The Cell Game

Sam Waksal's Fast Money and False Promises--and the Fate of ImClone's Cancer Drug

Alex Prud'homme

• Publisher: Harper Business
• Year: 2009
• Topic: Business
• eBook ISBN:
  9780061865626
• Subtopic: Business Biographies
• Index: Business

PART ONE

THE $2 BILLION ANTIBODY

ONE

Cancer Cells Are Smart

Six feet tall, trim, with white hair, a long-featured face, and intelligent hazel eyes, Dr. John Mendelsohn was one of the most accomplished cancer fighters in the world. He wasn’t loud or physically imposing, but his fecund mind, forthright demeanor, and implacable resolve drew people to him naturally. The son of a traveling salesman from Cincinnati, Mendelsohn had proven himself a brilliant researcher and teacher, an exceptional administrator and fund-raiser. Yet he was not the kind who took his talents for granted. John Mendelsohn was driven to “use science to improve life.”

One prize had eluded him, maddeningly, for over two decades: the commercialization of the monoclonal antibody C225, a potentially revolutionary cancer drug. C225, later called “Erbitux,” was Mendelsohn’s brainchild. It had alternately inspired and vexed him since 1980, when he and a small group of collaborators at the University of California, San Diego (UCSD), had made their earliest discoveries about “targeted treatment” cancer drugs. The lack of time and money had been their main constraints, as in most creative undertakings, but their novel ideas about how to fight cancer had also met with academic hostility and commercial resistance. Several times Mendelsohn had arranged deals with pharmaceutical companies to develop C225, only to have the agreement fall apart. He was quick to note that this is the nature of science, that developing new drugs is a risky and difficult business, that any worthwhile quest requires trial and error. “You haven’t crossed home plate until you’ve crossed home plate,” he’d say stoically.

Mendelsohn was convinced that C225 would one day extend the lives of many cancer victims, that it would be the most significant personal contribution he could make to the war on cancer. When he spoke of his campaign to bring the cancer drug C225 from idea to the laboratory to the marketplace and “get it into patients,” Mendelsohn’s voice would tighten, his brow would furrow, and his eyes would blaze intensely—revealing for just a moment the steely determination that lay beneath his genial exterior.

At the end of May 2001, Mendelsohn, who was 64, was the guest of honor at a luncheon in New York City for more than 100 members of the nation’s social and intellectual elite. The gathering was a fund-raiser for Houston’s M. D. Anderson Cancer Center, the nation’s largest cancer hospital, which Mendelsohn had run since 1996. The lunch was attended by President George H. W. Bush, a friend from Houston who sat on the board of visitors at the Anderson, and it was hosted by Martin Zweig, a Wall Street tycoon. Encompassing the entire top floor of the opulent Pierre Hotel, on 59th Street and Fifth Avenue, the Zweig apartment was like a castle in the sky: the walls were eclectically decorated with Renoir paintings, Beatles memorabilia, and the sparkling white dress Marilyn Monroe had worn to sing “Happy Birthday” to President Kennedy in 1962. Framed by its expansive windows were breathtaking views over the long greensward of Central Park and around the gray, crenellated cityscape of midtown Manhattan. As he stood in that fabulous aerie at the start of the new century, nibbling canapés, graciously accepting compliments and some $475,000 in donations for M. D. Anderson, no one could begrudge Mendelsohn his feelings of relief, fulfillment, and cautious optimism.

The week before, C225 had been the star of the 37th annual ASCO conference (American Society for Clinical Oncology), the largest gathering of cancer specialists in the world. There, ImClone Systems, Inc., the small Manhattan biotech firm that had licensed Mendelsohn’s drug, had made a stunning announcement: in clinical trials, 22.5 percent of colon cancer patients who had used a cocktail of C225 and irinotecan, a standard chemotherapy, had responded positively, meaning their tumors shrank by more than fifty percent. This was the best response rate ever achieved in patients who previously had no hope for survival. The oncology community had reacted with a thundering ovation. There had been a burst of media coverage. ImClone’s stock began to climb. And, to cap it all off, ImClone’s CEO, Sam Waksal, had begun secret negotiations with the pharmaceutical giant Bristol-Myers Squibb for a landmark deal that finally promised to bring C225 to market.

Circulating in the noosphere of the Zweig apartment, Mendelsohn’s gaze slipped out the window, and over the breathtaking views to fix on the bright, indefinite horizon. After all of the false starts and setbacks, he wondered, what could possibly go wrong now?

THE HISTORY OF modern biotechnology began on April 25, 1953, when James Watson and Francis Crick announced in the British journal Nature that they had unlocked the three-dimensional structure of the DNA (deoxyribonucleic acid) molecule. DNA is the “master molecule,” the structure of which is encoded with the information needed to create and direct the chemical processes of life. The gracefully spiraled structure, known as the double helix, was the key to understanding the technology of life. Watson and Crick’s discovery would earn them the Nobel Prize (Watson was only 34 years old at the time), and would raise many intriguing questions, foremost of which was: Could DNA be manipulated? Could life itself be manipulated?

It was a question, and a challenge, that would motivate an entire generation of scientists to produce some of the most exhilarating medical discoveries in history. It would also set off a philosophical debate: biotechnology was seen as either a Promethean quest to save mankind or a Faustian meddling. In his 1969 book about the discovery of DNA, The Coming of the Golden Age: A View of the End of Progress, Gunther Stent described man’s ability to manipulate DNA as a sign of the end to social and economic evolution.

As a Harvard junior in 1957, John Mendelsohn became the first undergraduate student in the lab of James Watson. There Mendelsohn was introduced to the exciting new field of molecular biology, which became his intellectual passion in life.

In his first two years at Harvard, Mendelsohn had studied physics and chemistry, but found that he wasn’t enjoying himself. As a sophomore he dropped organic chemistry and physics and took a range of humanities courses—philosophy, the government of the Soviet Union—and slowly came to the conclusion that he did not want to devote himself to pure science. How would he apply himself, then? At the time, Watson and his collaborators were learning to apply molecular biology and genetics to the study of cells and the problems of human disease. Once he learned of it, this combination of hard science and humanistic medicine immediately appealed to Mendelsohn. “I liked people,” he’d say. “I wanted to be a doctor.” He would spend the next two years working at the Watson lab, in addition to carrying his normal course load, playing tennis, and socializing. (He met a Mount Holyoke chemistry student named Anne Charles at a party in Harvard yard; they would marry in 1963.)

The lab work was intensive and nearly all consuming, but Mendelsohn didn’t mind. He was thrilled to immerse himself in every aspect of the job—running experiments, delving into research, learning how to analyze data, and even washing test tubes. There were a dozen people in the lab, most of whom were Ph.D. candidates and postdoctoral students, each of whom had a specialty that Mendelsohn could learn from. He enjoyed toiling late into the night, over weekends, and during a hot summer. He researched bacteria and learned about the chemistry of life and how to use new technologies to answer age-old questions. He was paid a modest stipend, which barely covered his housing and food, but he probably would have paid for the opportunity to work for the “brilliant and inspiring” Watson.

Looking back on this apprenticeship, Mendelsohn would recognize these crucial years as the intellectual crucible that shaped his life’s work. “I love science,” he’d say, “I love teaching. I really love clinical medicine. If you care about what makes people tick, and they have a serious illness, then medicine allows you to get close to them very quickly. All the phony-baloney barriers go down. You help them, not only with your knowledge of disease, but with their human needs.”

Mendelsohn’s father, a classic “middleman” who traveled from store to store in the Midwest, toting a sample case full of men’s apparel—belts, suspenders, cuff links—and his mother, a housewife and active community volunteer, had not been especially inclined toward science or medicine. But they always stressed the importance of education and encouraged John to “follow your nose.”

Mendelsohn was always a voracious reader, and as an adult he would be especially drawn to books on religion, philosophy, and history. Indeed, religion is a constant theme for Mendelsohn. He was raised Jewish; his wife was raised half Quaker and half Episcopalian; and they and their three boys attended a Unitarian church. Unlike many scientists, Mendelsohn, who has attended services at synagogues, churches, and Quaker meeting houses, is unembarrassed to say: “I am a religious person.” When asked about the tension between science and religion, he answered by paraphrasing Einstein: “Science doesn’t have all the answers. When you contemplate the vastness of the universe, you have to believe in a God.”

As a 22-year-old Fulbright scholar, Mendelsohn spent a year at the University of Glasgow in Scotland. During the week, he’d study nucleic acids and grow cells in test tubes in the lab. On weekends, he’d backpack through the Scottish highlands—a terrain he fell in love with and still returns to. On holidays, he’d hike the Alps or tour the Continent in a rented car with friends from home. In his diary from this year in Scotland, he wrote that he had decided once and for all to dedicate his life to “using molecular biology to cure human disease.”

Mendelsohn returned to the States and graduated from Harvard Medical School in 1963. Over the next three years he did his medical residency at Harvard’s Peter Bent Brigham Hospital (now Brigham and Women’s Hospital), then went on to study chromosomes at the National Institutes of Health (NIH) in Washington, D.C. At Washington University in St. Louis, he taught and researched hematology and oncology. It would prove a fortuitous combination of experiences and disciplines.

IN 1970, the biotech industry did not yet exist and San Diego, California, was not yet one of its most fertile breeding grounds. The war was raging in Vietnam and the nation was about to reach a defining moment. Most young people were far more turned on by tuning out and marching against the Establishment than by spending hour after grinding hour doing scientific research in a lab.

Mendelsohn headed west that year to begin his professional career on the faculty of the two-year-old medical school at the University of California, San Diego (UCSD). As things turned out, his timing and placement would be inspired.

Because cancer is such a widespread and terrible disease—it is the leading killer of Americans, after heart disease—it has long been the focus of intensive medical research. Surgery and radiation remain the most prevalent methods of fighting cancer: “the cold knife and hot rays” have proven relatively effective, “saving” nearly a third of all patients with cancer, which is to say they are still alive five years after their first diagnosis. (This number could be raised to 50 percent, Mendelsohn believed, if people would only take the basic precautions—don’t smoke, exercise regularly, eat well, and submit to regular checkups—that have proven to be useful deterrents.)

In the meantime, there has been an ongoing quest for alternative treatments. At the start of the 20th century, the American surgeon William B. Coley treated cancer patients with a rudimentary vaccine made of killed bacteria—an early example of immunotherapy, a form of medicine that helps the body’s immune system to fight disease.

In 1910, the German chemist Paul Ehrlich suggested that chemotherapy—that is, treatment with chemicals—might prove to be a “magic bullet” against disease. So-called cytotoxic (“cell killer”) chemotherapy (chemo) drugs have proven remarkably effective. Chemo treatments arrest the growth of certain tumors by interfering with cell function. But their success comes at a price. Chemo drugs are in effect poisons, the outgrowth of experiments with mustard gas in World War I, and patients using them become nauseated, shed hair, and lose their appetite and weight.

By the early 1970s, the search was on for a new kind of “magic bullet.” It was an exciting time in oncology. Much like the giant strides in physics research in the early 1900s—when Einstein, Bohr, and Heisenberg made their findings about the atom and its powers—the 1970s and 1980s witnessed an enormous upwelling in cancer research in America, with great leaping improvements in surgery and the use of X-rays, radiation, and chemotherapies. These advances were not a random accident. They were the result of a concerted and unprecedented national effort, which would provide both a conceptual launching pad and a practical framework for what Mendelsohn called the “intellectual odyssey” that led him to C225.

In 1971, President Nixon declared a national “War on Cancer,” with the objective of curing the disease in time for the nation’s bicentennial in 1976. It was a supremely worthy, ambitious and unrealistic goal. The War on Cancer was launched in the midst of the Vietnam War and had been inspired in part by NASA’s successful lunar program. Like those grandiose undertakings, the War on Cancer required millions of dollars in federal money and the establishment of a new bureaucracy—in this case, the National Cancer Institute (NCI), which would fund and oversee research into the disease.

“The analogy was the moon shots,” Mendelsohn recalled. (If America can put a man on the moon, then surely it can whip cancer!) “The feeling was that if the government was willing to bring significant financial resources to bear, there was enough known about the disease that we could make a major breakthrough.”

The NCI was smart enough not to be too rigid or specific about how its grants were used. “Scientists often do their best work when they follow their nose,” Mendelsohn says. “Often, a result is totally unexpected.” He hinted that such unexpected results were the best, or at least his favorite, kind of discovery. Nixon’s War on Cancer did not lead to victory. But Mendelsohn believed that it “paid off” in spades, because it lead to the development of important scientific tools and a vast knowledge base from which we continue to benefit.

The first step in battling cancer was to discover how its processes worked and how to interrupt them. It wasn’t easy. Part of what makes cancer so difficult to treat is that it is not just one disease: “cancer” is really an umbrella term for about 200 related diseases, each of which is driven by a different set of factors, and which behave in different ways in different patients. Lately, scientists have discovered there are 30,000 genes in the genome: about 500 of them control the critical cell functions that are involved in the proliferation and replication of cells’ DNA. When these genes begin to malfunction the cell usually dies off, which is normal; but sometimes the cells divide in an uncontrolled frenzy, which is cancer. But at the time, physicians didn’t really understand how cancer cells function.

“When I started at UCSD, in 1970, we didn’t have a clue as to what caused cancer,” Mendelsohn recalled. “The leading hypothesis was that the disease was the result of a virus,” as it often was in lab animals. Cancer was typically diagnosed by a physician looking at a biopsy, or by studying a patient’s blood through a microscope. The disease was most often treated with surgery or radiation, although doctors would sometimes consult a list of a few highly toxic chemotherapy drugs. Specific chemo drugs were prescribed for specific cancers—methotrexate for leukemia, say—and then patient and physician would essentially hope for the best. (The first successful use of chemotherapy to cure a cancerous tumor was just a few years earlier, in 1963.)

The belief that viruses were cancer agents led to an intensive period of research. Funded as part of Nixon’s War on Cancer, virus research led to several important discoveries and a far more nuanced appreciation for how genetic mechanisms worked. One of these discoveries was the recombinant DNA technique—the process of cutting and recombining DNA fragments as a way to isolate or alter genes—which has proved a huge boon to medicine. In the early 1980s, the use of recombinant DNA helped doctors figure out how the AIDS virus works relatively quickly, which allowed them to devise treatments within a few years.

Research into viruses led to a far more detailed understanding of how cells function, and a surprising discovery. Cancer in humans, it turns out, is not usually caused by a virus. Rather, it is caused when some of the cell’s own genes are disrupted and the cell begins to malfunction. Cells normally divide and multiply only as the body signals that it needs them. This process is controlled in part by oncogenes (the genes that stimulate cell growth) and by tumor-supressor genes (which inhibit cell growth). Some cancers occur when a malfunctioning oncogene sends out protein signals that set off a wild division of cells. The resulting cancerous cells spread throughout the body. The tumor-suppressor genes that would normally curtail such proliferation may also be malfunctioning.

In the 1970s and 1980s, researchers slowly built their understanding of this process. In 1977, Dr. J. Michael Bishop and Dr. Harold Varmus identified the first human oncogene, which controlled cell growth. One of the most important molecules produced by an oncogene is called the epidermal growth factor (EGF) receptor. While EGF is found in many normal cells, it is wildly abundant in most cancerous cells. The surface of cells—both healthy and cancerous—have “receptors,” which allow the EGF to bind to the cell, and thus trigger a cascade of enzymes inside the cell, which help to stimulate and sustain the tumor. But while the surface of a normal cell ...

Table of contents

• Cover
• Title Page
• Dedication
• Epigraph
• Contents
• Prologue
• Part One
• Part Two
• Part Three
• Part Four
• Epilogue
• Notes
• Searchable Terms
• Acknowledgments
• About the Author
• Copyright
• About the Publisher