Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (5 page)

To his credit, the accounts of his experiments on nerve conduction by Alan Hodgkin—subsequently awarded the Nobel Prize in 1963—are openly characterized by such phrases as “discovered by accident when trying to test something quite different,” “to our surprise…,” “chance and good fortune,” and “a great piece of luck.”
³⁴

Thomas Starzl, a surgical pioneer in the field of liver transplantation, wrote about his early career in a personal letter to a colleague: “I have a very difficult confession to make. Practically every contribution I ever made in my professional life turned out to be exactly the opposite of my expectations. This means that all my hypotheses turned out to be wrong, and usually spectacularly so. Naturally, I would not admit this to anyone, but an old friend!”
³⁵

Based upon a series of serendipitous events in his own research, Aser Rothstein observed: “Many of our advances in biology are due to chance, combined with intelligent exploitation… It is for this reason that the image of the scientist is not a true one. He comes out as a cold, logical creature when in reality he can fumble around with as
much uncertainty as the rest of humanity, buffeted by an unpredictable environment.”
³⁶

Peter Medawar has asserted that “any scientist who is not a hypocrite will admit the important part that luck plays in scientific discovery.”
³⁷
Writing in 1984, after a distinguished career in immunology with the National Institute for Medical Research in England, J. H. Humphrey stated: “Most of [my experiments] that led to anything novel or interesting arose because of some unexpected or chance observation that I was fortunate in being able to follow up.”
³⁸
Humphrey felt obligated to make the point not only in his recollection but eventually in the
British Medical Journal,
where he wrote rather forcefully: “I am aware from personal experience or from acquaintance with the people concerned how little the original purpose of some important experiments had to do with the discoveries which emerged from them. This is rarely obvious from the published accounts…. By the time a paper is published the findings have usually been married with current ideas and made to look as though they were the logical outcome of an original hypothesis.”
³⁹
Some observers have euphemistically termed this process “retrospective falsification.”
⁴⁰
Others have baldly termed it “fraud.”
⁴¹

Those instances of rare and belated admissions underscore the deliberate omission of the creative act that originated the medical discovery. The general scientific paper simply does not accurately reflect the way the work was actually done.

At times, one can detect an inchoate longing among scientists themselves for a forum for recounting the distractions, obstructions, stumblings, and stepping-stones in the process. Richard Feynman, the plainspoken physicist, affirms in his 1966 Nobel lecture:

We have a habit in writing articles published in scientific journals to make the work as finished as possible, to cover up all the tracks, to not worry about the blind alleys or describe how you had the wrong idea first, and so on. So there isn't any place to publish, in a dignified manner, what you actually did in order to get to do the work.

It is not hard to understand why most scientists remain circumspect. Embarrassment and fear of loss of stature may inhibit them from making full disclosure. They do not wish to jeopardize their chances to raise funds, win grants, earn publication, and advance their careers. It is unsettling for scientists to have to admit that so many discoveries came about purely by accident.

Reflecting on nonlogical factors in research, Rothstein concluded that “there is no body of literature to which one can turn… that reveals or collates the factor of chance and serendipity in research.”
⁴²
It is precisely this complaint that this book attempts to rectify.

A N
EW
S
CIENTIFIC
M
ETHOD
?

“Unless you expect the unexpected,” warned the Greek philosopher Heraclitus, “you will never find truth, for it is hard to discover and hard to attain.”
⁴³

Can a serendipitous discovery be predicted? Of course not. We cannot forecast that something—especially something valuable—will be found without specifically being sought. Does randomness play a role? Although chance implies unpredictability, it does not mean total randomness. In a random occurrence, there is complete absence of any explanation or cause. Randomness is generally seen as incompatible with creativity, as improbable as the writing of
Hamlet
by the legendary band of monkeys with typewriters in the basement of the British Museum.

Three things are certain about discovery: Discovery is unpredictable. Discovery requires serendipity. Discovery is a creative act. In the words of Peter Medawar:

What we want to know about the science of the future is the content and character of future scientific theories and ideas. Unfortunately, it is impossible to predict new ideas—the ideas people are going to have in ten years’ or ten minutes’ time—and we are caught in a logical paradox the moment we try to do so. For to predict an idea is to have an idea, and if we have an idea it can no longer be the subject of a prediction.
⁴⁴

Yet, despite the examples given, and all that follow, medical research stubbornly continues to assume that new drugs and other advances will follow exclusively from a predetermined research path. Many, in fact, will. Others, if history is any indication, will not. They will come not from a committee or a research team but rather from an individual, a maverick who views a problem with fresh eyes. Serendipity will strike and be seized upon by a well-trained scientist or clinician who also dares to rely upon intuition, imagination, and creativity. Unbound by traditional theory and willing to suspend the usual clinical set of beliefs, this outsider will persevere and lead the way to a dazzling breakthrough. Eventually, once the breakthrough becomes part of accepted medical wisdom, the insiders will pretend that the outsider was one of them all along.

So the great secret of science is how much of what is sought is not actually found, and how much of what has been found was not specifically sought. Serendipity matters, and it benefits us greatly to understand the true dynamics of the discovery process for many reasons: Because we are affected so directly by medical advances. Because directed research—in contrast to independent, curiosity-driven research that liberates serendipity—is often costly and unproductive. Because we need to be sound in our judgment of the allocation of funding and resources. Because profound benefits and consequences to society may be at stake. And—perhaps an equally compelling reason—because we thrill to hear and understand the many fascinating stories that lie at the intersection of science, creativity, and serendipity.

Part I

The Dawn of a New Era:
Infectious Diseases and Antibiotics,
the Miracle Drugs

Chance favors only the prepared mind.

—L
OUIS
P
ASTEUR

1

How Antony's Little Animals Led to the Development of Germ Theory

In today's era of the electron microscope, the Hubble telescope, and satellite transmission of images from the surface of Mars, the observations of an unschooled shopkeeper in Delft in the 1670s of a hitherto unknown world prove even more astounding.

Antony van Leeuwenhoek (pronounced
Lay-ven-hook
) earned his living as a draper but surely ranks among the greatest self-taught geniuses in the history of science and medicine. Having become skilled in grinding and polishing lenses to inspect cloth fibers during a youthful apprenticeship in Amsterdam, this amateur scientist of limited education designed and built simple microscopes with astonishingly high magnification and resolution. With these he first observed microorganisms.
¹

Leeuwenhoek not only used his lenses to more closely inspect small structures that the naked eye could discern—duck feathers, seeds, mold, the parts of a bee—but he also had the curiosity to move beyond the understanding held by more learned contemporaries and peer into what had been an invisible world. Leeuwenhoek lived during the much-heralded age of exploration, which introduced to Europe, among many other products, spices from far-flung continents. Leeuwenhoek wanted to find out, by the microscopic examination of macerated peppercorns, why pepper is hot. (He thought the peppercorns
might have spikes on their surface). Examining a suspension in water, he was surprised to see what he called “very little animalcules,” which were without question bacteria.

His observations were detailed over the next fifty years in 375 letters, frequently illustrated, to the Royal Society of London for Improving Natural Knowledge and published in its
Philosophical Transactions.
²
It was his famous Letter 18, dated October 9, 1676, that caused a sensation and earned him immortality for his discovery of protozoa and bacteria. His descriptions allow us to share his wonder at the microscopic appearance of a new world of “little creatures” in rainwater that had been left in a barrel for several days, well water, and seawater. He saw that what modern science knows as protozoa (“first animals”) use tiny “legs” or “tails” to swim in the tiny drop of water that was their world. We can share his sense of awe as he observed that “the motion of most of these animalcules in the water was so swift, and so various upwards, downwards, and round about, that ’twas wonderful to see.” He observed protozoa entangled in a filament expand and contract their shape, “struggle by strongly stretching themselves,” to extricate themselves. And he marveled when an “animalcule” brought on a dry place “burst asunder.” Observing no skeletal parts or obvious skin in an animal whose body consisted of soft “protoplasm” was a considerable novelty at this date.

These observations would not be followed up until Letter 39, dated September 17, 1683, when he examined the plaque from his own teeth and was stunned at the number of bacteria he found. He estimated that “there are more animals living in the scum on the teeth in a man's mouth than there are men in a whole kingdom.” From this microscopic menagerie, he clearly described and illustrated all the morphological types known today: round (cocci), rod-shaped (bacilli), and spiral-shaped (spirochetes).
³

Leeuwenhoek came tantalizingly close to grasping the germ theory of disease, when he found animalcules swarming in the decaying roots of one of his teeth and in the plaque from his own and other people's mouths. He noted that people who cleaned their mouths regularly had much less plaque than those who did not. And coming
within hailing distance of heat pasteurization, he saw that the animal-cules in plaque “could not endure the heat of my coffee.”

It took two hundred years from Leeuwenhoek's first observations until the germ theory of disease and the first effective germ-fighting treatments were established. The delay was in large part due to the fact that all biological processes are chemically based and mediated, and thus progress in medicine was intertwined with progress in chemistry.
⁴

Frenchman Louis Pasteur discovered the role of bacteria in the causation of disease. A chemist and not a physician, Pasteur was working on problems besetting burgeoning French industries. They quickly led him from chemistry to reveal the workings of biology.

Looking at wine under a microscope, he unraveled the fermentation roles played by living yeast organisms and bacteria in the delicate balance between wine and vinegar. But Pasteur wondered: If these organic changes were caused by tiny living microbes, where did they come from? Were they in the air, waiting for favorable conditions to multiply, or were they generated spontaneously by the lifeless matter itself? By 1864, in a series of ingenious experiments, he proved that living organisms do not spontaneously arise but are present in any material because they are introduced, then reproduce. He showed that the air is never free from living organisms.

The first disease Pasteur attributed to a living organism was one that was devastating the silkworm industry. By 1870 he showed that it was due to a protozoan infesting the grain the silkworms were fed.

Pasteur was elected to the Académie de Médecine in 1873. On February 19, 1878, before the academy, he presented his germ theory of infection. He laid out his conviction regarding the causal relationship between microorganisms and disease: that specific organisms produce specific conditions; that destroying these microorganisms halts transmission of communicable diseases; and that vaccines might be prepared for prevention. A revolutionary dictum now illuminated the way toward productive research, practice, and therapeutics. However, this was not universally greeted with acclaim. Some doctors called it “microbial madness” and disdainfully asked Pasteur, “Monsieur, where is your M.D.?”

Are Your Hands Clean?

Meanwhile, an English surgeon named Joseph Lister, inspired by Pasteur's work, inaugurated the era of modern surgery. In 1865 he began a program to prevent sepsis by using carbolic acid as a disinfectant, markedly reducing the incidence of postoperative infections. As the remonstrations of Ignaz Semmelweis in the late 1840s and 1850s against the unwashed hands of obstetricians received the scorn of his colleagues, so did Lister's technique meet the rigid objections of the surgical establishment before it was generally accepted two decades later.