Authors: Dan Fagin
One of the very first scientists to begin to lift the curtain on the hidden mechanisms of carcinogenesis was an underappreciated giant of biology named Theodor Heinrich Boveri.
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Born in the Bavarian city of Bamberg in 1862, Boveri was a brilliant student, winning a fellowship in 1885 that allowed him to pursue any scientific question he wanted for five years. Boveri chose heredity. He wanted to understand how traits are passed from one generation to the next through fertilization, or from cell to cell through division. Working first with the eggs of roundworms and then of sea urchins, Boveri focused his observations on the squiggly, rod-shaped objects he saw inside the nuclei of cells as they divided. The pliable rods were one of the few parts of the nucleus that could be seen through the microscopes of the day—they stood out when stained, which is why they were called chromosomes, or “colored bodies”—and their behavior fascinated Boveri. During cell division, they shifted and danced like a squad of synchronized swimmers before receding into invisibility in the two new daughter cells.
Unlike many of his fellow biologists, Boveri believed that chromosomes were the structures of inheritance, the engines that made Darwinian evolution possible by transmitting an individual’s variable traits to the next generation. He set about trying to buttress his belief by systematically observing the movement of chromosomes in animal cells. What looked a freeform dance of the chromosomes during cell division, he discovered, was actually a precise and highly organized gavotte in which the rods divided individually and then into separate but identical clusters, each going its separate way as the cell split.
Boveri also noticed that chromosomes did not dissolve after the division was complete, as many biologists thought at the time, but instead lived on in compacted form inside the nuclei of the daughter cells until they unspooled again during the next round of cell division. He spent the rest of his life trying to convince skeptics that chromosomes were the carriers of hereditary information and that variations in individual chromosomes were responsible for the inherited variations in all living things.
Cancer was a key reason for Boveri’s theories about chromosomes. He chose to study roundworms because they had just two chromosomes, both of which were large enough to see through a microscope. He then moved on to sea urchins because a single urchin egg could be fertilized by two sperm. Whenever that occurred, the resulting zygote had an unbalanced number of maternal and paternal chromosomes. If the egg was then able to divide, the anomaly was passed on to the daughter cells. Those “unbalanced” urchins, Boveri realized, often had developmental problems, including cancer.
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In an astonishingly farsighted book he wrote in 1914, a year before his death, Boveri asserted—correctly, as it turned out—that vulnerability to cancer could be inherited via mismatched or unstable chromosomes.
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The rapid cell growth of tumors, he correctly theorized, could be triggered by growth-promoting chromosomes (he did not know about genes, the subunits within chromosomes that actually carry hereditary information) or by the absence of growth-inhibiting chromosomes or by chromosomal abnormalities that appear only after many generations of cell division.
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The same year his book was published, Katsusaburo Yamagiwa managed to induce malignant tumors by painting rabbits’ ears with coal tar. His success, combined with Boveri’s observations, strongly suggested that carcinogens did their mischief by triggering mutations within chromosomes. In fact, Boveri was sure that pollution-induced mutations—and the resulting cancers—would be found in industrial workers who handled coal tar.
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He was right about that, too.
What about young children with cancer? Could an environmentally induced mutation really be passed down from one generation to the next, just like hair or eye color? Hermann Joseph Muller thought
so. Another in a long line of brilliant but abrasive biologists, Muller had been thinking about that question for practically his whole life. When he was a young boy in New York City, in 1899, his father had taken him to the American Museum of Natural History and explained, with the help of a display of horses’ hooves, how organisms evolved via natural selection acting on accidental variation. His father died soon afterward, but the lesson stayed with his eight-year-old son. If evolution could occur naturally, Muller thought, surely the deliberate actions of humans could affect the future evolution of his own species—for good or ill.
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Small and bellicose—he compensated for his size by standing on tiptoe while arguing—Muller was a social misfit who, like Boveri, was prone to depression.
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Despite his unhappiness, or perhaps driven by it, Muller did brilliant work as a young researcher at the University of Texas. He conducted a series of experiments in which he irradiated fruit flies with X-rays, which were already widely known to trigger cancerous tumors in animals and humans alike.
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In 1927, Muller was ready to divulge his results, which caused an immediate sensation. By exposing the sperm cells of fruit flies to X-rays, Muller reported, he was able to generate heritable mutations—white eyes in male flies instead of red, for example—almost at will. Many of those mutations were lethal, triggering a wide range of abnormalities, including sterility.
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Carcinogens could mutate genes; Muller had validated Boveri’s prediction. Not all mutagens triggered cancer, and not all carcinogens did their work via mutation, but there was a strong correlation between the two—as the people of Toms River would learn when they found out what was in their drinking water. More broadly, Muller helped to solidify the view that genes, with their unique ability to copy themselves and transmit information to daughter cells, must control cell development and therefore the growth of the entire organism. Genes were the wellspring of life—and also of death, depending on the particular the message they carried. Muller had answered the question that first occurred to him as a young boy at the museum: Yes, human beings could manipulate their genes in ways that would affect not only their survival as individuals but the long-term viability of
their species. Muller was awarded a Nobel Prize for his genetics research in 1946, just after the atomic bombings of Hiroshima and Nagasaki. He spent the next twenty years studying fruit fly mutations and campaigning against the use of radiation in weaponry, industry, and medicine—“time bombing our descendants,” he called it.
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The sins of one generation, Muller suggested, would be visited on the next through genetic mutation and cancer.
One of the Toms River children whom Linda Boornazian met on the oncology ward at The Children’s Hospital of Philadelphia in the early 1990s was Michael Anderson. He was ten years old when he was first admitted to CHOP in September of 1991, the culmination of a summer of intensifying agonies that began with a sore thumb on May 8. Mike’s birthday was May 11, but by then he was already too sick to enjoy it—his ankles and hands ached, and he was running a fever. A month-long course of antibiotics did not help. By July, he was in a wheelchair, his feet and hands bent like an old man’s and too painful to move. On an initial visit to Philadelphia, the doctors diagnosed juvenile rheumatoid arthritis, but the medications they prescribed proved as useless as the antibiotics. His mother, Melanie, had to feed and wash her son as if he were a baby. When Mike went back to school, his mother went with him, carrying him up and down the stairs. His father, Bruce, who worked as a reactor operator at the Oyster Creek nuclear power plant, began to worry about the family’s health insurance. Mike’s three brothers—ages seven, thirteen, and sixteen—watched, terrified, as the unchecked and unidentified disease ravaged his small body. Circle-shaped bruises appeared all over him. They were not the impact bruises Mike used to get from playing soccer or riding his bike—the bruises all rambunctious young boys get—but something deeper, stranger.
His parents suspected leukemia, but the doctors said that was impossible; the blood tests were negative. Even so, Bruce and Melanie Anderson insisted on another examination in Philadelphia in September of 1991. This time, a new pediatric rheumatologist saw Mike. His name was Steven Goodman, and he was only a few years out of medical school. He looked at Mike’s case in a new way—asking more
questions, conducting a more thorough physical exam. Examining Mike’s fingers, Goodman noticed that Mike’s bones, not arthritic joints, were the source of his pain. He ordered another set of blood tests, and this time the results were different. Mike’s platelets were low, and his white blood cell count was high—the same lethal combination Rudolf Virchow had dubbed
leukemia
after observing it under his microscope in 1845. The Andersons got the catastrophic news on Friday the Thirteenth: Mike had a rare form of leukemia that was essentially a combination of the two most common types, acute lymphocytic leukemia, known as ALL, and acute myelogenous leukemia, or AML. The prognosis was dire; the required double dose of extended chemotherapy would be vicious.
The next three years were “a roller coaster through hell,” as Bruce Anderson would remember them. After six weeks of intensive chemotherapy at the hospital, Mike went home to Toms River, returning at least once a month for another debilitating round of chemotherapy drugs, administered through a catheter surgically attached to his chest. There were many other trips to the hospital, too—harrowing, late-night runs across New Jersey whenever Mike had a high fever. The regimen of chemotherapy and steroids was gradually killing the cancer cells, but it was also wrecking Mike’s immune system, leaving him open to an array of opportunistic infections, any of which could have killed him. Melanie learned to keep an overnight bag packed and ready at all times in case they had to rush back to Philadelphia. She and Bruce also learned to be assertive with the nurses and doctors. They asked questions, checked medication dosages, and insisted that all of Mike’s visitors first wash their hands. The Andersons connected with Linda Gillick via Ocean of Love, a support group she had formed in 1988. Raising money in the community for families struck by childhood cancer, Gillick delivered Easter baskets, Thanksgiving turkeys, and Christmas gifts to the Andersons and other families. She organized summer picnics and trips to Broadway shows. And for families who needed it, she would provide direct financial support—including for funeral expenses. She was driven, and she was tireless. The Andersons were amazed by Gillick’s devotion to other sick children, even as her own son’s condition remained perilous.
Very gradually, as Mike Anderson’s health improved and the sense of perpetual crisis that had enveloped his family began to ease, his parents allowed themselves to ponder the deeper questions raised by their son’s illness. Bruce Anderson knew about Linda Gillick’s map of local childhood cancer cases, and he came to share her conviction that a chilling pattern was emerging—a cluster.
Robert Gialanella thought so too. He had met Linda Gillick in 1989 in a store checkout line at the Ocean County Mall, while she was waiting to pay for a huge basketful of holiday toys for the children. He was a local physician, and within a few weeks he was also a board member of Ocean of Love, where he would remain for thirteen years. Gialanella’s oldest son was born one day before Michael Gillick, and he came to think of the Ocean of Love children as extensions of his own family. “Linda was so committed to these kids,” he remembered. “I just felt I wanted to be involved.” Gialanella was a gastroenterologist, not an oncologist, and he treated adults, not children. But he knew a bit about epidemiology, and in 1991 he and Gillick became alarmed as the number of pushpins on her map proliferated across Ocean County and especially in Toms River. If something in the environment really was causing those cancer cases, it seemed to be gaining potency every year. Gialanella decided to try to find someone at the state health department who might be willing to investigate. It took a while to locate the right person, but in 1991 Gialanella spoke to Michael Berry, the same health department employee who five years earlier had responded to a very similar request from Chuck Kauffman of the Ocean County Health Department.
That earlier study had found no statistically significant elevation in the local childhood cancer rate, but Berry agreed to Gialanella’s request that he take another look because this time a few more years of registry data could be included in the analysis, increasing the overall number of cases and slightly reducing the effects of chance. In fact, there were enough cases by now that Berry could try to look at some specific categories of diseases instead of lumping all childhood cancers together. Also, there had been some improvements at the cancer registry in collecting data from out-of-state hospitals, so it was more likely that at least some of the Toms River children treated in Philadelphia
and New York would be included this time. One problem, however, had gotten worse: The registry was now four years behind schedule; the most recent full year of data was 1987. The cases Chuck Kauffman had heard about in 1984 and 1985 would show up in Berry’s second study, but all of the cases that Linda Gillick had heard about in 1989, 1990, and 1991 would not. The state cancer registry was like a surveillance camera whose film took four years to develop. By the time the pictures were available, the world had moved on.
Berry ran the numbers, and this time the results were ambiguous—the number of cases was higher than expected, but not by much. Gialanella was disappointed, but not surprised. “We knew there were more kids than were documented in the state reports,” Gialanella remembered. “We were looking at real-time data, all of the kids we knew about. I think we kind of said to ourselves that if the state had more current data it might show something more significant.” Berry’s inability to confirm the existence of a cluster was extremely frustrating to Linda Gillick and Bruce Anderson, who by now were convinced the cluster was real and getting worse. Ocean of Love stopped asking the state to investigate—that route now seemed hopeless—but Gillick kept adding pins to her map, and Anderson started reading everything he could find about environmental causes of cancer.