Thinking Outside the Cell 

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

Why do we get cancer? For years, conventional wisdom held that cancer begins solely with a DNA mutation that causes cells to run amok and reproduce uncontrollably. Dr. Mina Bissell, who holds the title of Distinguished Scientist at Lawrence Berkeley National Laboratory, is not big on conventional wisdom. For thirty years, she has preached a heretical gospel: half the key to cancer lies outside the cell.

Take, for example, people born with a mutation linked to breast cancer, Bissell's special area of study. If cancer was the inevitable result for any cell with that mutation, shouldn't these people have cancer in every part of their bodies, not just the breast? And why is it that breast cancer develops in adulthood if the gene mutation has been there all along?

Bissell notes that while bodies are made of many different organs, every single cell shares the same DNA. "This has the same gene," she says, pointing to her nose. "This has the same gene," she says again, pointing at her elbow. "This has the same gene," she adds, indicating her eye. If inheriting a single DNA mutation was enough to cause cancer, your entire body should be cancerous. "You would be a lump!" she exclaims — a gigantic tumor.

A crucial part of cancer formation, Bissell believes, is not just what goes wrong inside the cell, but what goes wrong in the way it interacts with its extracellular matrix, the 3-D architecture that surrounds and supports the cell. If Bissell is right, her insight will revolutionize not only how cancer is understood and treated, but perhaps even what it means to have the disease. She champions a startling idea: that cancers can be reversed. "Until very recently, people thought that once you became a mutated cancer cell you always behaved as a mutated cancer cell," she says.

Instead, Bissell and her group have shown, in lab cultures and in animals, that tumor cells with DNA mutations and active cancer genes could be induced to behave normally again by restoring their cellular architecture. "That reversibility gives this hopeful view of cancer," Bissell says, although no one yet knows how to reformat solid tumor cells in a human patient. Still, she speaks of a day in which cancer is a nonlethal, chronic condition that can be kept in check with drugs.

Bissell was not the first to claim that a cell's microenvironment plays a role in the formation of tumors. But she showed how this happens, by proving that disturbances in the cell's environment can cause mutations. She has produced spectacular lab results to support her claim. Still, she modestly maintains that her most important contribution is that she hammered away at her point for thirty years.

For much of that time, people ignored her. Hers are radical propositions: not only that tumor cells can be normalized, but that organ structure dictates function. She made these claims throughout the '80s and '90s, a time when DNA was king and molecular biology's hot topic was the single oncogene, or cancer-producing gene. It was a much more atomistic approach to understanding cancer: unpacking one molecule at a time, rather than trying to see it in the broader context of tissue function. Yet Bissell has always maintained that cancer is not a disease of single cells. "Cancer is a problem of the organs," she says.

Over the past few years, however, Bissell's work has itself become a hot topic. Academic honors and research money have begun to pour in. The National Cancer Institute started a program to study the tumor microenvironment. Bissell busily globetrots, talking to students, scientists, and pharmaceutical companies interested in her work. Nature ran an article hyping the 3-D matrix as "biology's new dimension," and heralding Bissell as its pioneer. The number one champion of the importance of the outside has become, suddenly, very in.

A radical message requires a radical messenger, and Bissell has happily worn her badge as a rebel. She is tiny, animated, forceful. She radiates an extraordinarily high wattage, a combination of sternness and motherly warmth that she uses to alternately chastise, then buck up, the postdoctoral fellows in her lab group. She calls everybody "honey" and gives everyone hugs. She thinks of all of her postdocs, even the ones who've left the lab, as her "kids."

Bissell is convinced of the artistry of science. Over and over in lectures she uses the word "beautiful" to describe a data set, a tissue slide, an illustration of how breast cells organize themselves. Bissell will stop an academic lecture to run out into the hall and invite inside a woman trying to sign people up for a breast cancer walkathon, because she wants that woman to understand the science, too. At the same time, she is unabashedly political, an ardent supporter of Amnesty International, a sharp critic of the president (both the American one and the one in her home country, Iran). "You have to go against the establishment if it is suppressive," she says. "You owe it to your intelligence.

Despite her prodigious gift for science, Mina Bissell very nearly was an English major.

She was born in Tehran, Iran, into a highly-educated, well-off family. After becoming the top high school student in her country, she was offered a college education in the United States. She enrolled at Bryn Mawr, and struggled to choose a major. "Biology interested me, but I didn't want to be a medical doctor because everybody had said if you are a medical doctor it is harder to have children, and I had thought I wanted to have children," she recalls.

"I debated very much between English literature and chemistry. I loved literature," she says. "But I then finally decided, 'Oh, literature, I can read that on my own, but I won't learn chemistry on my own."

After two years she transferred to Radcliffe, where she finished her degree in chemistry and married her first husband, another student from Iran. She enrolled at Harvard Medical School to study bacteriology.


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