Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (22 page)

Colorectal cancer is the third most common type of cancer and the second leading cause of cancer deaths in the U.S. In 2006 the American Cancer Society predicted, about 148,610 cases would be diagnosed in the United States and 55,170 people would die of it.

Colon cancer progresses through recognizable stages. It changes from a tiny polyp, or adenoma—a benign overgrowth of cells in the lining of the colon—to a larger polyp, a precancerous growth, and then to a cancer that infiltrates the wall of the colon. The final stage is metastasis, when the cancer spreads through the body.
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About 20 percent of people over the age of fifty have polyps. Polyps generally grow about a millimeter a year, and once they get to 10 millimeters (1 centimeter) they have a higher chance of being malignant. It typically takes about ten years for a benign polyp to become cancerous. While most polyps never develop into cancer, this understanding of the potential
sequence provides an important rationale for public health screening: if polyps can be detected and removed by colonoscopy, colon cancer can be prevented. (The value of screening by colonoscopy was underscored in the summer of 1985 when a colon polyp harboring cancer was removed from President Ronald Reagan, who, in his characteristically plainspoken way, explained to the public, “I don't have cancer. I had something inside me that had cancer. And they took it out.”)

Over several years it had been incidentally noted that patients taking aspirin regularly for arthritis had a decreased incidence of colon cancer. But since this primary nonsteroidal anti-inflammatory drug (NSAID) was sold cheaply over the counter, drug companies had no incentive to invest in research to determine whether it truly had anticancer effects.

Then, in the late 1970s, a physician stumbled upon amazing evidence. Dr. William R. Waddell at the University of Colorado Health Sciences Center was treating a thirty-one-year-old woman with a rare inherited condition known as familial adenomatous polyposis, or FAP. In this disease, the colon is carpeted with hundreds—in some cases, thousands—of polyps. Since these polyps invariably undergo cancerous changes in time, doctors had surgically removed her colon when she was only twenty-three. As sometimes happens to people with this condition, within a few years, noncancerous scarlike tumors called desmoids grew in her abdomen. Waddell placed her on an anti-inflammatory drug for an upset stomach, and, much to his surprise, the tumors disappeared. Wondering if the startling effect could have been caused by the anti-inflammatory, he prescribed the drug to three of the woman's relatives who also had FAP. Amazingly, the colonic polyps either completely disappeared or shrank dramatically.

Waddell knew that he had stumbled upon a major finding, but his report was rejected by major medical journals. Finally he published it in the
Journal of Surgical Oncology
in 1983.
²

Six years elapsed before Dr. Francis M. Giardiello, a colon cancer specialist at Johns Hopkins University School of Medicine in Baltimore, began a clinical trial testing an NSAID in twenty-two patients with FAP. His results showed a marked decrease in the number and
size of colon polyps, which he described as “astounding.” His 1993 report in the
New England Journal of Medicine
drew national attention, spurring basic research and clinical trials.
³

Older NSAIDS, such as aspirin and ibuprofen, work by inhibiting a pair of enzymes called COX-1 and COX-2 (for cyclooxygenase) needed to produce hormonelike substances called prostaglandins, which cause pain and inflammation. Research disclosed that the blocking of COX-2 is what actually relieves pain, whereas blocking COX-1 prevents platelets from clumping and so can cause bleeding and stomach ulcers. In response to the new finding, pharmaceutical companies designed drugs to selectively inhibit COX-2. Pfizer came up with Celebrex, and Merck, notoriously, with Vioxx. A long-term study of the effects of Vioxx in inhibiting colon polyp growth surprisingly revealed an increased risk of heart attacks and strokes, and Merck withdrew Vioxx from the market in September 2004. Pfizer continues to market Celebrex under highly restrictive guidelines. Celebrex has received FDA approval for treatment of FAP. Although their polyps are greatly reduced in number, FAP patients still need surgery.

And then a finding provided the stunning explanation for aspirin's ability to shrink polyps: colon polyps make huge amounts of COX-2, and the increased prostaglandins can help cancers flourish. Inhibiting COX-2 not only decreases pain, it may slow cell growth, promote cell death, and prevent tumors from generating blood vessels for nourishment.
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Furthermore, there is increasing evidence that drugs that block COX-2 might thwart not only cancers of the colon but also those of the breast, lung, bladder, skin, and esophagus. These cancers also make greatly increased quantities of COX-2.

As of the beginning of 2006 the National Cancer Institute has about forty studies under way that are designed to find out whether COX-2 drugs can treat or prevent various other forms of cancer. Although the Vioxx study on colon cancer was halted, no increased risks turned up in other studies, and they were continuing.

Thus, the chance observation of a single doctor thrust commonplace drugs to the forefront of cancer research.

16

Thalidomide

From Tragedy to Hope

A German pharmaceutical firm, Chemie Grünethal, stumbled across thalidomide in the 1950s while doing experiments aimed at developing new antibiotics. Searching for a simple, inexpensive method for manufacturing antibiotics from peptides—the bonds that hold amino acids together to form biologically active molecules—they produced a new molecule they called thalidomide. The company's research program was headed by an ex-Nazi officer, Dr. Heinrich Mückter, a medical scientist for the army of the Third Reich, who seized upon a surprising finding: the drug seemed to have a calming effect in animals. Based on that finding alone, in 1954 the company gave out free samples of the drug across Germany. Then, without having done any tests on either its safety or its effectiveness, the company began marketing thalidomide in 1957 as the first over-the-counter sedative. A British pharmaceutical firm, Distillers Company, signed up to distribute the drug in the UK the following year. By 1961, after a massive marketing campaign, thalidomide was the best-selling sedative in Germany and was being sold in forty-six countries throughout Europe, Asia, Africa, and the Americas.
¹

A well-known public health disaster ensued, as pregnant women who took it for morning sickness and as a sedative soon saw its horrifying effects. Thalidomide is a teratogen, an agent that causes
malformation of the fetus. In 1960 a physician in Liverpool, England, created a registry after seeing five children born without arms. The drug was withdrawn from the German and UK markets in December 1961. Two weeks later, in a one-hundred-word letter published in the
Lancet,
Dr. William McBride, an Australian obstetrician, reported severe congenital abnormalities in a fifth of women taking thalidomide during pregnancy.
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Infants born with severe cardiac and gastrointestinal malformations often did not survive their first year.

The striking defect that characterized many survivors was severely malformed or deficient extremities, a condition known as phocomelia. Belated experiments investigating thalidomide's toxicity showed that the drug could harm the embryos of mice, rabbits, chickens, and monkeys. Sadly, these experimental results were too late to alert doctors to the risks of the drug in pregnant women. Between 1957 and 1962, as many as twelve thousand children were affected, mostly in Europe, Canada, and Japan. Through the vigilance and courage of a legendary FDA official, Dr. Frances O. Kelsey, the drug was blocked in 1961 from being distributed in the United States. This incident stimulated more stringent drug regulation and strengthened the FDA through new laws. The thalidomide catastrophe was so shocking that it chilled the postwar euphoria of an imminent medical utopia.

Remarkably, within three months of McBride's alert, Gerard Rogerson, a doctor from Shropshire, England, raised the possibility, in another letter to the
Lancet,
that since thalidomide inhibits growing tissue in these circumstances, it might be investigated as an anticancer drug.
³
However, it was not until 1994, thirty-two years later, that Robert D'Amato, a member of the Judah Folkman laboratory, discovered that thalidomide acts as a mild inhibitor of the growth of new blood vessels critical to tumor formation. Thalidomide stunted fetal limb development by inhibiting the growth of blood vessels. Its potential as an anti-angiogenesis agent was overshadowed by the discovery of angiostatin.
⁴

Thalidomide's most striking effect appears to be in multiple myeloma, an aggressive cancer of the plasma cells—derivatives of white blood cells in bone marrow—that affects 50,000 people a year in the United States.
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The cancer can lead to bone pain, anemia, kidney failure,
and recurrent infections. Thalidomide currently appears to be the first new drug in three decades to have a beneficial effect on multiple myeloma. Its mechanism of action is not clear. Although the drug blocks growth of new blood vessels, this action does not appear to explain its effect. Rather, it may have a potent influence on the immune system or may even kill myeloma cells directly. It is used along with stem cell transplants.

Thalidomide is marketed by Celgene, a New Jersey–based pharmaceutical company, and most of its sales are for multiple myeloma. Since thalidomide has been known for decades and the composition can't be patented, Celgene has patented its elaborate distribution system. This involves physician training and patient education, which includes mandatory contraceptive measures. Thalidomide has many possible side effects and complications; therefore, any real hope for its use lies in the new drugs that might be derived from it—so-called analog drugs. One analog, Revlimid, is more potent and has fewer side effects.
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17

A Sick Chicken Leads to the Discovery of Cancer-Accelerating Genes

In 1909 a Long Island poultry farmer brought a Plymouth Rock hen that had developed a conspicuous tumor in its right breast to Peyton Rous, a young medical researcher studying cancer in animals at the Rockefeller Institute in New York City. The farmer, referred by his local farm bureau, feared that this might indicate an infection, such as chicken cholera, that could threaten his entire flock.

Dr. Rous took a biopsy and determined it was a malignancy of the muscle known as a sarcoma. Seizing the opportunity to work with a cancer that had spontaneously arisen in an animal, he initiated research directed toward finding the mechanism through which the tumors in one animal might be transmitted to another, in the hope of preventing it from happening. His first step was to implant a small piece of the tumor into another hen of the same species. To his excitement, a sarcoma developed.

In a series of classic experiments, he ground the tumor tissues to an ultrafine consistency and passed the material through silica filters with pores so small that they would eliminate all possible cancer cells and bacteria. As the cell-free tissues still caused the disease, he assumed the cause to be a virus. (The concept of a virus at this time was poorly understood. A virus was seen as an invisible poison that seemed to have a life of its own.)
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Rous was able to transmit the tumor through
several generations of hens. He was the first to demonstrate that a virus could cause a malignant tumor.
²

Rous published his findings in 1911 in the
Journal of Experimental Medicine,
the official publication of the Rockefeller Institute.
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The scientific community scoffed at his theories, as the prevailing dogma held that most cancers were not contagious or the result of infection. Experience had long implicated environmental agents, such as chimney ash, but how this or other chemicals might cause malignant tumors remained a mystery. Some cancers were known to run in families, but there was no understanding of the hereditary factors. “These revolutionary findings were generally disbelieved,” Rous recalled decades later in a 1966 interview. His peers believed that either the growths were not tumors or the agents were tumor cells the filters had let through. Discouraged by the lack of support, Rous soon abandoned these experiments, bitterly deeming cancer research “one of the last strongholds of metaphysics.”

The idea of a viral cause for cancer was, for the most part, put into the mental attic of researchers for decades thereafter. It was not until the 1940s that the Rous sarcoma virus was identified by electron microscopy. As twentieth-century medicine progressed, researchers came to better understand viruses and even came to attribute viral origins to some tumors as well as to leukemia.
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In 1955 the first issue of the new journal
Virology
appropriately carried an article on Rous's work on chicken sarcoma.

Fifty-five years after his breakthrough discovery, at age eighty-five, Peyton Rous was awarded the Nobel Prize in 1966. The insight—the “pregnant hint,” as Walter B. Cannon liked to say—had to await a favorable intellectual climate and technologic advances.

To reproduce, cells and many viruses must copy their DNA into RNA. The Rous sarcoma virus, like some other tumor-causing viruses, was known to consist not of DNA but of RNA. As early as 1963, Howard Temin conjectured that this virus's lifestyle was to insert itself into a host cell's DNA, where it would reproduce viral RNA. This idea—revising the accepted concept of the flow of genetic information from DNA to RNA—was largely rejected until 1970 with the
independent discovery by Temin and David Baltimore of reverse transcriptase, an enzyme that directs such an operation. Such viruses came to be termed “retroviruses,” and it was speculated that the viral RNA in a host's cell not only facilitates the virus's replication but might remain dormant until expressed as a cancer-causing infectious agent, perhaps activated by external carcinogens such as radiation, various chemicals, or even other viruses—in effect, commandeering the cell's genetic machinery.