Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (24 page)

But knowledge of how to do that is still lacking in most cases. The magic bullet has yet to be found. Many of the new cancer drugs are targeting things in cancer cells that may or may not be driving that cancer. The drugs in use by many patients in clinical trials work for only a minority. In truth, scientists cannot really identify, in most cases, the Achilles’ heel of a cancer cell or understand very well the targets at which they are shooting. And as the tumor grows, the target is ever changing. The successes claimed seem, at times, to be merely instances of drawing a bull's-eye around the spot where the arrow landed.

Even here, serendipity may be grafted upon imperfect knowledge. The story of the drug Iressa illustrates the point. Iressa blocks the activity of an enzyme that stimulates cell division. As the enzyme is over-abundant in 80 percent of lung cancers, researchers hypothesized that the drug would be an effective treatment for most lung-cancer patients. They were both disappointed and perplexed when only 10 percent had a strong response. It then became evident that the patients who did respond well not only had lots of the enzyme, they also had a mutant form of it. By contrast, those patients who had either no response or a partial response had only the normal version of the enzyme.

In the recent case of a promising experimental drug targeted against melanoma, serendipity played a major role. The drug, developed by the German company Bayer and by Onyx Pharmaceuticals, a California biotechnology company, goes by the awkward code name BAY 43-9006. The drug is the first to block a protein called RAF, one of a family of enzymes called kinases, which relay a cascade of signals leading to cell growth. The drug is most effective in kidney cancer, but
not
mainly by blocking RAF. Thanks to “dumb luck,” in the words of Dr. Frank McCormick, founder of Onyx and director of the cancer center at the University of California at San Francisco, it turns out that the drug also blocks a protein involved in the flow of blood to the tumor. In another discovery unforeseen by Bayer and Onyx, scientists in Britain found that RAF was mutated in about 70 percent of melanomas. When combined with chemotherapy, BAY 43-9006 shrunk melanomas in seven of the first fourteen patients.
⁶

In his 1998 book
One Renegade Cell,
Robert Weinberg, a pioneering scientist at MIT, put these discoveries and potentials into perspective:

Until recently, the strategies used to find the genes and proteins that control the life of the cell have depended on ad hoc solutions to formidable experimental problems, cobbled together by biologists who lacked better alternatives. Time and again, serendipitous discoveries have allowed new pieces to be placed in the large puzzle….

Discoveries of critically important genes often have depended on little more than dumb luck….

Those who engineer these successes [technologies, gene mapping of cancers, targeted drug therapies] will view the discoveries of the last quarter of the twentieth century as little more than historical curiosities…. We have moved from substantial ignorance to deep insight.
⁷

Nevertheless, can one doubt that serendipity will continue to play a role?

19

From Where It All Stems

In the late 1950s treatment of leukemias and other cancers of the blood involved radiation to kill cancerous blood cells and subsequent bone marrow transplantation to replace them. It was known that bone marrow transplants (a procedure then in its infancy) replenished the essential cells of the blood system, but there was no understanding of the source of these cells.

The three different types of blood cells had been identified in the late nineteenth century: red blood cells, which transport oxygen throughout the body; white blood cells, which protect against germs; and platelets, which keep us from bleeding. It was known that they came from inside the bones—in the bone marrow—where trillions are made every day. Immature forms could even be identified. But how they were produced was a great mystery.

Meanwhile, outside the laboratories, the Cold War was raging, and many people feared a nuclear war. Researchers were looking for ways to treat people, most likely military personnel, who might be exposed to whole-body irradiation from nuclear weapons. Ernest McCulloch, a physician, and James Till, a biophysicist, at the Ontario Cancer Institute in Toronto, were part of this effort. They set out to measure the radiation sensitivity of bone marrow cells and to determine how many bone marrow cells were needed to restore blood cell production in irradiated mice.

The design of their study called for a group of the irradiated mice
to be killed ten days after transplantation of various numbers of marrow cells. Normally, on a weekday, a lab technician would be the one to “dispatch” the animals, cut them open, collect the specimens, and hand them over to the scientists. As luck would have it, in 1959 day 10 fell on a Sunday. McCulloch himself, not a laboratory technician, came in that afternoon to do the dirty work. When he opened up his irradiated mice that Sunday, McCulloch was intrigued to find nodules on the surface of their spleens.
¹

This observation, which easily could have been overlooked, revealed changes that would have remained undetected within the bone marrow except under the most meticulous examination. The nodules were foci of new blood cell formation. Blood cell formation in the bone marrow, sequestered deep within the cavities of the bone, occurs among its interweaving lattice of supporting connective tissue only at specific scattered sites. In the mouse, however, blood cell formation occurs also in the spleen. The observation itself was thus not very surprising. What was surprising was that individual nodules contained dividing cells, some of which were differentiating into the three main types of blood cells: red cells, white cells, and platelets. This finding meant that something capable of making all blood cell types, a blood-forming stem cell, was trapped in the spleen. Moreover, it was as rare as Waldo among the transplanted marrow cells, since as many as 10,000 of these had to be injected for each nodule observed.

Establishing an accurate ratio between the number of marrow cells transplanted and the number of nodules observed suggested the possibility of a single formative source.
²
But how to prove it? The nodules had newly formed blood cells not only of the various types but also of varying stages of maturity. Where did these colonies stem from? McCulloch and Till would have to work backwards, like tracing a family tree back to the primary ancestor. And then fortune smiled. With the assistance of Andrew Becker, a graduate student, they devised an ingenious and elegant experiment using mutated cells that arose from irradiated bone marrow. By documenting that the blood cells in each spleen nodule bore a particular genetic signature, the investigators proved that diverse blood cells come from individual stem cells.
³

Since there is no specific feature that allows stem cells to be identified by microscopy, this discovery was a huge conceptual achievement. McCulloch proudly called this “hematology without a microscope.”
⁴

The concept of stem cells had been around since at least the early 1900s, but efforts to find them using the light microscope and histological stains had failed because the stem cells were so few in number and indistinguishable from other blood cells by appearance alone. Said Till, “Our work changed the emphasis from… form to… function…. We stumbled across a way of looking at the developmental potential of stem cells by looking at the descendants they could give rise to.”
⁵

McCulloch and Till established the two main properties of stem cells: self-renewal and differentiation into specialized cells that have limited life spans. Genes in the stem cells and factors in the tissue environment are important in promoting normal stem cell duplication and specialization.

When a stem cell divides, each new cell has the potential to either renew itself for long periods through continued cell division or, under certain physiologic or experimental conditions, become another type of cell with a more specialized function. Unlike embryonic stem cells, which are defined by their origin in a three-to-five-day-old embryo (called a blastocyst), adult stem cells in mature tissues are of unknown origin. The adult tissues in humans that are now believed to contain stem cells include bone marrow, blood, brain, blood vessels, skeletal muscle, skin, and liver. There is a very small number of stem cells in each tissue, where they may remain dormant (nondividing) for many years until they are activated by disease or tissue injury. The discovery of stem cells has opened up the exciting possibility of cell-based therapies to treat disease. Some examples of potential treatments include replacing the dopamine-producing cells in the brains of Parkinson's patients, developing insulin-producing cells for Type 1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

But there is a dark side to stem cells, one that offers a fascinating line of study for researchers and a ray of hope for the human race.
Growing evidence suggests that stem cells are also the wellspring of cancer. A research group in Madrid reports that stem cells taken from adults can turn cancerous if they are allowed to multiply for too long outside the body.
⁶

A better understanding of the mechanism whereby undifferentiated stem cells become differentiated may yield information on how cancer arises through abnormal cell division and differentiation. Cancer stem cells might continually replenish tumors. Indeed, this might explain why treatments that can shrink tumors don't always cure the disease. Perhaps the treatments are less effective at killing the cancer stem cells. Cancer stem cells use a variety of biochemical pathways to survive. Identification of the biochemical switches they use to reproduce could provide the target for a silver-bullet drug.

In 2005 McCulloch and Till received the Albert Lasker Award for Basic Medical Research. In an article published a month later, they paid tribute to the vastly undercredited elements of both luck and astute observation: “We weren't deliberately seeking such cells, but thanks to a felicitous observation, we did stumble upon them. Our experience provides yet another case study of both the value of fundamental research and the importance of serendipity in scientific research.”
⁷
Reflecting on his work in an interview in 2006, McCulloch said he had always thought that the idea of “the scientific process” was overblown.
⁸
He knows that “typically a successful scientist may start with an experimental design but then makes an unexpected observation that leads a prepared mind to follow a chance event.”
⁹

20

The Industrialization of Research and the War on Cancer

The word “cancer” derives from the Greek
karkinoma
and the Latin
cancer,
for “crab,” suggested by the long, distended veins coursing from lumps in the breast. During the first half of the twentieth century, “cancer” was an almost unmentionable word. Public figures were never described as dying from cancer, and obituaries obliquely referred to a “prolonged illness.” An overpowering mood of powerlessness and fear, mixed with a sense of shame attached to the suffering caused by the disease, fueled a widespread cancerphobia.

The ramifications of this pervasive fear are graphically described by James Patterson in his book
The Dread Disease,
a cultural history of cancer in the United States.
¹
Patterson includes an experience recounted by George Crile Jr., a surgeon at the Cleveland Clinic. A seventy-five-year-old woman who suddenly could not speak was referred to Dr. Crile by her family physician, who suspected that thyroid cancer had spread to her brain. After a series of tests, Crile informed the family that the disease was far worse than cancer, which he might have been able to treat. “There is nothing to be done,” he told her adult children. “Your mother has suffered a stroke from a broken blood vessel. The brain is irreparably damaged. There is no operation or treatment that can help.” After making this difficult speech, Crile was taken aback by what came next.

The oldest daughter leaned forward, tense, and with a quaver in her voice, asked,

“Did you find cancer?”

“There was no cancer,” Crile replied.

“Thank God!” the family exclaimed.
²

By midcentury the stage was set for a divisive conflict over the nature of cancer research that would persist for decades. It involved a fundamental distinction between a
targeted categorical disease approach
and a
basic research approach.
The former requires a coordinated attack on a particular disease, whereas the second relies upon independent scientific studies of the processes of the human body. On one side of the conflict were those favoring centralized management and specifically targeted research. Even though such an approach typically involved a needle-in-the-haystack search for a useful agent, supporters were confident that triumphs were within reach. Others—particularly those in academic medicine—were highly skeptical of the role of “regimented direction” of biological research, fearing that it would lead to a certain loss of serendipity and would favor a technological approach over independent, curiosity-driven basic research.
³
As early as 1945 the medical advisory committee reporting to the federal government on a postwar program for scientific research emphasized the frequently
unexpected
nature of discoveries: