Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (26 page)

By 1980 C. Gordon Zubrod, director of the medical cancer program at the NIH Clinical Center, was forced to pay homage to the contribution of serendipity. He woefully concluded: “For the most part, the original discoverer of biological activity [of cancer drugs] was not aiming directly at discovering drugs for treatment of cancer. The original rationale for the biological study of a drug that later is proved to cure cancer may come from almost anywhere—basic research, targeted research, university, industry—but mostly from areas other than cancer. So one cannot program the initial discovery of drugs.”
²⁰

Michael Shimkin, a longtime NCI physician-investigator, in 1983
astutely likened the national cancer activities to the Strategic Air Command: “One third of the force is always in the air, coming and going to project site visits, reviews, conferences, and meetings in which the same people talk on the same subjects to the same audience…. It is time to try longer investments in smaller laboratories, and leave them alone to reach for the brass ring.”
²¹

In 1986 a report in the
New England Journal of Medicine
shattered the myth of progress and boldly declared that “we are losing the war against cancer.”
²²
This assessment was based on hard statistics. Combination chemotherapy had yielded amazing success against childhood leukemia, but the overall number of these cases was too small to have had any real impact on national cancer statistics. By this time, the government had spent upward of $8 billion through a vast national superstructure. One critic estimated that a
trillion
dollars had been spent on cancer treatment and research since the beginning of Nixon's war on cancer.
²³

In 1997 biostatisticians John C. Bailar III and Heather Gornik reported an updated and more sophisticated analysis entitled “Cancer Undefeated” in the same journal.
²⁴
This showed a 6 percent
increase
in age-adjusted mortality due to cancer from 1970 through 1994. The best strategy against cancer, they urged, was prevention, which could be promoted by convincing people to quit smoking and by urging doctors to use screening methods, such as mammography, Pap smears, and colonoscopy, to detect cancers while they were still curable.

Only Taxol, originally isolated from the bark of a yew found in the Pacific Northwest, finally achieved FDA approval in 1992 for use in the treatment of breast, lung, and ovarian cancers.
²⁵
Indeed, Taxol was the greatest treasure find in the government's thirty-year screening program. Marketed by Bristol-Myers, it proved to be the first billion-dollar blockbuster drug in the history of cancer chemotherapy.

Overall, the few dramatic increases in cure rates and patient longevity occurred in a handful of less common malignancies—including Hodgkin's lymphoma, some leukemias, cancers of the testes and thyroid gland, and most childhood cancers. Sadly, these successes have not had a major impact upon the inexorable prevalence of
cancer in our society. And the fact cannot be escaped that many of these successes came about in the early days of the war on cancer, or before war was even declared.

The Pap Smear

In 1928 the Greek-American pathologist George Papanicolaou, while investigating the reproductive cycle by using vaginal smears obtained from human and animal subjects, observed the presence of cancer cells in people who were not known to be sick. That a cancer could be found this early, through the examination of cells (cytology), was a totally revolutionary idea. Its elaboration is a classic example of medical serendipity by which an important discovery about cancer came from research in an unrelated area. (Papanicolaou said the first observation of cancer cells in a smear of the uterine cervix was “one of the most thrilling experiences” of his entire scientific career.)

Papanicolaou went on to develop the famous Pap smear test—so called from the first three letters of his name—which was not routinely adopted until the early 1940s. Cervical cancer, once the leading cancer killer among American women, is now, thanks to Pap smears, a distant seventh.

In June 2006 the FDA approved a new vaccine—Gardasil, made by Merck—which had proved highly effective at preventing cervical cancer in women. It works by providing immunity to two types of a sexually transmitted virus (human papilloma-viruses) that cause 70 percent of the cases of the disease.

By the mid-1990s the National Cancer Institute redirected money to fundamental research into molecular processes, the relationship between diet and cancer, and prevention. The statistics, however, remain alarming. In 2004 almost 564,000 Americans died of cancer, and nearly 1.4 million new cases are expected to be diagnosed in 2006. In recent years, cancer has surpassed heart disease as the top killer of Americans younger than 85. In people 45 to 64 years old,
cancer causes more deaths than the next three causes (heart disease, accidents, and stroke) put together. Such dismal statistics are all the more upsetting when compared with those for heart disease and stroke. Age-adjusted death rates for these diseases, which strike mostly older people, have been slashed in the United States by an extraordinary 59 percent and 69 percent, respectively, during the last five decades.

Following the testing of nearly half a million drugs, the number of useful anticancer agents remains disappointingly small. Expressions of discontent with the methodology of research and the appalling paucity of results were, over the years, largely restricted to the professional literature. However, in 2001 they broke through to the popular media. In an impassioned article in the
New Yorker
magazine entitled “The Thirty Years’ War: Have We Been Fighting Cancer the Wrong Way?” Jerome Groopman, a respected clinical oncologist and cancer researcher at Harvard Medical School in Boston, fired a devastating broadside. “The war on cancer,” he wrote, “turned out to be profoundly misconceived—both in its rhetoric and in its execution. The high expectations of the early seventies seem almost willfully naïve.” Regarding many of the three-phased clinical trials, with their toxic effects, he marveled at “how little scientific basis there was and how much sensationalism surrounded them.” Groopman concluded that hope for progress resided in the “uncertainty inherent in scientific discovery.”
²⁶

Groopman's pull-no-punches article ripped off the curtain to expose the failings of those claiming to be wizards. The sad reality is that chemotherapy drugs are primitive, blunt-edged weapons of mass destruction. They interfere with the cellular process involved in the rapid divisions of cancer cells, but also act on other body cells with high metabolic rates and high cell turnover, including the bone marrow, intestinal wall, and hair follicles. Chemotherapy's ill effects on the bone marrow—the very foundation of the body's immune system—often result in blood-deficiency diseases (diminished white blood cells, decreased platelets, aplastic anemia) that lead to overwhelming infections. Furthermore, chemotherapy is of little or no use against many common cancers, including those that invade the gastrointestinal and
respiratory tracts. It was never a very good answer to the problem of cancer.

Three years later, in 2004,
Fortune
magazine published a cover story lamenting the sad fact that “we're losing the war on cancer” due to a misguided approach. The emphasis, it asserted, should be on prevention and early detection.
²⁷

Interferon

Ironically, the NIH's effort in the 1960s and 1970s to find a cancer virus led to a discovery that was of great value years later in another field. By the 1980s this effort had run its course. Only limited success had been achieved, most notably the discovery of virus particles in cells of lymphoma patients in Africa—the Epstein-Barr virus, the causative agent of Burkitt's lymphoma—and of an antiviral protein given off by cells when they were attacked by viruses. This protein, dubbed interferon, became an overhyped biotechnology product. But the viral work brought scientists a wealth of knowledge about retroviruses, which can copy their own RNA information into the DNA of the host cell. When HIV arrived in the United States, scientists were able to promptly identify the retrovirus, work out its biomechanisms of growth and replication, and target its cellular weak spots.

The truth remains that over the course of the twentieth century, the greatest gains in the battle against cancer came from independent research that was not under any sort of centralized direction and that did not have vast resources at its disposal. As we have seen, such research led to momentous chance discoveries in cancer chemotherapy and a greater understanding of the mechanisms of the disease that have resulted in exciting new therapeutic approaches.

21

Lessons Learned

What has the saga of the discovery of anticancer drugs taught us?

The reigning image for all diseases in Western culture is that of war. It is in the area of cancer that military metaphors are most often applied. We speak of how the disease “strikes” or “attacks,” setting in motion the “body's defenses.” We speak of “struggle” and “resistance” in the “battle against cancer.” Modern medicine hunts for “magic bullets” in the “crusade” or “war” against this malignant foe. In exploring the cultural mythologizing of disease in her book
Illness as Metaphor,
writer Susan Sontag condemns the militaristic language around cancer as simultaneously marginalizing the sick and holding them responsible for their condition. Yet one overwhelming fact persists: cancer will kill more Americans in the next fourteen months than perished in all the wars the nation has ever fought—
combined.

Biomilitarism, however, oversimplifies the problem by clouding the fact that cancer is a catchall term for a class of more than 110 separate malignancies. One military metaphor labeling America's cancer campaign as a “medical Vietnam” proved to be woefully apt. Francis Moore's congressional testimony in 1971 and the Institute of Medicine's analysis on “the war against cancer” were sadly prophetic. No clinically important scientific breakthrough, Moore argued, had ever resulted from such directed funding.

It is clear that programmatic research dictates unhealthy rigidity that inhibits creative minds and constrains a critical feature of the
discovery process: serendipity. The more narrowly a scientific goal is defined, the more the discovery process is obstructed. Scientific discoveries so often happen when they are least expected.

Cancer has for too long been treated with some combination of surgery, radiation, and chemotherapy in a program derided by some as “slash, burn, poison.” In this war on cancer, in which all cancers were considered the same, this was a scorched-earth policy. A new understanding of this enormously complicated disease was desperately needed. Fortunately, by the 1970s, molecular biologists made revolutionary insights into the characteristics within the cell that lead to the initiation of cancer. But these resulted from determined efforts in the fields of cell biochemistry, tumor virology, and medical genetics.

There are more than ten thousand billion cells in the human body. In most tissues, cells are continually dying and being replaced, and control of the equilibrium is critical in maintaining the normal architecture. The complex biological blueprints for the behavior of cells are controlled by their genes. Humans have 20,000 to 25,000 distinct individual genes, and genetic information is carried in DNA molecules. The human genome is estimated to include 3.08 billion units of DNA. The complexity of what the cell's machinery can generate is indicated by the fact that a few thousand genes can make trillions of combinations of proteins. Cells multiply ten million billion times during the course of each human lifetime. Mutations, random changes in the design of a gene's DNA structure, occur constantly, because there is an intrinsic error rate when DNA is copied. In extreme errors, the cell will self-destruct; otherwise, the aberrant cell survives.

Starting in the last decades of the twentieth century, sophisticated genetics and molecular biology have been aimed toward a more precise understanding of the cell's mechanisms. Yet, even here, chance has continued to be a big factor. Surprising discoveries led to uncovering cancer-inducing genes (oncogenes) and tumor-suppressing genes, both of which are normal cellular genes that, when mutated, can induce a biological effect that predisposes the cell to cancer development. A search for blood substitutes led to anti-angiogenesis drugs. Veterinary medicine led to oncogenes and vaccine preparations to tumor-suppressor genes. In one of the greatest serendipitous discoveries of
modern medicine, stem cells were stumbled upon during research on radiation effects on the blood.

Experience has clearly shown that major cancer drugs have been discovered by independent, thoughtful, and self-motivated researchers—the cancer war's “guerrillas,” to use the reigning metaphor—from unexpected sources: from chemical warfare (nitrogen mustard), nutritional research (methotrexate), medicinal folklore (the vinca alkaloids), bacteriologic research (cisplatin), biochemistry research (sex hormones), blood storage research (angiogenic inhibitors), clinical observations (COX-2 inhibitors), and embryology (thalidomide).

Part III

A Quivering Quartz String Penetrates the Mystery of the Heart

Experimental ideas are often born by chance, with the help of some casual observation. Nothing is more common, and this is really the simplest way of beginning a piece of scientific work.

—C
LAUDE
B
ERNARD
, 1865