Toms River (41 page)

Anderson’s personality was as forceful and stubborn as Gillick’s, but his intensity smoldered, while hers often burst into flames. He had an engineer’s mind; he liked to pull things apart and see how they worked. He also liked to build with his own hands, including the house on Malcolm Street where the family had lived since 1984. Now he applied that same meticulousness to the process of learning everything he could about the causes of childhood leukemia, including the possible role of environmental pollutants in combination with inherited vulnerabilities. One of his son’s doctors had mentioned something called the “two hit” theory of carcinogenesis, developed by a researcher who was now in Philadelphia. The idea intrigued Anderson; he wanted to know more.

More than forty years earlier, in another hospital ward in another city, the father of the two-hit hypothesis, Alfred Knudson, first encountered
the mystery and pathos of childhood cancer. He would go on to become one of the world’s most influential cancer geneticists, but in March of 1949 he was a twenty-six-year-old medical resident on a one-month rotation in the pediatric oncology ward at Memorial Hospital in New York City. Most of the patients in the twenty-bed ward had acute lymphocytic leukemia, and for the first time there was some hope of curing them. A new class of chemotherapy drugs seemed to slow tumor growth by impeding the function of folic acid. “Before the antifolates, there was nothing you could do except just watch the leukemia kids die. It would usually take three or four months,” Knudson remembered many years later. “I was with those kids all of the time for that one month on the ward. It was total immersion, and it was exciting because there were remissions for the first time in leukemia.”

Knudson’s rotation in the ward soon ended, and so did the remissions. Most of the children with leukemia relapsed within a few months, with little to show from the experimental treatment except a few extra months of life and an awful array of debilitating side effects. Antifolate drugs would later become a useful part of the standard chemotherapy regimen, but their early failure was a wrenching experience for the young doctor-in-training. “When you see twenty kids all together on the ward,” he said, “it just suddenly hits you: Why, and how, do these kids get cancer?”

His memories of those helpless young patients, many of whom would never go home, stuck with Knudson—so much so that he later decided to give up clinical medicine for a research career focused on trying to understand the causes of childhood cancer. In 1964, he was at the City of Hope Medical Center in California when Hermann Muller came through as a visiting researcher. The diminutive leftist was now seventy-five years old and was still working with fruit flies; briefly hospitalized for a heart ailment while in California, he insisted that an assistant bring his flies to his bedside so that he could inspect them. He was also still buzzing energetically over the unsolved problems of mutation and cancer. Why did it often take many years—or several generations, in the case of fruit flies—for radiation exposure to trigger cancerous tumors? The answer, Muller believed, was that several mutation “events” were required to transform a healthy cell
into a malignant one.
¹¹
Cancer, in other words, was more like a long-distance relay than a solo sprint.

Alfred Knudson agreed with his eminent visitor. To Knudson, a multistage sequence of carcinogenesis fit the evidence. He and Muller were not the only scientists who thought so. The idea had been embraced by cancer researchers as diverse as Katsusaburo Yamagiwa, Ernest Kennaway, and Wilhelm Hueper, each of whom knew from firsthand experience that inducing tumors in rabbits, mice, dogs, or other experimental animals required many toxic doses over long periods of time. They also knew that some individuals were especially vulnerable to carcinogenic exposures and that most victims were elderly. Those observations all suggested that there were multiple steps to malignancy and that the journey could take many years. Richard Doll theorized that carcinogenesis required six or seven mutations.
¹²
But that was just an educated guess, an estimation based on Doll’s observation that the cancer death rate for the elderly was more than seven times higher than for young adults.

Knudson wondered whether he could push the multistage hypothesis beyond guesswork. He had read Theodor Boveri’s groundbreaking 1914 book on mutation and cancer and was excited by a burst of recent findings that seemed to confirm many of Boveri’s ideas. Genetics was in the midst of a revolution in the 1960s. James Watson and Francis Crick’s success in elucidating the double helix structure of DNA in 1953 at last revealed exactly how hereditary information is stored in the chromosomes of living organisms, as Boveri had predicted sixty years earlier. Now researchers could peer inside the twenty-three pairs of chromosomes in every human cell and identify DNA segments, or genes, associated with specific traits and bodily functions—and malfunctions, too.

Many of the breakthroughs that followed concerned cancer. The most famous was the 1960 identification of a mutation known as the Philadelphia chromosome, named for the city where it was discovered. The bone marrow cells of 95 percent of adults with chronic myelogenous leukemia carried the telltale genetic defect. It was the first direct evidence that chromosome alterations preceded cancer and thus was another confirmation of Boveri’s ideas. The Philadelphia
mutation was a scramble: A chunk of DNA from Chromosome 9 swapped places with a chunk from Chromosome 22. What was puzzling was that not everyone whose cells had this chromosomal translocation got leukemia; many did not. To Knudson, that was additional evidence that more than one mutational event was required. The identification of the Philadelphia chromosome and other translocations associated with cancers would eventually lead to the discovery of oncogenes, the rogue mutations predicted by Boveri that promote the rapid cell division of cancer. But even the presence of an oncogene in a cell was not a surefire indicator that malignancy would result—one mutation was often not enough.

The multiple-hit theory of carcinogenesis made sense to Knudson, but his experience treating childhood cancer patients led him to doubt Richard Doll’s suggestion that six or seven successive mutations were needed to trigger a malignancy. After all, some of Knudson’s young patients were born with neuroblastoma; others developed leukemia as infants. Mutations were rare events; surely a baby had not lived long enough to take a half-dozen genetic hits. On the other hand, it did not seem to make sense that only one mutation was necessary. The human body produced one hundred billion white blood cells daily, yet leukemia was still a relatively rare condition. If just one mutation was required, why didn’t everyone have it? With those questions in his head, Knudson began looking for a childhood cancer he could study to test his ideas about multiple hits.

He found retinoblastoma. Like Michael Gillick’s neuroblastoma and Randy Lynnworth’s medulloblastoma, retinoblastoma begins with the malignant transformation of precursor stem cells, in this case, in the eye. These retinoblasts produce the specialized light-sensitive cells that line the retina, making vision possible. A very rare disease, afflicting one in fifteen thousand children, retinoblastoma comes in two varieties: hereditary and sporadic. Hereditary retinoblastomas, about 40 percent of all cases, afflict children who have a family history of the disease, while sporadic cases do not. What caught Knudson’s attention were three quirks that apply only to hereditary retinoblastomas. First, they sometimes skip a generation: A grandparent is afflicted, a parent is not, and then the disease returns
in a grandchild. Second, kids with a family history of retinoblastoma usually develop the disease very early in childhood—even during infancy. And finally, children with hereditary retinoblastoma very often develop more than one tumor in one or both eyes.

Knudson developed a theory that could explain all of retinoblastoma’s quirks. He called it the “two hit” hypothesis, and it was based on the idea that a retinoblast cell required two mutations to become malignant. Children with hereditary retinoblastoma, Knudson believed, were born with a mutation they carried in all of their cells and thus required just one more mutation “hit” in any retinoblast cell to develop a tumor. With about one hundred million cells per eye, there were many opportunities for that second mutation. In fact, it could easily occur in several cells in one or both eyes, triggering a separate tumor each time. The timing was interesting, too, because cell divisions, opportunities for mutation, occurred most often during the last months of fetal growth and the first few months after birth, when the eyes were developing most quickly.

The two-hit hypothesis thus explained why children with hereditary retinoblastoma tended to be younger and more likely to have multiple tumors. Children with sporadic retinoblastoma, on the other hand, got the disease only after an individual retinoblast cell suffered two mutational events—akin to lightning striking twice in the same place. Knudson’s theory even explained why hereditary cases sometimes skipped generations, since the parent in the cancer-free middle generation carried the inherited mutation but luckily avoided the second hit. “It all fit together,” Knudson recalled. “With these retinoblastoma kids, it just seemed obvious that inheriting this gene isn’t enough to make the cancer. Something else has to happen. There has to be a second hit.”

By the time he was ready to test his theory, in 1970, Knudson was working in Texas and had access to the medical records of forty-eight children treated for retinoblastoma. Twenty-three of them had tumors in both eyes, which meant that they were almost certainly hereditary cases. The next step was to set up a statistical test: If two-eyed cases required just one mutation while one-eyed cases needed two mutations, how many of each kind would be expected in a typical
group of forty-eight children with retinoblastoma, and how old would each child be at diagnosis? Knudson calculated an expected distribution and then looked to see if they matched the actual results from the forty-eight cases. He was thrilled to discover that he got a hand-in-glove fit for all of his most important predictions. He had predicted, for example, that the average number of tumors among the two-eyed cases would be three—a prediction that fit the hospital data almost perfectly.
¹³
Knudson was right: Retinoblastoma was a two-hit cancer—the first multistep cancer with a fully plotted pathway to malignancy.

It is almost impossible to overstate the impact Knudson’s discovery had on research into carcinogenesis, including the role of pollutants in places like Toms River. He would move on to Fox Chase Cancer Center in Philadelphia in 1976, continuing his cancer work and happily watching researchers around the world expand his findings in sometimes surprising ways.
¹⁴
The biggest surprise came in 1983, when the inherited “retinoblastoma gene” in the human genome was finally identified. The gene was on Chromosome 13, which is where Knudson had predicted it would be found back in 1976. The surprise was that it turned out not to be a villainous oncogene like the leukemia mutation created by the Philadelphia translocation. Instead, the newly named “Rb” gene was a hero—a new type of gene whose existence had yet again been foretold by Boveri seventy years earlier. It was a tumor-suppressor gene, and it was ultimately found to protect against not only retinoblastoma but also bone cancer and other malignancies. The problem for children with hereditary retinoblastoma was that their cells contained only one functional copy of the Rb gene instead of the normal complement of two, one from each parent. If a second mutation knocked out the remaining copy, then the affected cell would lose its ability to regulate its rate of replication. It would become a cancer cell.

The multi-hit model Knudson laid out for retinoblastoma became the dominant paradigm for carcinogenesis, the default assumption of how cancer begins. A few cancers required just one “hit,” but most were now assumed to be the products of complex sequential processes that began with inherited mutations and continued with additional
genetic “hits.” If those subsequent mutations occurred at critical times, especially during fetal development or early childhood when so many cells were dividing, the results could be calamitous. That lesson would not be lost on the families of Toms River.

There was another, even more powerful message for Toms River in Knudson’s work: Most of the chemicals that loomed large in the town’s unhappy environmental history were mutagens—they were capable of altering DNA. As he developed his two-hit theory, Knudson did not speculate on the possible causes of the non-inherited mutations that were essential steps on the road to carcinogenesis. His mathematical model for retinoblastoma assumed that these mutations occurred randomly—due to collisions with cosmic rays, for example, or because of DNA copying errors during cell division. But Knudson and everyone else in the field knew that there were other sources of mutations. Hermann Muller had proved that X-rays were mutagens, and by the late 1970s, the California biochemist Bruce Ames—using the genes of bacteria, which were even easier to work with than fruit flies—had proved that dozens of known carcinogens, including many industrial chemicals, were also capable of mutating DNA.
¹⁵

Just about any stray sample of soil, groundwater, or air from Ciba-Geigy or Reich Farm was likely to contain at least one mutagenic compound.
¹⁶
Many coal tar derivatives were mutagens, including benzene, benzo(a)pyrene, and benzidine. Epichlorohydrin, the resin feedstock that had so terrified Ciba-Geigy workers in the 1960s, was mutagenic too. Over at Reich Farm, meanwhile, the underground pollution plume seeping south toward the Parkway wells included several of the same mutagens, plus a few others.

For a town where mutagenic chemicals were now part of the landscape, the implications of Alfred Knudson’s research were clear: If a substance was capable of delivering a “hit” to DNA, it was a cancer risk, and no one was more likely to take a hit—or two or three—in a short period of time than a fast-developing fetus or a young child. When Bruce Anderson and other Ocean of Love parents heard about that, they wondered how many hits their children had endured, and who had delivered the blows. Before long, the State of New Jersey and
the United States of America would be spending many millions of dollars to try to find out.