Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (25 page)

Discoveries in medicine have often come from the most remote and unexpected fields of science in the past; and it is probable that this will be equally true in the future. It is not unlikely that significant progress in the treatment of cardiovascular disease, kidney disease, cancer, and other refractory conditions will be made, perhaps unexpectedly, as the result of fundamental discoveries in fields unrelated to these diseases…. Discovery cannot be achieved by directive. Further progress requires that the entire field of medicine and the underlying sciences of biochemistry, physiology, pharmacology, bacteriology, pathology, parasitology, etc., be developed impartially.
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Their statement “discovery cannot be achieved by directive” would prove to be sadly prophetic.

At this time there arose two figures who would play a commanding role in biomedical research in the United States, Albert Lasker, a wealthy advertising magnate, and his wife, Mary. As president of Lord & Thomas Company, the world's largest advertising firm, Albert had ironically pioneered for the Lucky Strike account the promotion of smoking by women in the 1920s and 1930s with the slogan “Reach for a Lucky instead of a sweet.” In 1942 the couple established the Albert and Mary Lasker Foundation to support biomedical research. It was based on organizing a small lobby of key professional and legislative people that would persuade Congress to allocate funds for a national effort. In 1946 the Lasker Foundation began giving out the highly prestigious Albert Lasker Awards in Medical Research. The most prominent spokesman in cancer was Dr. Sidney Farber, the scientific director of the Children's Cancer Research Foundation in Boston and the discoverer in the late 1940s of the success of the antifolic acids in combating acute childhood leukemia.

Albert Lasker's death from colon cancer in 1952 reinforced his wife's determination that medical research provide answers, and Mary became an increasingly influential figure. She had energized a small, rather inert American Society for the Control of Cancer founded in 1913 by an elite group of surgeons and gynecologists into becoming the massive publicity and fund-raising machinery of the American Cancer Society and added businessmen to its board.

The U.S. government had undertaken support of cancer research in the late 1930s with the establishment of the National Cancer Institute (NCI). Even at this early stage, skepticism about the role of centralized management with “regimented direction” arose. Several doubted the wisdom of large-scale federal support for biomedical research. During the war years, it was a somnolent enterprise until funds from the defunct Office of Scientific Research and Development were transferred to the National Institutes of Health (NIH).

Shortly after the war, Alfred P. Sloan Jr., chairman of the board of General Motors, and Charles Kettering, GM's vice president and
research director, gave $4 million to establish at Memorial Hospital in New York the Sloan-Kettering Institute of Cancer Research. It became the largest private cancer research facility in the world. Cornelius Rhoads, its director, was known for his energy, initiative, and tenacity in the face of great challenges. He was driven by two compelling beliefs: chemical agents could be found that would stop cancer cells from dividing, and research could be organized on the principles of the leading industrial labs of the day, like Bell Labs, which linked scientific inquiry with efficiency and high output. (The industrialists who sat on his board encouraged him a great deal in the latter belief.)

Scientists at Memorial Sloan-Kettering tested more than 1,500 forms of nitrogen mustard and other alkylating agents on animals and occasionally on patients between 1946 and 1950. Basic and clinical research was so industrialized that by 1955 about 20,000 chemical agents had been tested.
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Rhoads was featured in a
Time
cover story in 1949 as a confident investigator-administrator and pictured with a crew cut and a white lab coat against a background illustration of a sword with serpents wrapped about its hilt (the symbol of the American Cancer Society) plunging through a crab (cancer).

Rhoads zealously stated, “Some authorities think that we cannot solve the cancer problem until we have made a great basic, unexpected discovery, perhaps in some unrelated field. I disagree. I think we know enough to go ahead now and make a frontal attack with all our forces.”
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Some may have found his disdain for “unexpected discovery, perhaps in some unrelated field” surprising in a man who had been involved with the serendipitous medical benefits of the military disaster at Bari just a few years earlier.
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By 1955, under lobbying pressures spearheaded by Rhoads and Sidney Farber, the center of drug testing had shifted from Sloan-Kettering Institute to the NCI. The NCI was the jewel in the crown of the federally supported NIH in Bethesda, Maryland, which funds most biomedical research. The hopes raised by the enormous potential breakthrough that the two drugs, nitrogen mustard and methotrexate, could bring about cannot be exaggerated: it was believed that what sulfa drugs and penicillin had done for the scourge of infectious disease, chemotherapy would do for cancer.

In 1953 an article in
Look
magazine predicted that cancer would be conquered within a decade.
Newsweek
anticipated that a vaccine against cancer would shortly be developed. In 1958
Reader's Digest
wrote approvingly of experiments being conducted on Ohio prisoners who had volunteered for injection of cancerous cells to test their immunity. The article considered this experiment a “history-making research project that could lead to a breakthrough in the struggles to understand this dread killer.”
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In the same year,
Life
quoted John “Rod” Heller, then the head of NCI, as saying, “I've spent many years in cancer research. Now I believe that I will see the end of it. We are on the verge of breakthroughs.”

By 1957 the chemotherapy program was immense, taking up nearly half of the NCI's budget and testing thousands of chemicals each year.
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Yet even the director of the NCI's drug development program, Kenneth Endicott, was highly skeptical of the approach. “I thought it was inopportune, that we didn't have the necessary information to engineer a program, that it was premature, and well, it just had no intellectual appeal to me whatever,” he said a decade later.
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In 1971 the U.S. government finally launched an all-out “war on cancer.” In his State of the Union address in January 1971, President Richard Nixon declared: “The time has come in America when the same kind of concerted effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal.”

As the country debated a bill known as the National Cancer Act, the air was filled with feverish excitement and heady optimism. Popular magazines again trumpeted the imminent conquest of cancer. However, some members of the committee of the Institute of Medicine, a part of the National Academy of Sciences, which was asked by the NCI to review the cancer plan envisioned by the act, expressed concern regarding the centralization of planning of research and that “the lines of research… could turn out to be the wrong leads.” The plan fails, the reviewers said in their confidential report, because

It leaves the impression that all shots can be called from a national headquarters; that all, or nearly all, of the really important ideas are already in hand, and that given the right kind of administration and organization, the hard problems can be solved. It fails to allow for the surprises which must surely lie ahead if we are really going to gain an understanding of cancer.
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The vigorous lobbying efforts, testimonies, and debates in congressional hearings in the eleven months before the act's final passage remain highly instructive today and provide a template for the differing perspectives and dilemmas regarding the nature of creative discoveries. During the hearings, long-simmering opposing viewpoints were sharpened.
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A war within the war flared up over how much centralized control the proposed national cancer authority would exert. What is the best way to direct the path of meaningful research? Is it accomplished best under central direction, or should it be left more independently to curiosity-driven scientists? What role does serendipity play in medical discoveries? Can discoveries be anticipated and therefore targeted for funding and clinical trials, or do they often arise unexpectedly from basic research in a variety of disciplines? How important is the revelation of a fundamental finding in one field—chemistry, physics, pharmacology, physiology—to another? Is the term “war” in this context even appropriate, given that cancer is not a single entity and has multiple causes and manifestations?

In numerous testimonies before congressional committees, Sidney Farber of Boston Children's Hospital had long served as a forceful spokesman for clinically targeted research reflecting, it was believed, the immediate needs of patients. Impressive and dignified, he spoke deliberately and had a flair for the dramatic anecdote. Farber argued that it was not always necessary to know the cause of a disease in order to cure it or even to prevent it. His stand was vigorous: “The history of medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures—from vaccination, to digitalis, to aspirin.”
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Sol Spiegelman, director of Columbia University's Institute of Cancer Research, stated that “an all-out effort [to cure cancer] at this time would be like trying to land a man on the moon without knowing
Newton's law of gravity.” The emphasis, many declared, should clearly be on basic biological research rather than on centralized direction, which inhibits creative minds. A particularly compelling case was made by Francis Moore, M.D., professor of surgery at Harvard Medical School and surgeon in chief at Peter Bent Brigham Hospital in Boston. Moore's opinion was diametrically opposed to Farber's. Moore's logical review of medical history at the hearings pointed out that if there had been a diabetes institute in the late nineteenth century, it would not have supported the work of Paul Langerhans on the pancreas, work that ultimately led to the discovery of insulin.
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At the time, the relation between the pancreas, insulin, and diabetes was simply not known. Similarly, he noted, a government institute on polio would likely have not supported the work of Dr. John Enders in the late 1940s in attempting to grow the mumps virus, work that found the method that ultimately proved critical to producing the polio vaccine. Moore argued that many medical advances come from creative research by “often young people, often unheard of people” in universities.
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Nevertheless, the act was passed on December 23, 1971, signed into law by President Nixon, and hailed as a bountiful Christmas gift for the American people.
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When the dust settled, the National Cancer Institute was given substantial autonomy and markedly increased funding.

The scope of the NCI's enterprise was breathtaking. By 1960 the program had begun screening 30,000 compounds annually for antitumor activity. These required almost 300,000 tests using three different types of mouse tumors. There were two major sources of chemicals: random “off the shelf” selections and active programs of synthesis. By 1970 the potential of some 400,000 drugs had been explored.

Over the years, the American Cancer Society tried to sustain the public's hope for continuous progress, often using phrases such as “on the threshold of a golden age of medicine” and “a cure is just around the corner.” At times the evangelism even became reckless. In 1977 a former president of the American Cancer Society defended the society's aggressive promotion of X-ray mammography by declaring that, even though there might be a potential of increasing a woman's risk of
breast cancer in the future, “there's also an excellent chance that by that time science will have learned to control the disease.”
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In time, the odds against finding the needle in the haystack proved overwhelming. Only about 1 in 2,000 of those compounds screened for activity would be selected for clinical trials; the odds of a compound making it as a commercially available anticancer drug was at best 1 in 10,000.
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The NCI conducted extensive national clinical trials. Phase I, generally involving a few dozen volunteers, determined the drug's toxicity and maximum tolerated dose. Phase II, involving perhaps a few hundred patients, assessed any benefit and established the schedule of treatment. Phase III studies, typically involving thousands of patients, compared the treatment's safety and benefits with standard therapies. If the results were favorable, the drug would be submitted to the FDA for approval.
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Despite this Herculean effort and enormous expense, only a few drugs for the treatment of cancer were found through NCI's centrally directed, targeted program. These attacked the fast-growing, disseminated forms of cancer, such as leukemias and lymphomas, found primarily in young individuals.

Over a twenty-year period of screening more than 114,000 plant extracts, representing about 15,000 species, not a single plant-based anticancer drug reached approved status. This failure stands in stark contrast to the discovery in the late 1950s of a major group of plant-derived cancer drugs, the
Vinca
alkaloids—a discovery that came about by chance, not through directed research.