Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (4 page)

Creativity is a word that most people associate with the arts. But the scientific genius that leads to great discoveries is almost always rooted in creativity, and creativity in science shares with the arts many of the same impulses. Common to both are the search for self-expression, truth, and order; an aesthetic appreciation of the universe; a distinct viewpoint on reality; and a desire for others to see the world as the creator sees it. The novelist Vladimir Nabokov bridged the tension between the rational and the intuitive in his observation that “there is no science without fancy and no art without fact.”

Among artists, the creative urge with its sometimes fevered
obsession has entered our folklore. Legend has it that one day, when Sir Walter Scott was out hunting, a sentence he had been trying to compose all morning suddenly leaped into his head. Before it could fade, he shot a crow, plucked off one of its feathers, sharpened the point, dipped it in the bird's own blood, and recorded the sentence.
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In the twentieth century, Henri Matisse, bedridden in his villa near Nice during his recovery from abdominal surgery, could not restrain himself from using a bamboo stick with chalk at its tip to draw on his bedroom wall. Among scientists, the creative urge is no less compelling.

Henri Matisse, ca. 1950. Photo by Walter Carone.

Creative people are open-minded and flexible in the face of unusual experiences. They are alert to the oddity of unexpected juxtapositions and can recognize a possibility even when it is out of context. In his massive work
The Act of Creation,
Arthur Koestler proposes that bold insights are produced by juxtaposing items that normally reside in different intellectual compartments, a process he terms “bisociation.” In many scientific discoveries, he asserts, “the real achievement is seeing an analogy where no one saw one before.”
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In the late 1940s the biologist Aser Rothstein saw such an analogy. He was working at a unit of the then-secret Manhattan Project established at the University of Rochester. At that time, the cell membrane was basically an abstract notion, and the leading concept simply regarded diffusion across it as being of a passive nature. Rothstein was studying the toxic action of uranium salts on cells. Laboratory data were coming out well and reproducibly until, suddenly, everything went wrong. There was no progress, and no two results were the same.

One day, when Rothstein walked into his lab, he noticed a box of detergent that was used in the lab to clean glassware. On the box, surrounded by a flashy red star, were the words “New Improved Dreft.” Comparing its label to that of an old box of Dreft, Rothstein saw that the new version contained an added ingredient—a water softener. As it turned out, this softener coated glass tenaciously and chemically bound the material Rothstein was studying (uranium ions) to the surface of the glass. His creative mind then made an extraordinary leap. He wondered about a possible analogy: If there is binding on the surface of glass, could there be binding on the surface of a cell?

Seizing upon this capability of the chemical in the water softener, he went on to prove that there are binding sites on the cell surface as well. Fortune had provided him with a contaminant similar to the natural enzymes involved in transport across the cell membrane. But Fortune might have come calling in vain if not for Rothstein's ability to draw the essential analogy. Some ten years before the cell membrane could actually be seen with the development of electron microscopy, Rothstein's “accidental” discovery enabled him to show that it was a metabolically
active
structure containing enzymes critical in transport mechanisms.
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Analogical thinking has certainly been a cornerstone of science. The seventeenth-century English physiologist William Harvey compared the heart to a pump. The physicists Ernest Rutherford and Niels Bohr pictured the atom as a tiny solar system. “Every concept we have,” writes the cognitive scientist Douglas R. Hofstadter, “is essentially nothing but a tightly packaged bundle of analogies.”
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Drawing analogies is one part of the creative discovery process, but an equally important one is seeing things that don't quite make sense. Thomas Kuhn introduced the idea that revolutions in science arise from the recognition of anomalies. Kuhn observed that the accumulation of anomalies—findings that cannot be assimilated into an accepted scientific framework, tradition, or paradigm—paves the way for scientific revolution. A single anomalous observation may stimulate an initial inquiry, but most productive to an alert mind is a special sort of anomaly, one that clearly falls into a
class
of anomalies. Resolving just one can provide insight into a whole category of more complicated ones. For example, the era of cancer chemotherapy was initiated by the recognition of never-before-seen symptoms in sailors saturated for long periods with liquid mustard gas during a military disaster in World War II. From this came the development of alkylating chemical agents, followed by a series of different categories of anticancer drugs.

In the early 1950s Nathan Kline, a psychiatrist at Rockland State Hospital in Orangeburg, New York, exploited an anomalous reaction in patients receiving the drug reserpine for hypertension. He noticed that it tranquilized agitated, restless patients. It was later shown that reserpine affected the levels of serotonin, dopamine, and adrenaline in the brain. This was truly a “Eureka!” finding because it steered psychiatry onto a whole new path that focused on brain chemistry. Kline's pioneer efforts in introducing the use of tranquilizers to the practice of psychiatry in the United States was followed by the development of a host of psychoactive drugs influencing the brain's neurotransmitters, culminating in today's multibillion-dollar mood-altering-drug industry.

Creative thinkers tend to take analogies and anomalies to higher levels. They have a gift for seeing
similar differences
and
different similarities—
phrases coined by the British theoretical physicist David
Bohm. True creation, Bohm argues, relies upon perceiving a new fundamental set of similar differences that constitutes a genuinely new order.
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Indeed, it is the recognition of anomalies, discrepancies, inconsistencies, and exceptions that often leads to the uncovering of a truth, perhaps one of greater magnitude than the one originally pursued. Writing of Charles Darwin, his son said: “Everybody notices as a fact an exception when it is striking and frequent, but he had a special instinct for arresting an exception. A point apparently slight and unconnected with his present work is passed over by many a man almost unconsciously with some half-considered explanation, which is in fact no explanation. It was just those things that he seized on to make a start from.”
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The ideal scientific mind comfortably incorporates unanticipated factors into an established body of work or, more likely, follows it in completely new directions. Such a mind handles error, inconsistencies, and accidents in a characteristic way that represents a special mark of creativity. In other words, the open mind embraces serendipity and converts a stumbling block into a stepping-stone. As Winston Churchill whimsically observed, “Men occasionally stumble across the truth, but most of them pick themselves up and hurry off as if nothing happened.”

W
HEN
I
NSIGHT
S
TRIKES

A perceptive breakthrough may be likened to grasping the “hidden” figure in a Gestalt diagram. In the 1950s Rosalyn Yalow, a biophysicist, and Solomon Berson, a physician, at the Bronx VA Hospital began using radioisotopes—radioactive forms of chemical elements—to study diseases. At that time, it was believed that the high levels of sugar in the blood of adult diabetics were due to insulin deficiency. Some researchers hypothesized that it was probably destroyed by a liver enzyme once it entered the bloodstream.

To their surprise, the researchers found that injected radioactive insulin remained longer—albeit uselessly—in diabetic patients who had received insulin than in people who had never received insulin before. Further studies led to an astonishing discovery: a large plasma
protein, a gamma globulin antibody, was called forth as part of the body's immune system, inactivating the insulin and keeping it in the bloodstream.

Then a “Eureka!” moment occurred that would have delighted the Gestalt psychologists of perception. Because both natural insulin and injected radioactive insulin compete for sites on the antibody molecule, the amount of the natural hormone present in a patient's body can be measured. A curved line viewed from one side is convex but viewed from the other side is concave. As Yalow put it, “Once you saw it one way, you saw it the other way.”
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The inverse would measure the hormone itself. In this way an unexpected finding combined with a flash of insight, and the method of radioimmunoassay (RIA) was born.

The term was aptly chosen because the method used radioactively tagged substances to measure antibodies produced by the immune system. Circulating throughout the human body in solution in the blood are a multitude of hormones and other regulatory substances. They are each infinitesimal in quantity but exert profound effects. To understand bodily functions, it is necessary to determine the presence and amount of each substance.

Yalow and Berson discovered by accident a technique so sensitive that it can detect the equivalent of a sugar cube dissolved in Lake Erie. This revolutionized endocrinology and its application to virtually every system in the body. RIA is now routinely used to detect such things as hepatitis-associated antigen in the blood of patients and donors and the presence of steroids in the urine of athletes, and to ascertain blood levels of therapeutic drugs. Its discovery resulted from experiments initially designed to answer another question.
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Yalow acknowledged the role of serendipity: “It was luck… to discover that insulin disappears more slowly from one group of patients than from another…. That's what you mean by discovering something by accident. You make an observation. But it isn't by accident that you interpret the observation correctly. That's creativity.”
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No one would expect much science to come out of a university dining hall experience. Nevertheless, Richard Feynman, as a twenty-eight-year-old at Cornell, was eating in the school cafeteria when
someone tossed a dinner plate into the air. Its two simultaneous movements caught his attention. His eyes following the red medallion insignia of Cornell on one rim of the plate, he saw not only that it was spinning but also that it was wobbling. He noticed something amiss: the spinning rotation and the wobble were not precisely synchronous. Feynman turned his characteristic playfulness and unbridled curiosity to this trivial observation:

I had nothing to do, so I start to figure out the motion of the rotating plate. I discover that when the angle is very slight, the medallion rotates twice as fast as the wobble rate—two to one. It came out of a complicated equation! Then I thought, “Is there some way I can see in a more fundamental way, by looking at the forces or the dynamics, why it's two to one?”

“There was no importance to what I was doing,” he wrote later, “but ultimately there was. The diagrams and the whole business that I got the Nobel Prize for came from the piddling around with the wobbling path.” That “whole business,” as he charmingly called it, was the application of his observation about the Cornell plate to the spin of electrons, known as nuclear precession, and the reformulation of quantum electrodynamics, the strange rules that govern subatomic reality.
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D
ON'T
A
SK,
D
ON'T
T
ELL

Relatively few investigators have spontaneously acknowledged the contribution of chance and accident to their discoveries. Scientific papers in the main do not accurately reflect the way work was actually done. Researchers generally present their observations, data, and conclusions in a dry passive voice that perpetuates the notion that discoveries are the natural outcome of deliberative search. The result, in the words of Peter Medawar, winner of a Nobel Prize for his pioneering work in immunology, is to “conceal and misrepresent” the working reality.
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Virtually without exception, scientific literature imposes a
post
facto
logic on the sequence of reasoning and discovery. The role of chance would never be suspected from the logically rigorous sequence in which research is reported.

Too much is at risk for scientists early in their careers to admit that chance observations led to their achievements. Only years later, after reputations are solidly made, do they testify to the contributions of such mind-turning factors as unexpected results, fortuitous happenstances, or exceptions to a premise. The truth is aired in award-acceptance speeches, autobiographies, or personal interviews. Wilhelm Röntgen, who won the Nobel Prize in 1901 for his discovery of X-rays, readily acknowledged the accidental nature of his discovery in a lecture to his local physics society. However, it is typically not until the Nobel Prize acceptance lectures that the laureate will for the first time clearly acknowledge the role of chance, error, or accident—as happened with Charles Richet (immunology, 1913), Alexander Fleming (the first antibiotic, 1945), Baruch Blumberg (the hepatitis B virus, 1976), Rosalyn Yalow (radioimmunoassay, 1977), and Robert Furchgott (the signal molecule nitric oxide, 1998).