cancer researcher with a background in chemistry, and as she tells us, the standard explanations for exactly what cancer was didn’t make sense to her. Her career has been driven by a tremendous question — what makes cancer become cancer?
She starts by giving us a short primer in developmental biology: We all start from one cell, and grow to 10-70 trillion cells, “each with the same genetic information.” The dominant theory of cancer, she says, “is that a single oncogene [a gene mutated in a particular way] in a single cell is sufficient to cause cancer.” But that never made sense to her; if it was true, every malignant cell in our bodies would become a tumor, and “you’d be one big lump of cancer.” Instead, we get cancer in discrete parts of our bodies. But why? Her insight — which she’s spent her career pursuing — is that cancer development might be caused by “context and architecture.”
She started by looking at a particularly ugly tumor in chickens. Researchers had traced it to a single gene transmitted by the first virus known to cause cancer, discovered in 1911. Her lab put a tracer on the gene and found that if they injected it into chickens, it would cause cancer. But if they injected it into chicken embryos, it wouldn’t. Why the difference? To her, that suggested that “the micro-environment in which the cancer cell resides dominates the cancer gene itself.”
To explore further, they looked at an acinus, the basic unit of a mammary gland. They separated out some epithelial cells (which in the mammary glands produce milk) and put them by themselves in a petri dish. Within three days, the cells had completely changed and became non-functional and distorted, and also stopped producing milk. This indicated that something around them, something else in their micro-environment, was also necessary for milk production.
They made a section of the mammary gland, looking at the parts around the acinus, which had been thought of as simply scaffolding, mere support for the “important” cells. But maybe this scaffolding also sent signals. So they grew some epithelial cells in culture near the scaffolding, and they again began producing milk, indicating that context was important as well.
Next, she tested the flip side of the theory: “If tissue architecture and context are part of the message, then tumor cells with abnormal genomes should be capable of becoming ‘normal’” if grown in a healthy micro-environment. She and her students tested that hypothesis with some malignant cells and growing them on a healthy scaffolding. And yes, they were able to revert the malignant phenotype to a normal one. They could even inject the cells into mice, where they didn’t cause tumors, unlike malignant cells, which would cause cancer. This, says Bissell, indicates that there is another way to look at cancer, in which the cancer genes are regulated by the environment around them.
It was a big idea, and it was not initially welcomed. But, as she quotes Einstein: “for an idea that does not first seem insane, there is no hope.”
Where do they go now? They’d like to take this insight into the clinic, but before that, they have work to do. “There are so many discoveries left to be made,” Bissell says. “We have sequenced the human genome… but we know nothing — I mean nothing — about the language and alphabet of form.” As she tells her grad students, “You need to always think what else needs to be discovered.”
She leaves us with powerful words: “Don’t be arrogant, because arrogance kills curiosity.”
Photos: James Duncan Davidson