The cell game sam waksals fast money and false promises and the fate of imclones cancer drug

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The

Cell Game
Sam Waksal’s Fast Money
and False Promises–and the Fate
of ImClone’s Cancer Drug

Alex Prud’homme

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To Sarah


Scientific theories . . . begin as imaginative constructions. They begin, if
you like, as stories, and the purpose of the critical or rectifying episode in
scientific reasoning is precisely to find out whether or not these are stories
about real life.
—Peter Medawar, Pluto’s Republic
There is a weird power in a spoken word . . . And a word carried far—very
far—deals destruction through time as the bullets go flying through space.
—Joseph Conrad, Lord Jim

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Contents
Epigraph

iii

Prologue

vii

PA R T O N E : THE $2 BILLION ANTIBODY
1. Cancer Cells Are Smart

3

2. The Idea of the New

17

3. Family Business

42

4. The “Miracle”

67

5. Small and One-Armed

89

6. A Very High-Risk Opportunity

117

7. The $2 Billion Antibody

140

PA R T T W O : REFUSAL TO FILE
8. The Letter

167

9. “We Screwed Up”

185

PA R T T H R E E : CLINICAL TRIAL
10. Inquiries

205

11. The Disconnect That Wouldn’t Go Away

219

12. Who Knew What and When?

235

13. Coincidences Piling Up

261

14. In the Light of October

277
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Contents

PA R T F O U R : THE ONCE AND FUTURE MIRACLE DRUG
15. Art, Death, and Taxes

313

16. Icarian Actions

335

Epilogue

355

Notes

369

Index

393

Acknowledgments
About the Author
Credits
Cover
Copyright
About the Publisher

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Prologue

t 9:01 A.M. on December 27, 2001, an unemployed, 27-year-old actress named Aliza Waksal sold 39,472 shares of a small Manhattan
biotech firm called ImClone Systems, Inc. It netted her some $2.5 million. At 9:41 A.M., Jack Waksal, Aliza’s 80-year-old grandfather, sold approximately 111,336 shares of ImClone, for about $7 million. Both
trades had been allegedly prompted by Sam Waksal, who was Aliza’s father and Jack’s son; he was also the cofounder and CEO of ImClone.
A short while later, Sam attempted to transfer an additional 79,797
shares of his own ImClone holdings—worth some $5 million—into his
daughter’s Merrill Lynch account for another sale. His instructions said
the stock transfer was “urgent” and “imperative.” But Merrill compliance officers grew wary. This was not normal behavior for a CEO and
his family. Because Sam was a company insider, his second trade in
Aliza’s name was denied. It didn’t take long for word of this activity to
filter into Wall Street, where the rumor mill reported something fishy at
ImClone Systems.
In 2001 ImClone was the undisputed star of biotech. A small Manhattan firm, it owned the license to the hottest cancer drug of the moment—a monoclonal antibody called Erbitux—in the latest class of

cancer treatments, so-called targeted therapies. Health care was now a
$1.3 trillion industry, and cancer drugs alone constituted a $10 billion-ayear business. A flurry of articles and a 60 Minutes story had hailed targeted treatments, and Erbitux in particular, as the biotech equivalent of
“smart bombs,” which promised a new era in the war on cancer.

A

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“Erbitux is going to be huge, one of the biggest drugs in the history
of oncology—a drug that is going to alter the way cancer therapy is
done from now on,” Sam declared with an intense, nearly evangelical
fervor. And then he’d add: “This drug will be a billion-dollar-a-year
product.”
He was a charming, reedy, olive-skinned man in his mid-50s, with
thinning dark hair, roaming almond-shaped eyes, and a tricky grin. He
had cofounded ImClone in the early 1980s with his younger brother,
Harlan, to make a fortune conquering “big” diseases such as AIDS and
cancer. After years of failure, ImClone had what every biotech company
in the world wanted: Erbitux appeared to be a “silver bullet,” a seemingly magical cancer drug that would not only help thousands of dying
patients, but would also make its sponsors rich and famous.
Sam spent years refining his pitch for Erbitux at investor meetings
and leading hospitals across the country, in the halls of Congress, at
biotech conferences in Europe and Japan, he’d let people in on a little
secret: ImClone is no ordinary investment, he seemed to whisper. Sure, Erbitux will soon be a billion-dollar-a-year drug, but it’s more than that. Much more.
This is a miracle compound, a cutting-edge biopharmaceutical breakthrough. It will

save the lives of thousands of dying cancer patients, and could change the very nature
of science. Your investment will bring you not only gold but glory—you could help us
to make history!
It was a very seductive message, coming from a very persuasive
man, and many bright and substantial people bought into it. Noted financiers like Robert Goldhammer, former vice chairman of Kidder
Peabody, joined the ImClone board. So did world-famous oncologists
like Dr. Vincent DeVita, the former head of the National Cancer Institute. Twenty-six leading hospitals around the nation, led by the
esteemed Dr. Leonard Saltz, of Memorial Sloan-Kettering, had participated in the drug’s clinical trial.
Sam had whetted investors’ appetites by predicting that his drug
would be on the market by June 2002, well ahead of its nearest competitors—AstraZeneca’s Iressa and OSI Pharmaceutical’s Tarceva, which
were at least a year or two behind (a number of other targeted treatments were behind them, too). In the highly competitive and lucrative
pharmaceutical business, such a “first-mover” advantage to market can
be critical to a product’s success. The market responded by pushing
ImClone’s stock price up in little excited jumps.
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All Erbitux had to do was to pass muster with the U.S. Food and
Drug Administration (FDA), the federal body that regulates new drugs.
That wouldn’t be a problem, Sam promised, because in February the
agency had granted his drug special “fast-track” status, the quickest
route to approval. Besides, the data spoke for itself: to win the FDA’s
blessing ImClone had to prove that Erbitux works to quell tumors in 15
percent of the patients in clinical trials; when used with chemotherapy,
Erbitux had proved effective in 22.5 percent of patients—far more than
what the FDA required.
“Unless I’m sitting here and just boldly lying to you, which I’m not
in the habit of doing, I am telling you categorically the FDA told us that

these studies will stand alone as full studies for approval,” Harlan Waksal assured an analyst in the spring of 2001. “We believe we will cruise
through [the FDA approval process]. There will be a groundswell of activity . . . because this drug is setting a new standard. There’s never been
a drug that’s been able to achieve this [result].”
The press began to run prominent stories about the drug, and ImClone employees, and even their friends, were bombarded with requests
from cancer patients around the country desperate for “compassionateuse” access to the still-experimental drug. ImClone galvanized the entire
biotech market, and in September the company signed a record-setting,
$2 billion partnership with pharmaceutical giant Bristol-Myers Squibb.
From April to July, ImClone’s stock price surged from $27 to $53 per
share. By early December it had reached $75 a share, and Sam and Harlan Waksal had exercised options with a combined worth of some $111
million.
AND NOW, on December 26, 2001, just as years of painstaking work
were about to pay off, something was going wrong. Sam had been vacationing on the resort island of St. Bart’s, partying with his art dealer,
Larry Gagosian, and Harvey Weinstein, of Miramax, when his brother
called with bad news: the FDA was about to reject Erbitux—not because the drug didn’t work, but because ImClone’s data was sloppy and
incomplete.
Keeping mum, saying he’d return to the resort island soon, Sam immediately jetted back to New York on his leased private jet. Arriving
back at his 5,000-square-foot loft in SoHo that night, he began to work
the phones—first calling his father, Jack, and then, the next morning,
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Prologue

his daughter. Unbeknownst to almost everyone, Sam—the highestpaid CEO in biotech—was carrying a personal debt of $80 million, $65
million of which was on margin, secured by his ImClone stock. His
monthly margin bill was a cool $800,000. If ImClone collapsed, he
would be ruined. He panicked.
Early on the morning of the 27th, Sam instructed Aliza to sell her

shares. She sold at $63.20 a share, and the stock began to head down toward $60. Sam attempted to shift some of his own shares to her account. He knew the SEC monitored stock trades by company insiders
and their families, but he didn’t stop to think about what he was doing;
he was just acting. For years he had shuffled money offshore, or through
an account he had secretly established in Aliza’s name—he’d forged her
signature—and he figured it would all work out in the wash. He was
doing good for humanity; his drug was about to change cancer medicine. So what if he cut a few corners? But just in case things didn’t work
out as planned, he took out an insurance policy by buying ImClone “put
options” through an anonymous Swiss bank account: if the stock price
dropped dramatically, he’d profit by betting against his own company.
At noon, Sam and Harlan—skiing with his family in Telluride—
began frantically calling a senior official at the FDA’s Center for Biologics to find out if Erbitux would be rejected. The official had no
comment.
At 1:43 P.M. that afternoon Martha Stewart had Merrill Lynch execute the sale of all her 3,928 shares of ImClone, for $228,000. (She
made a relatively insubstantial profit of $64,000.) Also at 1:43, she called
Sam’s office. His phone log reads: “Martha Stewart . . . something is
going on with ImClone and she wants to know what . . . She is on her
way to Mexico . . . she is staying at Los Ventanos.”
About an hour later, a Merrill Lynch biotech analyst got on the
squawk box to alert the firm’s 15,000 brokers: it was rumored that the
FDA was about to reject Erbitux. ImClone looked vulnerable. “Sell!”

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PA R T ONE

THE $2 BILLION
ANTIBODY

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ONE

Cancer Cells Are Smart

ix 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

S

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THE CELL GAME

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 tu4


Cancer Cells Are Smart

mors 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
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THE CELL GAME

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
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Cancer Cells Are Smart

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
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THE CELL GAME

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
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Cancer Cells Are Smart

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
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THE CELL GAME

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 may have some 10,000 EGF receptors, cancer
cells can have a million or more EGF receptors.

In 1980, it was discovered that a viral oncogene had an internal signaling enzyme called a tyrosine kinase, which stimulates cell growth. Dr.
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Cancer Cells Are Smart

Stanley Cohen discovered that the portion of the EGF receptor inside
the cell was also a tyrosine kinase. His work on EGF and its receptor
would win Cohen the Nobel Prize in Physiology and Medicine, and
caught the attention of John Mendelsohn and his band of researchers at
UCSD. Also in 1980, Dr. Michael Sporn and Dr. George Todero published a paper in The New England Journal of Medicine that established the
autocrine hypothesis—that cancer cells can bypass restrictions on their
growth by making their own growth factors and “autostimulating” receptors on the cell’s surface. The growth factor was the mechanism that
triggers cell proliferation. This insight suggested wide new possibilities
for cancer treatment.
“If we can block the function of the EGF receptor, will that stop
cancer cells from growing?” Mendelsohn and Dr. Gordon Sato, his colleague at UCSD, looked at each other with eyebrows raised. It was now
the fall of 1980, and the rangy, energetic Mendelsohn and the shorter
and quieter Sato would spend weeks brainstorming about what makes
cancer cells tick.
Gordon Sato was a nisei, a second-generation American of Japanese
descent, and during the Second World War he had been interned in a
camp in California. After the war he worked as a gardener: while using
blood from a slaughterhouse as a fertilizer, he became interested in
serum and in learning about how things grow. The president of CalTech
was impressed with Sato’s inquisitive mind and sponsored his formal
education and Ph.D. In 1980, Sato was just finishing a decade’s worth of
research that demonstrated that serum is required for cells to grow in
culture because it provides growth factors.
Sato and Mendelsohn enjoyed each other’s company and the intellectual challenge of imagining what was happening inside the body at a

microscopic level. Their speculations required deep scientific knowledge, rigorous medical training, creative intuition, and a degree of stubbornness occasionally leavened by flights of pure imagination. Two
decades later, Mendelsohn would look back at this rolling conversation
with Sato as the moment when “all sorts of half-formed ideas and vague
questions were brought into sharp focus.” It was the kind of freewheeling and deeply penetrating scientific discussion that he wished he’d had
hundreds of times in his life but in fact has had only a few times.
“Cancer cells are smart,” Mendelsohn observed, meaning they are
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THE CELL GAME

cumvent chemotherapy. The word cancer is derived from the Greek word
for “crab”: the disease seems to crawl relentlessly throughout the body;
for centuries it was tantamount to a death sentence.
By 1980, it was known that EGF is expressed in a third of all cancers—including tumors of the head and neck, gastrointestinal tract,
lung, kidney, breast, and prostate—and several researchers began to research ways to block EGF receptors (EGFr) as a means of attacking the
disease. This approach was met with a degree of skepticism. At the time,
many in the medical community considered EGF a poor therapy target
because it is found in healthy as well as cancerous cells, raising the
specter of significant side effects if the growth factor were blocked.
Mendelsohn and Sato believed that healthy cells had other growth
mechanisms that could compensate for the loss of EGF function.
In the fall of 1980, Sato said: “John, you have a background in immunology and the cell’s growth cycle. I have a background in growth
factors. Let’s sit down and try to figure out a way to block cancer cell
growth.”
If they could block the receptor, they wondered, would that stop
the tumor from spreading? Theoretically it would.
Put simply, if the EGF could not bind to its receptor, and thus

could not activate the tyrosine kinase, then a cancer cell would not be
able to proliferate. Put more completely, Mendelsohn and Sato hypothesized that a monoclonal antibody—an immune system protein created
in the lab rather than in the body—that binds to EGFr and blocks the
binding of either EGF or TGF-a (transforming growth factor-alpha)
could prevent cell proliferation by inhibiting the signaling pathways that
depend on EGFr.
In explaining to laypersons how this might work, Mendelsohn said:
“If you think of the receptor as a lock, and the growth factor as a key,
then the monoclonal antibody works just like sticking gum in the lock. It
blocks it up.”
For the next two years Mendelsohn, Sato, and a small laboratory
team that included Tomo Kawomoto and Sato’s son, Denry, worked intensively to develop a monoclonal antibody from mouse cells that
would attach to the EGF receptors before the growth factor could. It
was slow and grueling work. Finally, the antibody that proved most effective was named “225” because it was the 225th antibody they had
tested. (They were conducting experiments in test tubes. The “C” in
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Cancer Cells Are Smart

C225 stands for “chimera,” and would be added later. In Greek mythology a chimera is a monster made of incongruous parts—a lion’s head, a
goat’s body, and a serpent’s tail, say. A “chimeric antibody” is made up of
part mouse and part human protein.)
AT THIS POINT different cancers were treated as discrete diseases: lung
cancer was treated differently than, say, head-and-neck cancer. But in
fact as cancer cells metastasize they travel all over the body, so that cancerous cells from a patient’s leg could end up in his brain. If C225
worked to block tumor growth, the UCSD researchers concluded, then
someday it might be possible to tailor a therapy to combat a type of cancer, regardless of where it originated. Today such “targeted therapy” is
at the center of modern oncology. But at the time it was a novel approach, and many cancer traditionalists resisted the approach.
When Mendelsohn and Sato applied for funding from the NCI in

1982, they were turned down. “They felt it wouldn’t work,” Mendelsohn
recalled, a bit stiffly. “There’s always conservatism in science. Some new
ideas are not seen as plausible at first.”
Relying on funds from philanthropies, he and Sato pressed on and created a nude mouse colony, one of the first in America, in which to study
tumor growth. When they showed that C225 indeed stopped the growth
of tumors in mice, Mendelsohn was ecstatic. This was the first real indication that they were onto something, that their wild ideas about “putting
gum in the lock” might actually prove correct. But he knew enough not to
get carried away. “You can dream of the potential, but, well, a lot of times
things are discovered that don’t end up being important therapies.”
In 1983 and 1984, Mendelsohn, Sato, and their colleagues published
a series of papers demonstrating that blocking the EGFr with the antibody 225 could inhibit the spread of cancer cells, both in culture and in
human tumor xenografts; further, it inhibited the activity of the tyrosine
kinase. As things turned out, they had targeted a cellular oncogene. This
novel approach—inhibiting tyrosine kinases and oncogene products—
has been expanded to include numerous other targets. There is evidence
that the combination of an EGFr inhibitor like C225 and chemotherapy
or radiation is especially effective against tumors. “I believe this will be
the major way that agents that block signaling pathways will be used in
the clinic [and] will enhance the efficacy of cancer therapy,” Mendelsohn predicts.
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