By Robert Bazell

Random House

(C) 1998Robert Bazell
All rights reserved.
ISBN: 0-679-45702-X

CHAPTER ONE

Discovering Cancer

    One morning in the fall of 1978, Anne McNamara showered while her husband, Jeff, tended to Luke, their one-year-old son. As she soaped and scrubbed, she felt something unfamiliar in her left breast. "Uh-oh," she thought, a chill going down her spine. She had a history of fibrocystic disease. She tried to convince herself that all this could be was just another benign growth. Silently she recited the statistics: she was thirty-two; in premenopausal women, just one out of twelve tumors turns out to be cancerous. Fighting the impulse to panic, she sought comfort in the knowledge that there was no history of cancer in her family.

    Anne McNamara brought uncommon understanding to her discovery. Having been a biology major and a chemistry minor in college, her first job had been in a laboratory of a scientist at Yale Medical School, who was carrying our medical research. She tested the effects of radiation and chemotherapy on cancer cells. Much as she wanted to believe that this lump, like many others she had previously had, would go away as she moved through her monthly hormonal cycle, she had a feeling that this one was different. In unguarded moments over the next couple of weeks, she probed the new growth. Had it changed? Did it feel different? Once you find a lump, she says, "You check it three times a day." After more than a month had passed without any change in the lump, she went to see her gynecologist, who said he thought it was just a cyst. Nonetheless, he sent her to a surgeon for a biopsy. Just to be sure.

    A few days later, McNamara met with her doctor, James Finn, who offered her the choice that most women in her position then faced: he could do the biopsy and wait until McNamara came out of the anesthesia to give her the results, or they could agree ahead of time that he would remove her breast if the tumor turned out to be malignant. McNamara, typically matter-of-fact, chose the second option, the course of least emotional complication. As Jeff remembers it, "She did not fear the worst, but she prepared for the worst."

    Anne's delicate appearance and honeyed Georgia accent belie her toughness. Her face settles naturally into a warm smile, and when she talks in her straightforward and low-key manner, her large green eyes and her high-arched eyebrows give the listener a clear window on her emotions. She's now a youthful fifty-two years old, with auburn hair flowing to her shoulders. Jeff, a muscular man with a neatly trimmed mustache and ice-blue eyes, had just returned from a four-year stint in the Air Force and was finishing up his business degree when they met. They lived in the same apartment building in New Haven; when Anne had totaled her motorcycle, and Jeff, an inveterate tinkerer, saw it crumpled in a corner of the garage, he asked her if he could take a crack at fixing it. They've been together ever since.

    Anne's surgery was scheduled for the week after Thanksgiving. Jeff stayed home with the baby and awaited word from the hospital. In the operating room, the surgeon was stunned by the lump's size: five centimeters, the size of a lemon. Moments later, a pathologist confirmed that it was a tumor and it was indeed malignant. Dr. Jim (as the McNamaras called him) phoned Jeff from the operating room. "It's not good, Jeff." "How not good?" "Bad." Jeff paused to collect himself and then said, "Do what you've got to do. Take care of her the best way that you know how."

    McNamara remembers slowly coming out of the anesthesia. "I was still extremely groggy, and I was trying to figure out if my breast was gone or not. I knew if it was, then it meant I had cancer. But I was so groggy that I clutched at my chest and I couldn't figure it out." As the anesthesia wore off, she realized that her torso was wrapped in a bandage. "I knew what that meant."

    Her doctor was flabbergasted. "We were all flabbergasted," said McNamara. "Because it was cancer, and there I was, thirty-two years old, although now it's getting more and more common to happen in younger and younger women. But in 1978 it was still unusual enough that the doctor just couldn't believe it. Who knows where it came from? But it had probably been there seven or eight years by that time, they say, before you can feel anything."

    In 1978, the initial treatment of breast cancer had not changed much since the end of the nineteenth century. Like Anne McNamara, most women undergoing surgical biopsy would drift off into the oblivion of anesthesia and grab at their chests when they awoke to learn whether they had lost a breast or not. When McNamara underwent surgery, enlightened doctors still considered the radical mastectomy, a decades-old procedure, the best choice for cases like hers.

    McNamara's first question on learning that she had cancer was whether she needed chemotherapy. Even though she knew all about the side effects, like nausea and hair loss, she thought it might help keep the cancer at bay. But Dr. Jim tried to assure her that he had gotten all traces of the disease and recommended against it. McNamara felt relieved, but suspicious. "I remember thinking to myself, `He doesn't really know that,'" she says. She spent enough time around cancer research to know that rogue cancer cells often escape to other parts of the body before surgery. Why not have chemotherapy as insurance against spread or recurrence? Dr. Jim argued that chemotherapy could actually spur cancer to recur and cited very preliminary Russian studies on pre-menopausal women that purported to show how chemotherapy could actually induce the spread of breast cancer. Those studies were soon discredited, but they illustrated a truth about medicine: state-of-the-art practices come and go as medical science proves and then discredits its latest thinking. Even the most immaculately reasoned advice can be faulty.

    In fact, by the time Anne McNamara had her mastectomy, clinical trials were already under way that would prove the usefulness of chemotherapy immediately after breast-cancer surgery. McNamara did not care about trends in cancer treatment; she only wanted to take every precaution against her disease, and her instincts told her that chemotherapy would increase the chances of eradicating her cancer. While disheartened, she did not challenge Dr. Jim. As happens so often, the patient was protecting the caregiver. "He was trying to comfort me, and he was a friend." Thinking back on it now, McNamara wonders if chemotherapy might have saved her from the terror of recurring cancer. Then she dismisses the thought: "That was the accepted protocol at the time."

    McNamara's instincts turned out to be better than her surgeon's. Ten years after her mastectomy, the National Cancer Institute issued an emergency clinical alert to physicians, recommending that chemotherapy follow soon after surgery for all but the least threatening breast-cancer cases. Clinical trials had demonstrated convincingly that chemotherapy administered right after cancer surgery--called adjuvant chemotherapy--could help prevent the disease from returning and could thus improve the patient's chances of survival. Nowadays, adjuvant therapy is the standard of care for most breast-cancer patients.

    McNamara had good reason to be so cautious. Breast cancer in a thirty-two-year-old woman is extremely rare and especially frightening. For reasons no one clearly understands, when the disease occurs so early in life, it tends to grow aggressively. In the United States, the chance that a thirty-two-year-old woman will be diagnosed with breast cancer is less than one in four thousand. Only 6 percent of breast cancers in the United States strike women under the age of forty. The odds only grow worse as women age; the chance that an eighty-five-year-old woman will have developed breast cancer over the course of her lifetime is one in eight. In McNamara's case, the only relatively good news was that tests showed that the cancer had not yet spread to her lymph nodes, meaning that the chances of a recurrence were less than they would otherwise have been.

    Though half of all women with breast cancer never suffer a recurrence after the initial treatment, they are still sentenced to a life of uncertainty, never sure if they will join the half that does have a recurrence; and when the cancer reappears, it is always deadlier than it was the first time around. For Anne and Jeff, breast cancer brought a particularly severe disappointment: Luke would have to be their only child. Female hormones can fuel the growth of breast-cancer cells, so a pregnancy, with its massive hormone surges, can greatly accelerate a recurrence, especially if diseased cells have managed to escape the surgeon's knife. Nowadays doctors will allow some breast-cancer survivors to risk a pregnancy, but when Anne was diagnosed it was out of the question. "That was a blow," says Anne. "We had waited for seven years after we got married to have Luke." With her hands folded calmly in her lap, she explains, "I knew it would be silly to have another infant if there was a chance I wouldn't be around to raise it. I didn't want to leave my husband with a new baby, and I didn't want to leave a new baby without a mother."

    With her knowledge from the cancer lab, Anne could interpret the facts. Jeff had no similar understanding to temper his fear. He only knew that Anne might not always be there, and even twenty years later he is visibly upset at the thought, and he speaks freely about his confusion, fear, and frustration. His take-charge attitude had worked for him during his four years in the Air Force, and it had brought him success as a consultant to high-tech companies. But here was a problem that he couldn't solve. "If it had been a hole in the roof, I could have fixed it. But there wasn't anything I could do but be around to keep our life together. I just couldn't do much else."

    "I mean, I was upset," he continues. "Not traumatized, but certainly upset. But Annie puts on a very good face, and is not an outwardly worrying type. And I think that has a lot to do with it." He pauses to laugh. "I mean, she's got a steel backbone."

    McNamara left the hospital a week after her mastectomy, but she still faced reconstructive surgery. Her surgeon had recommended that she not have it immediately, so she waited nearly a year. "[He] said, `Don't do it right at first because even months afterward, whatever reconstruction you have done, it's never going to look like a real breast. It's just not the same.'" She smiles wryly when she remembers the rest of their conversation: "He said, `If you wait a while, then when you have it, you will be so glad to have a breast again that you won't be so picky that it doesn't really look like the other one.'" She pauses while the listener savors the full arrogance of that advice. McNamara is loath to launch an attack on her doctor for his clumsy statement. She simply dismisses his comment as "a male point of view."

    Waiting for reconstruction was the hard part. "I didn't feel feminine. I didn't want to have to worry with the stupid prosthesis; I wanted to be able to go swimming and wear a bathing suit and not have to worry about the dumb thing."

    In the meantime, she was determined to return to her life. A computer programmer since just after her marriage, she had taken a leave of absence to care for Luke full-time. She gave whatever time she had left over to her gardening and community work. She exercised as the surgeon prescribed and recovered full use of her left arm, which had been somewhat incapacitated by the surgery. "I put cancer out of my mind," she says.

    McNamara is a modest woman who is reluctant to talk about herself. She maintains a quiet reserve and regards her misfortune as her own business, never telling people about treatment except for some very good friends. She says that many people, not those to whom she felt close, just don't know what to say. "It scares them. Yes, it terrifies people, especially breast cancer, and other women particularly. And because they don't know what to say, they don't treat you like a normal person. I don't want to talk about it with casual friends. I want them to invite me over and not have the topic of conversation be illness. Oh, how are you, isn't it awful? How do you feel? You look so pale." But others did not share her sense of discretion.

    "Word got out," she says. Friends were stunned, particularly because she was so young. When she ran errands in downtown Branford, Connecticut, mere acquaintances would race across the street to say, "I just heard the most unbelievable thing. It can't be true!" The attention and sometimes tactless concern embarrassed her. "It affected me so," she says softly. "Once people know you have cancer, that's all they remember about you. They don't know what to say, and they avoid the situation. They don't mean to, but they write you off." She stops for a moment and then adds, "I just wanted to be treated like a normal person with a future."

    There were some oddly funny moments, too. She describes how some friends would glance down at her chest as they were trying to figure out which breast was real and which had been reconstructed. "They just couldn't help themselves," she chuckles. After the initial burst of concern, people began to lay off the subject. And for a while, she was able to put cancer out of her mind.

Until this century, cancer was considered mostly a woman's disease, and it often carried the stigma of shame. Without modern diagnostic tools, physicians could more easily recognize cancers of the breast, cervix, and ovaries. Untreated breast tumors bulge and can break through the skin; untreated cervical and ovarian cancers lead to prodigious bleeding. Thus physicians believed erroneously that cancer strikes women more often than men. Until the last twenty years or so, cancer, and most especially cancer of the female organs, was not a topic of polite conversation. In the atmosphere of denial, women were all too often left to suffer with their illness alone, unable to find support as the disease destroyed them physically and emotionally.

    When Anne McNamara's breast cancer struck, the shame associated with the disease was diminishing. Since the turn of the century, improved diagnostic techniques were proving cancer to be an equal-opportunity disease. But treatment for breast cancer has improved little over the last several decades, remaining a variation on the themes of surgery, radiation, chemotherapy, and hormone treatment. Separately and in combination, these options can be effective treatments and can sometimes bring about a remission that lasts long enough to be reasonably called a cure.

    Surgery does not always excise the cancer entirely. Chemotherapy and radiation are often just random attacks on the problem, destroying much but not necessarily all of the cancer and usually harming healthy tissue in the process. Hormone treatment works for some breast cancer. The new approaches, such as adjuvant chemotherapy, can bring profound benefits, but they amount to little more than adjustments to the standard procedure. The problem is that breast cancer is unpredictable. Sometimes it is wholly contained in a tumor. But all too often it spreads from the tiniest tumor long before it can be detected or removed. Why do some cancers produce micrometastases, tiny bits of cancer that migrate from the original mass? No one knows.

    The death rate for breast cancer stands as a dismal monument to ignorance. It has changed little in half a century. Every year the disease strikes more than 180,000 women in the United States and kills about 44,000. In 1950, the first year the government kept such records, 264 out of every 1 million white American women died of breast cancer. Twenty-five years later, that death rate was exactly the same. By 1985, it had risen to 275. In the 1990s, it began falling slightly; by 1995 the rate had dropped to 248, 6 percent less than it had been forty-four years before. The picture for African-American women is even more discouraging. Initially, the government kept no records of breast cancer in black women. In 1973, the first year that such records were compiled, the death rate from breast cancer for black women was 263 for every 10,000. By 1995, it had soared to 319.

    Many scientists believed those statistics could improve only with profound new insights into the nature of cancer itself. For almost a century, scientists have been raising research funds by promising that such breakthroughs were imminent. In 1898, Dr. Roswell Park, a surgeon in Buffalo, persuaded the New York State legislature to create the Institute for the Study of Malignant Disease by declaring that "the cure is just around the corner." The state built the institute, which was named after Roswell Park following his death. But the reality was that no one understood the fundamental biology of cancer--a word that covers approximately 110 distinct ailments.

    The National Cancer Act, signed by Richard Nixon on December 23, 1971, amounted to a leap of faith based on exaggerated claims worthy of Roswell Park and on the perennial belief that the government can solve any problem by simply throwing money at it. The War on Cancer, as it was called, brought unheard-of sums of money to the field. Between 1971 and 1979, the budget of the National Cancer Institute climbed from $230 million to $940 million. Grant money did flow to cancer research, so much so that scientists seeking funding for other areas of basic research, like the fundamentals of the chemical reactions in cells, often justified their applications by fabricating some hypothetical application of their research to cancer. But in 1971, money was hardly the only obstacle standing in the way of a cure. Cancer research remained a scientific backwater where no one seemed to be making any headway. Most distinguished scientists regarded cancer research as a bastion of mediocrity where less talented scientists followed the money to perform meaningless experiments. Robert Weinberg, a pioneer in cancer research, recalls a senior colleague admonishing him "never, ever, under any circumstance, to confuse cancer research with science."

Cancer, the uncontrollable multiplication of cells, has existed from the moment single-celled organisms joined together to form multicelled plants and animals. Cancers have been found on dinosaur bones and on Egyptian mummies. Growing and dividing is the most basic function of individual cells. It is the impulse by which life has survived and evolved for billions of years. Every cell in our bodies carries this evolutionary force. But when cells band together to form a higher organism, they must answer to a more advanced impulse. Strict controls govern the proliferation of the body's individual cells. If the body's control mechanisms fail and individual cells reproduce beyond the limits of the system, cancer is the result.

    What causes the deadly failure of control? Soon after the turn of the century researchers knew that radiation, chemicals, and viruses could trigger cancer. But this knowledge still failed to provide a satisfactory description of the actual change that is cancer itself.

    With James Watson and Francis Crick's landmark discovery of the structure of DNA in 1953, alterations in genes, the units of heredity spelled out in the DNA molecule, became obvious candidates for cancer's cause. Watson and Crick's double helix offered nothing less that the master blueprint for all of life. It followed that the double helix also held the secret of cancer.

    For centuries, biologists had theorized about the nature and function of genes, which are passed on from generation to generation and determine myriad characteristics, from physical traits to psychological dispositions. But until the Watson and Crick discovery, no one knew exactly what a gene was made of.

    Suddenly, it was clear. The DNA molecule is made up of a string of millions of pairs of units, called nucleotides, that contain one of only four bases--adenine, cytosine, thymine, and guanine--that spell the genetic code. A single gene is a string of the ACTG alphabet that carries the instructions for the cell to make a particular protein. The proteins in turn usually provide one of two essential components: the cell's structural scaffolding or the enzymes that guide biochemical reactions--the central engine for the entire organism. So the genes contained in every cell encode information that determines not only how the individual cells look and behave but also how the entire organism looks and behaves. By establishing what proteins a cell produces, the genes on the DNA helix direct the formation of all life, from blades of grass to the human brain. Wouldn't abnormal changes to this master blueprint be responsible for cancer? This sounded plausible, especially since X rays and many of the chemicals that cause cancer also bring mutations to DNA. According to Robert Weinberg, many scientists believed that with the discovery of the DNA structure, "answers to the cancer problem would be all there, waiting to be discovered." But no one could prove a connection between genes and cancer until the mid-1970s, when new technologies for manipulating and understanding genes led to a revolution in the understanding of the disease.

    Two researchers at the University of California, San Francisco, carried out the critical experiment that showed definitively that the roots of cancer lay in the genes of cells. Michael Bishop, a virologist, and his postdoctoral fellow, Harold Varmus, who went on to head the National Institutes of Health, were studying a chicken virus first discovered in 1911.

    Viruses are the smallest bits of life--often called tiny packets of trouble. They never divide as cellular organisms, including bacteria, do. While bacteria and cells in higher creatures carry tens of thousands of genes, viruses make do with much less--often fewer than a dozen genes. Viruses survive from generation to generation because the viral genes carry the program for a commando raid. Usually when a virus infects a cell, its genes take over the control of a cell's machinery and transform the cell into a virus-making factory that eventually explodes, spewing out thousands of new viruses. But occasionally a virus employs a different strategy. It does not kill the cell but transforms it into a cancer cell. Other scientists had determined that only one gene in the cancer-causing chicken virus was responsible for the malignant transformation. What was this gene? What was this single unit of information that could cause cancer?

    Initially, Bishop and Varmus--along with everyone else--thought that it was a viral gene. But certain viruses have a curious ability to act as gene kidnappers. Viruses occasionally capture a gene from a cell of the organism they invade and carry that gene as a passenger alongside its own set of genes. Bishop and Varmus found that the crucial cancer-causing gene was one of these accidental passengers carried by the virus. The Bishop and Varmus lab then determined that the gene dwells peacefully in chicken cells, where it performs some normal, harmless function. But in the virus, the same gene exists in a slightly mutated form.

    The only conclusion--and it was a monumental one--was that within the normal chicken cell is a gene that, at least under some conditions, has the potential to cause cancer. In this case, a virus triggers the gene's potential to cause cancer. But soon experiments would show that other factors could coax the gene to cause cancer. It turns out that the switch that transforms a cell from normal to cancerous is a class of genes given the name oncogenes. The potentially cancer-causing genes, called proto-oncogenes in their normal state, perform functions critical to normal cellular behavior. But when these normal genes mutate to become oncogenes, they cause the cell to grow out of control into a potentially life-threatening mass.

    This discovery of oncogenes brought mind-boggling implications: cancer might be triggered by some outside agent, such as radiation or chemicals, that might damage the gene, but the critical change actually takes place within the cell. Occasionally a human or other animal inherits an oncogene in the mutated form that gives rise to cancer. But far more often the gene mutates in the cell of the adult. Thus all cancer is genetic even if it is not usually inherited. In fact, all the cells of the body carry their own potential to become cancerous. With this first discovery came the rudiments of an accurate, detailed description of cancer. Only by understanding the foe could scientists even hope to devise significantly better ways of attacking it.

    The Bishop-Varmus discovery set off a frenzy of research to find out exactly how oncogenes carry out their insidious cellular conversion. Before long, researchers identified just a handful of genes that appeared to cause a wide variety of cancers. Soon words like src, myb, ras, and erb permeated the lexicon of cancer researchers (by convention, cancer researchers usually give oncogenes three-letter names). One gene could somehow spark lung, colon, pancreatic, and dozens of other cancers. Amazingly, the particular genes whose mutations could lead to cancer in humans appeared throughout the animal kingdom. The same gene could be found in mice, people, ducks, even lowly yeast cells. These genes, which when altered could make normal cells multiply out of control, have persisted for hundreds of millions of years. Clearly, they survived intact because they performed some crucial function in the cells that evolution could not afford to discard. They also sowed the seeds of cancer and offered the tantalizing possibility of curing it.

At the time that Anne McNamara's cancer struck, Robert Weinberg, a thirty-one-year-old assistant professor at the Massachusetts Institute of Technology, led the pack of scientists chasing oncogenes. Loquacious and erudite, Weinberg is physically unprepossessing. Five foot six, he sports a bushy black mustache and combs his hair horizontally across the top of his balding head. He is that rare scientist able to communicate the significance of scientific achievements, his own or others', with great clarity, insight, and humor. Weinberg is always quick to point out that others in his lab did the actual work. "They feared my presence at the lab bench; I screwed everything up," he confesses.

    Despite the professed deference Weinberg made huge contributions to basic research on cancer. He jumped into oncogene research as it was yielding its profound insights into the basic underpinnings of cancer. Among his earliest achievements was establishing that oncogenes themselves, not viruses, cause cancer. No one can say for certain what motivates the elders of the Karolinska Institute in Stockholm, but had Weinberg paid a bit more attention to a gene named neu, later Her-2/neu, he might have snared the great brass ring called the Nobel Prize.

    The big challenge in 1979 for Weinberg and the tiny band of top scientists with whom he competed was to clone a pure sample of the DNA stretch that makes up an oncogene. By the late 1970s, the science of cloning was just giving birth to the biotechnology industry and allowing researchers to study genes in detail for the first time; though by today's standards, the early technology was primitive and the process very painstaking.

    That year, while Anne McNamara was recovering from her surgery, a postdoctoral fellow in Weinberg's lab discovered neu. Lakshmi Charon Padhy, a young researcher from Bombay, extracted DNA from neurological tumors in rats and injected it into normal mouse cells, which then turned cancerous. Padhy then discovered that sometimes these cancerous mouse cells trigger an immune response in the mice because of a particular rat protein now on the surface of the mouse cells, a product of one of the genes from the rat tumors. Weinberg dubbed the gene that produced the cancerous cells "neu" because it first appeared in tumors of the neurological system.

    After naming neu, Weinberg more or less forgot about it. Over the years, he worked with it from time to time, but it never held a high priority. Other targets appeared more worthwhile. But as Weinberg would learn later, the neu protein was precisely the agent that the oncogene used to transform a normal cell into a cancer cell. If Weinberg had cloned neu, he would have had in hand the very protein the oncogene uses to make a cell cancerous. But Weinberg missed the opportunity and instead spent a frustrating two years trying to clone another oncogene called ras; it was produced in the neurological tumors Padhy and Weinberg were working with, but Weinberg went looking for it elsewhere.

    "I can flagellate myself," Weinberg says now. "If I'd been more studious and more focused and not as monomaniacal about the ideas that I had at the time, I would have made that connection." Weinberg could have carried out the key experiment years ahead of his competitors. "It would have been an overnight experiment. We just didn't do it," he admits, adding, "That's life. I can't complain or be embittered. It's not as if I didn't have my share of good luck."

    In the years to follow, achievements were such that, despite the missed opportunity of neu, Weinberg heard from friends that he would share a Nobel Prize with Bishop and Varmus. "Lots of people said to me, `You're next, Bob.'" But when Bishop and Varmus got the award in 1989, there was no third winner. Weinberg, who won every significant honor in science save the big one, tries to remain philosophical. "How much do you need to make you happy?" he asks. "And in fifty years, who will care who won the Nobel Prize?"

    No matter who got the credit, the discovery of oncogenes and the growing understanding of how they work revolutionized cancer research by providing the first understanding of the fundamental biology of the disease. A "magic bullet" therapy that would attack the disease at its root and halt its growth without inflicting any damage to healthy tissue had long been a dream in cancer treatment. But science needed a target. Now, finally, it had one. Researchers knew what they were looking for; they knew where to train their sights. In the late '70s and early '80s, scientists found dozens of oncogenes, along with a related class of genes called tumor suppressors that can also give rise to cancer. The neu oncogene, once bypassed by Weinberg, would play a key part in the struggle to bring the new genetic understanding of cancer out of the laboratory and to the patient's bedside.

CONTENTS Acknowledgments Introduction by Dr. Mary-Claire King Prologue 1. Discovering Cancer 2. A Limited Arsenal 3. A New Way of Doing Science 4. Courting the Thought Leader 5. A Fabulous Endowment 6. The First Life Saved 7. The Mayor of the Infusion Room 8. Fighting for Compassion and Access 9. Trials and Errors 10. Failure to Accrue 11. Strawberries and Champagne 12. Springtime in L.A. Epilogue Notes Index