Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (31 page)

Furchgott's mind, trained by early experiences with serendipity, was always alert to the benefits that could accrue from accidental discoveries.
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In 1951, while at Washington University, Furchgott started using a strip of rabbit aorta to study the effects of drugs. His goal was to characterize receptor sites in smooth muscle cells responsive to the actions of drugs. In the current era of Big Science, Furchgott's preparation now seems absurdly simple. He would cut by hand, with a small pair of scissors, strips of aorta and measure their changes in length when exposed to a variety of drugs.

A couple of decades later, in 1978, after Furchgott had moved to the State University of New York (SUNY) Health Science Center in Brooklyn, his method played a role in a serendipitous breakthrough that led to other discoveries. Furchgott himself admitted that “an accidental finding as a result of a technician's error completely changed the course of research in my laboratory.”
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The technician failed to wash out a drug from an earlier experiment, which brought about the opposite effect. Furchgott, not realizing the mistake, expected that the arteries would contract, and was surprised to see that they relaxed.

It was the first time he had seen the drugs under study produce such a reaction. He used this serendipitous observation to plan additional experiments, and it forced him to review his techniques of preparation—ones he had used for more than twenty-five years.

In that method, as a continuous strip was being cut by scissors from an aorta held in one hand, each newly cut portion of the strip was pulled over the tip of the middle finger of that hand so that the lengthening strip could hang free from that finger and not get in the way of the part of the aorta yet to be cut. The surface of the strip being pulled over the fingertip was the intimal surface! Moreover, the full strip was positioned with intimal surface down on a piece of moistened filter paper before being cut into smaller strips…. Now we found that if we cut…strips in a different way so that the intimal surface did not make contact with fingertips or other surfaces during the preparation, then such strips exhibited [classic responses].
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Further study led to an astonishing realization: Furchgott's unintentional gentle rubbing of the lining of strips in the course of preparing them had scraped off the lining's endothelial cells!

Furchgott had to face another embarrassing realization. Twenty-five years earlier, he had noted the same paradoxical response to this same drug, acetylcholine, a very potent vasodilator that elicited no relaxation but only contraction of the aortic strip. At the time, it was peripheral to his main research pursuits and he did not recognize its significance. Looking back, he ruefully noted: “Little did I suspect then what I was able to show many years later—namely, that relaxation of arteries by acetylcholine is strictly endothelium-dependent, and that my method of preparing the strips inadvertently resulted in the mechanical removal of all the endothelial cells.”

Furchgott quickly reported these early results and magnanimously included the name of his technician who had committed the oversight among the coauthors of the abstract.
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The experience led Furchgott to the quite unexpected and exciting realization that contraction and relaxation of blood vessels in response to many agents are dependent on the endothelium. The vascular endothelium eventually received the status of an organ, albeit a widespread one, responsible for widening blood vessels, helping to regulate blood pressure, initiating erections, battling infections, preventing formation of blood clots, and acting as a signal molecule in the nervous system.

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It was immediately apparent that stimulation of certain receptors of endothelial cells led to relaxation of the adjacent smooth muscle. The question was how this occurred. Furchgott hypothesized that the endothelial cells, in response to stimulation, release a substance that diffuses to and acts on the smooth muscle cells to cause relaxation. Pondering how to prove this, Furchgott said, “the idea came to me suddenly and unexpectedly one morning just as I was waking up.”

In a simple but ingenious experiment, he made a key discovery that set the stage for future breakthroughs. A strip of artery with
endothelium removed was mounted with another strip of the same length and width but with endothelial cells present—intimal surface against intimal surface. In this so-called “sandwich” preparation, the endothelium-free strip, which alone did not relax in response to acetylcholine, now exhibited good relaxation in response to that agent. In a report in
Nature
in 1980, Furchgott concluded that an unknown diffusible substance was produced in the endothelium and caused relaxation.
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This was a great discovery, and the hunt began in several laboratories for the identity of the endothelial factor. One of the areas of research involved nitro-compounds. Nitroglycerin had been used successfully for more than a hundred years for the treatment of angina, but its mechanism of action had not been clearly understood. Angina pectoris is a prominent symptom of a cardiac condition known as myocardial ischemia. This condition occurs when the heart muscle is deprived of the blood it requires.
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Precise investigative work by the pharmacologist Ferid Murad, first at the University of Virginia and then at Stanford University, showed that nitroglycerin acts by releasing nitric oxide gas. It remained only to close the loop by identifying the endothelial factor to be nitric oxide. At a scientific meeting at the Mayo Clinic in the summer of 1986, Furchgott and Louis Ignarro of Tulane University each presented this conclusion independently. (Years later Furchgott said in an interview, “To tell you the truth, it took an embarrassingly long time to understand what we had discovered.”)
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NO is a gas most commonly known as an air pollutant formed when nitrogen burns, for example, in automobile exhaust fumes. It is a chemical relative of the anesthetic gas nitrous oxide (laughing gas). It is a simple molecule, with two atoms—nitrogen and oxygen. As astonishing as the realization was that certain cells in the human body generate a gas, it was a truly revolutionary breakthrough to finally understand that blood vessels have the ability to control their own diameter and thereby their rate of blood flow and blood pressure. A new phenomenon had been discovered: an internally produced short-lived gas with the capacity to act as a signaling molecule between cells in
the body. In 1994 NO was named “molecule of the year” by the prestigious American journal
Science.

Scientists were astounded to learn that this simple molecule could also be an important neurotransmitter, and as a result of the new insight, biological research in the field of nitric oxide exploded. As research progressed, nitric oxide was shown to regulate an ever-growing list of biological processes, including blood pressure, blood clotting, bacterial endotoxic shock, the immune system, intestinal motility, behavior, and some aspects of learning.

In 1998, twenty years after discovering the presence of the vascular relaxing factor derived from the endothelium, the eighty-two-year-old Robert Furchgott shared the Nobel Prize with Louis Ignarro and Ferid Murad. In the personal introduction to his Nobel lecture, Furchgott gave serendipity its due: “I was very lucky to stumble on unexpected results in 1978 that led to the finding of endothelium-dependent relaxation and eventually to NO.”
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His discovery arose from what he simply termed “old-fashioned pharmacological research.”

Remarkably, Furgott had accomplished all his work throughout the years by using simple and easily reproducible techniques, without sophisticated instruments and technology. His experience is a reminder that an individual does not need a heavily funded laboratory equipped with state-of-the-art technology to uncover fundamental truths.

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“It's Not You, Honey, It's NO”

Throughout history, aging in men has been associated with depleted sexual vigor. In June 1889 a dramatic announcement was made. Charles-Édouard Brown-Séquard, a renowned seventy-two-year-old physiologist at the Collège de France in Paris, reported to spellbound doctors at a meeting of the Société de Biologie that he had injected himself with a “masculinizing factor” extracted from the testicles of guinea pigs that he claimed to have dissolved in water.
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Brown-Séquard said that animal testes harbored an invigorating principle that made him “tremendously rejuvenated,” sexually and in muscular strength. Later he wrote of how his impotence had been cured.

To many, it seemed the Elixir of Life had been found. However, it is now known that the male hormone is insoluble in water, so this aqueous extract could not have contained any testosterone; indeed, many years later, Ernst Laqueur required more than a ton of bulls’ testicles when he became the first scientist to isolate enough testosterone for a single course of injections.
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Clearly, the invigoration experienced by Brown-Séquard was due entirely to autosuggestion.

Therapies for impotence throughout most of the twentieth century were awkward, uncomfortable, and at times surgical in nature. They involved injecting drugs directly into the penis, inserting suppositories into the urethra, using a pump to draw blood into the penis, constrictive bands, and surgical procedures such as implantation of
penile prostheses. As recently as a few decades ago, men in need of erections were told to rub nitroglycerin paste on their genitals to increase blood flow to the organs.

A Memorable Science Exhibition

The annual scientific meeting of the American Urological Association is usually a pretty staid affair. But one meeting has entered the annals of folklore. In the early 1980s, during the course of his lecture on the effectiveness of injecting substances directly into the penis to increase blood flow, one urologist announced that he had performed such injections on himself only an hour earlier. Stepping from behind the lectern, he dropped his trousers and proudly demonstrated to the audience his own erect manhood. Urologists who attended this meeting still shake their heads at the memory.

By 1918 another possibility was opened up: testicle transplantation. Dr. Leo L. Stanley, the prison doctor at San Quentin in California, actually performed such transplants in five hundred inmates. He took testicles from executed prisoners and transplanted them into live inmates. He also surgically implanted “animal glands” from rams, goats, and boars into the scrotums of some inmates. Stanley's human experimentation was no secret, and his report on it was published in the journal
Endocrinology.
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For a quarter of a century, from 1918 to 1942, a dubiously certified physician, John R. Brinkley, performed “goat gland” transplants on thousands of men afflicted with impotence or flagging sexual capacities. Modifications of the procedure were offered at exclusive Swiss spas catering to the rich and famous.

Desperate men who heard about the “cure,” which was heavily promoted on Brinkley's own radio station, flocked to his office in Kansas (and later, as growing criticism compelled Brinkley to relocate,
in Texas and then Arkansas). Eventually his practice was branded as quackery by organized medicine.
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Around 1986 laboratory scientists working at Pfizer's research facility in Sandwich, in the United Kingdom, developed a new chemical compound, sildenafil citrate, and considered it a candidate for the treatment of angina. In early clinical trials in 1990 and 1992, its effect on circulation and heart function was disappointing. The researchers decided to alter the dose to see if it would make any difference.

It did indeed—but not in the way the scientists expected. Rather than boosting blood flow to the heart, it affected blood flow to the penis, with startling effect: many impotent patients experienced restored penile erectile function. Pfizer, of course, was astute enough to explore what its scientists had inadvertently stumbled upon, something entirely new in the annals of medicine.

Pfizer's large-scale clinical trials, initiated in 1993 at first throughout Europe and then in the United States, proved highly successful for the treatment of impotence and validated that the drug sildenafil cit-rate works only in response to sexual stimulation.

Meanwhile, a National Institutes of Health panel comprised of leading urologists, psychiatrists, psychologists, gerontologists, and surgeons, recognizing that the term “impotence” was confusing and had pejorative implications, created a more accurate definition of what came to be called “erectile dysfunction” (ED). Their report was published in the
Journal of the American Medical Association
in July 1993.
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A survey of almost 1,300 men at around the same time found that the combined prevalence of minimal, moderate, and complete erectile dysfunction in the United States was more common than previously thought—affecting about 52 percent of men—and now was considered a “major health concern.”
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In March 1998 the U.S. Food and Drug Administration granted market clearance for Viagra, a breakthrough oral treatment for ED. This diamond-shaped blue pill is popularly thought of as the first
pharmaceutical aphrodisiac. After its approval by the FDA, Viagra received an enormous amount of publicity.
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Even Pfizer did not anticipate the impact the drug would have on the culture. Within the first month, 40,000 Viagra prescriptions were filled each day.
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For a time, it was the fastest-selling drug in history. Worldwide sales were $788 million in its first nine months on the market in 1998. In 2004, some 250,000 to 300,000 men were taking Viagra weekly.