Toms River (24 page)

Until the twentieth century, the evidence that industrial chemicals could cause cancer rested almost entirely on the wobbly pillar of observational epidemiology. These were the anecdotal reports of people like Bernardino Ramazzini, Percivall Pott, and John Ayrton Paris, later bolstered by the more methodical analyses of Walther Hesse and others. They noticed unusually high rates of particular cancers in certain groups of people—scrotal cancer in chimney sweeps, lung cancer in cobalt miners, bladder cancer in aniline workers—who also had been exposed to unusually high levels of hazardous compounds, usually in complex mixtures. But their reports merely demonstrated an
association
between exposure and disease—a correlation, not a causal relationship. And their observations provided almost no help in determining which particular chemicals might be responsible for triggering cancer, from the hundreds of possible suspects that a chimney sweep or a miner or a dye worker might encounter.

To strengthen the case for environmental carcinogenesis, research would have to move from the outside world to the laboratory, from observation to experiment. For centuries, in dangerous places like the mines of Schneeberg, humans had been conducting uncontrolled experiments in the induction of cancer. The question now was whether those conditions could be replicated in the tightly controlled setting of a laboratory. Infectious disease research had made a similar transition in the late nineteenth century, and the results were spectacular. Louis Pasteur and Robert Koch were national heroes in France and Germany, respectively, for their microbiology work. Building on the real-world observations of John Snow and other epidemic-trackers, they grew pathogenic bacteria in Petri dishes and infected a menagerie of animals, from mice to chickens. Through his lab experiments, Koch isolated the microbes responsible for cholera, anthrax, and tuberculosis, laying the groundwork with Pasteur for vaccines and other strategies that would finally bring those ancient plagues under control in Europe and America. In the wake of Pasteur’s and Koch’s successes,
many of their disciples turned their attention to cancer, hoping for similar results.

Cancer had other ideas. As usual, what worked for infectious diseases did not work for cancer. Microbes like
Vibrio cholerae
could be cultured on a plate; cancer cells could not. (That would change in 1951, with the successful propagation of HeLa cancer cells into a perpetual cell line; until then, attempts to culture cancer cells had failed.) Koch and Pasteur had shown that some pathogenic bacteria could be transplanted from one mouse to another or even from human to mouse without losing their potency, but tumors proved to be extremely difficult to transplant, despite many attempts.
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By 1900, it was clear there would be no “eureka” moment when the mysteries of cancer would be dramatically revealed in the laboratory of an indomitable hero scientist, as cholera’s mysteries had been revealed to Koch.

The failure of the transplant studies cast doubt on the widely held belief that cancer was caused by living parasites in the human body, perhaps by the same bacteria implicated in infectious diseases. If not a mystery parasite, then what? Victorian-era scientists developed at least three alternative hypotheses for tumor formation, and all of them were linked to Rudolf Virchow, the pivotal figure in a great age of medicine—the “professor of professors,” as he was known.
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Virchow’s own “irritation” theory suggested that almost any kind of external trauma could induce a tumor as long as it occurred repeatedly over a long period. He asserted, but could not prove, that chronic irritation could lead to inflammation, cell damage, and then tumors in the epithelial cells that lined the cavities, organs, and other surfaces of the body—the cells where most cancers originate. A rival theory was advanced in 1875 by Virchow’s former assistant, Julius Cohnheim, who proposed that tumors arose from clumps of “embryonal rest”—fragments of embryonic tissue that persisted in adults and were composed of stem cells that never differentiated into mature cells capable of performing specialized functions. If those long-dormant cells were activated by an outside stimulus, tumors would follow, asserted Cohnheim, who based his theory in part on the fact that fetal tissue looked like cancerous tissue under the microscope. His idea was later modified into the theory of dedifferentiation, which
suggested that cancer began when specialized cells abruptly regressed into their more primitive state and began dividing rapidly.

All of those competing theories would eventually be shown (after major modification) to have at least some validity for certain types of cancer, but unless some yet-undiscovered microbe was to blame, they all failed to address the big question: Why does cancer begin? What type of catalyst could trigger Virchow’s cell irritation, activate Cohnheim’s embryonic rest, or cause specialized cells to begin regressing? As the twentieth century began, no one could say. Like an apparition, cancer seemed to arise out of nowhere, with no discernible initiator. Moving cancer research from field observation to laboratory experiment had yielded nothing but frustration and intense disagreement among the champions of various theories of tumor formation.

Katsusaburo Yamagiwa of Japan knew about those conflicts firsthand.
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Born in 1863 into a noble family of the samurai class that had lost most of its wealth, he proved to be such a brilliant medical student that the Japanese government in 1892 sent Yamagiwa and two other young scientists to Robert Koch’s lab in Berlin to study tuberculosis. They were not made to feel welcome. The precise reasons are obscure: The delegation may have shown up on Koch’s doorstep uninvited, Koch may have blamed them for the Japanese government’s mistreatment of a friend, or they may have found the work uninteresting—or perhaps all three. It surely did not help matters that the young scientists came from a nation viewed as uncivilized by many Europeans of that era, though there is no proof that attitude was shared by Koch, who later visited Japan and posed for photographs in a kimono. Whatever the reason, the Japanese quickly dispersed to other laboratories, with far-reaching consequences for cancer research because of where Yamagiwa ended up: at the Berlin laboratory of the great Virchow, the champion of cellular irritation theory and no friend of the upstart Koch and his focus on microbes.

Yamagiwa thrived under Virchow’s tutelage and fully embraced his mentor’s irritation theory of carcinogenesis. Virchow knew about the case studies from the Schneeberg mines and the aniline factories
suggesting that some pollutants might be carcinogenic. He also recognized the possibility that chemical exposures might provoke the irritation he believed led to malignancies. But Virchow had never tested that idea experimentally. It is likely that his new protégé Yamagiwa, during his sojourn in Berlin, resolved to try if he ever got the chance. Returning to Tokyo in 1894, Yamagiwa was initially assigned to study diseases that were hindering the expansion of the Japanese Empire. But his service ended in 1899 when he contracted tuberculosis, a disease Yamagiwa surely thought he had left behind when he departed Koch’s lab seven years earlier. For the rest of his life, he suffered from a hacking cough, shortness of breath, and chronic exhaustion. Confined to his Tokyo laboratory after a long and intermittent recovery, Yamagiwa returned to the consuming passion he had developed during his time with Virchow: the search for catalysts capable of initiating cancer via cellular irritation.

The suspected carcinogen Yamagiwa decided to study was, in many ways, an obvious choice. It was coal tar, the original industrial pollutant—bane of chimney sweeps and chief elixir of the chemical revolution ever since William Perkin used it to create the first synthetic dye in 1856 in his parents’ attic. Tar was already a leading suspect based on a long string of observational studies, from Pott’s chimney sweeps to reports of cancer in workers in the dye and kerosene industries, both of which relied on tar derivatives. In 1907, before there was any laboratory evidence that coal tar was carcinogenic, the British government formally recognized scrotal cancer as an industrial disease, declaring that “men engaged in handling pitch or other tarry products” would qualify for workers’ compensation if they developed scrotal cancer.
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Yet by the time Yamagiwa began his coal tar experiments in 1913, European scientists had given up trying to use it to induce cancer in animals. Several had reported failures after painting tar onto the ears of dogs or injecting it into rats; others had smeared azo dyes and kerosene onto the skin of rats. Most of those experiments had triggered lesions in the affected areas but no cancerous tumors. Coal tar research seemed to be at a dead end, especially after a dramatic announcement
in 1913 from Copenhagen: A former student of Koch’s named Johannes Fibiger declared that after six years of research, he had discovered a parasite that caused cancer. While dissecting wild rats infected with tuberculosis, Fibiger had noticed that many had stomach tumors. He eventually concluded that the cause was a microscopic nematode worm he called
Spiroptera carcinoma
, which lived in the stomachs of cockroaches that were then consumed by rats. (The nematode originated in South America and the Caribbean but was carried to Europe in the cockroach-infested holds of sugar ships.) Fibiger fed those infected cockroaches to mice in his laboratory and reported that he could reliably induce tumors in the rodents’ stomachs and esophagi. Fibiger even claimed to have transferred the stomach tumors from one mouse to another. The Danish scientist had seemingly won the race to confirm the first carcinogen—and it was a cancer microbe, not a chemical pollutant.

Word of Fibiger’s apparent breakthrough reached Tokyo after Yamagiwa and his assistant, Koichi Ichikawa, had already embarked on their coal tar experiments. Mindful of his mentor Virchow’s ideas about chronic irritation of epithelial cells, Yamagiwa made two choices that distinguished his work from that of his failed predecessors: He chose to experiment on rabbits because the insides of their long ears provided plenty of accessible epithelium, and he decided to paint those ears with coal tar over many months, not just a few weeks. Beginning on September 1, 1913, Ichikawa painted tar on the animals’ ears every two or three days. (Yamagiwa was too weak for the laborious work.) After 112 days, tumors appeared. On April 2, 1914, Yamagiwa excitedly reported the results to the Tokyo Pathology Society. But his audience, aware of the failed European experiments, was skeptical. The growths Yamagiwa saw on the rabbits’ ears were merely inflammation, not malignancies, several of his colleagues asserted.

Undaunted, Yamagiwa and Ichikawa secured a grant to purchase sixty more rabbits and began the process of repeating their lengthy experiment. Things were going well until, during the summer rainy season, an infectious disease swept through the cages and killed almost all of the rabbits. Among the few survivors, however, two developed
the same tumors the researchers had seen before, so Yamagiwa decided not to abandon the project. Instead, he bought more rabbits. By the time he formally presented the results to the Tokyo Medical Society on September 25, 1915, Ichikawa had painted coal tar on the ears of 137 rabbits over 250 days and had documented the presence of cancerous tumors on the ears of seven of those rabbits. This time, Yamagiwa got a much more favorable reception. To celebrate his success, Yamagiwa penned a haiku poem, famously translated into English as: “Cancer was produced! Proudly I walk a few steps.” He wrote up his results in a paper he dedicated to the memory of his mentor Virchow, who had died in 1902.

It was a historic moment, but few scientists were paying attention.
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While Johannes Fibiger’s fame spread quickly, Yamagiwa’s achievement got much less attention because of Japan’s remoteness. By the early 1920s, however, scientists in Europe and the United States (including Fibiger) were replicating Yamagiwa’s coal tar experiments in mice, rats, and dogs, confirming the carcinogenicity of tar and developing a template for testing other suspect compounds. Fibiger’s nematode experiments, meanwhile, could not be replicated. Even so, they were acclaimed as the synthesis of the two major schools of thought on carcinogenesis: Fibiger’s nematodes were microbial but allegedly caused tumors via irritation of the stomach and esophagus of their animal host, which is why his results excited disciples of both Koch and Virchow. Fibiger was repeatedly nominated for a Nobel Prize, finally receiving it in 1926, after the prize committee rejected splitting his award with Yamagiwa.

It was, in hindsight, one of the biggest errors in the history of the Nobel Prize. As was already becoming clear in 1926, Fibiger’s nematode was
not
the direct cause of the growths he saw in rats. By the 1930s, research had demonstrated that the stomach lesions Fibiger saw in rats were benign and appeared only in animals fed a diet deficient in vitamin A, which was the crucial cause.
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The nematodes were, if anything, merely a contributing factor because they caused tissue irritation (a realization that belatedly lent more support to Virchow’s irritation theory). Microbial carcinogens, both parasitic and viral,
would not be confirmed until the second half of the twentieth century.
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By the 1950s, Fibiger’s name had disappeared from many histories of cancer research. When his work was included, it was often as an illustration of experimental error.

Yamagiwa’s discovery, on the other hand, launched modern experimental cancer research, setting the stage for the identification of hundreds of chemicals that, at sufficient doses, cause cancer in lab animals. After Yamagiwa, cancer could no longer be dismissed as a vague threat confined to dangerous places like mines and factories, or as an uncontrollable illness that struck randomly and without apparent cause. The era of the carcinogen had arrived.

When Stephanie Wauters heard Ciba-Geigy’s Jorge Winkler describe the chemical composition of his factory’s wastewater as “ninety-nine percent water and a little salt,” she was furious. A former high school science teacher who had just started law school in 1984 (she would eventually become a prosecutor and then a judge), Wauters was no shrinking violet. She and her husband, John, an accountant, lived on Tunesbrook Drive, about a quarter-mile west of the site of the pipe leak. Like many of their neighbors, the Wauters had their own water well in the backyard, and Stephanie was upset when she learned that her children’s drinking water had come from the same shallow aquifer the leak had contaminated. She wondered how long the pipeline had been leaking. Then she heard Jorge Winkler’s comments, which made no sense to her at all. “Our motive initially was just to find out what was going on and to protect our children,” she recalled years later. “Then we heard that the waste was from Ciba, and that Ciba was claiming it was just diluted effluent. But how could it be just water and salt, especially if they were accepting waste from all those other companies in violation of their permit? They weren’t being honest. I felt we had to get more involved.”