Illustration by Evan M. Cohen
We routinely test for chemicals that cause mutations. What about the dark matter of carcinogens—substances that don’t create cancer cells but rouse them from their slumber?
In the nineteen-seventies, Bruce Ames, a biochemist at Berkeley, devised a way to test whether a chemical might cause cancer. Various tenets of cancer biology were already well established. Cancer resulted from genetic mutations—changes in a cell’s DNA sequence that typically cause the cell to divide uncontrollably. These mutations could be inherited, induced by viruses, or generated by random copying errors in dividing cells. They could also be produced by physical or chemical agents: radiation, ultraviolet light, benzene. One day, Ames had found himself reading the list of ingredients on a package of potato chips, and wondering how safe the chemicals used as preservatives really were.
But how to catch a carcinogen? You could expose a rodent to a suspect chemical and see if it developed cancer; toxicologists had done so for generations. But that approach was too slow and costly to deploy on a wide enough scale. Ames—a limber fellow who was partial to wide-lapel tweed jackets and unorthodox neckties—had an idea. If an agent caused DNA mutations in human cells, he reasoned, it was likely to cause mutations in bacterial cells. And Ames had a way of measuring the mutation rate in bacteria, using fast-growing, easy-to-culture strains of salmonella, which he had been studying for a couple of decades. With a few colleagues, he established the assay and published a paper outlining the method with a bold title: “Carcinogens Are Mutagens.” The so-called Ames test for mutagens remains the standard lab technique for screening substances that may cause cancer.
Scientists, including Ames, realized from the start that the test wasn’t a comprehensive method for catching carcinogens. Epidemiologists were learning, for instance, that exposure to certain estrogen-like chemicals, such as diethylstilbestrol (DES), increases the risk of vaginal, cervical, and breast cancer. (Toxicologists found similar results in mice and rats.) Yet DES wasn’t obviously mutagenic in cell cultures; its cancer-causing mechanism is still being explored, but probably involves driving the growth of hormone-responsive cells or changing the expression of cancer-linked genes. In time, additional classes of carcinogens were added to the list. One feature of cancer cells is that they avoid detection by the immune system. And so compounds that suppress the immune system, such as cyclosporine, were recognized as cancer-promoting chemicals, even though they don’t cause mutations in DNA.
But there were mysteries in carcinogenesis that continued to puzzle toxicologists. Earlier this fall, I discussed the issue with Allan Balmain, a cancer geneticist at the University of California, San Francisco. Balmain, who is in his seventies, was born in Wick, Scotland, and still speaks with a Scottish burr. He wore a cardigan that had a noticeable hole but matched the cornflower blue of his darting eyes. “Virtually every standard model for finding and classifying carcinogens has relied on what it does to the cancer cell,” he told me. Balmain had come to believe that we were thinking far too narrowly. He was hinting at unsolved mysteries in cancer epidemiology. The incidence of colorectal cancer in young men and women in the United States, for example, has nearly doubled since 1995. In certain pockets of the world, lung-cancer rates in young, non-smoking adults are rising dramatically. Although researchers have advanced various theories about why, there’s a sense that some cancer-inducing factors elude our apparatus of detection. It’s as if there were dark matter lurking in the cosmos of carcinogens.
We were standing on a catwalk that led to Balmain’s lab, within an airy, glass-lined atrium overlooking Third Street, in Mission Bay. A few blocks away, a colossal Mark di Suvero sculpture, a multi-ton steel assemblage with four ladder-like legs and outstretched beams, rose above a grassy hill. I was struck by how much the landscape made the art. Without the grass and the hill, the piece might be taken for one of the construction cranes that hover over the campus. Balmain, too, was talking about context. Cancer cells live and grow surrounded by normal cells—buried in a landscape of normal tissue. Shouldn’t we extend our focus to the larger ecosystem where cancers arise?
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