Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (30 page)

—
NORBERT WIENER
,
INVENTION:THE CARE AND FEEDING OF IDEAS

On a winter day in 1953, an elderly man in acute distress appeared in the emergency room of the Columbia-Presbyterian Medical Center in upper Manhattan. He had severe back pain and low blood pressure, and doctors could feel a pulsating mass in his abdomen. The diagnosis was clear: the patient was suffering from a ruptured abdominal aortic aneurysm—in medical shorthand, a “triple A.” The aorta, the large vessel coursing from the heart through the abdomen to supply blood to the abdominal organs, had widened and ballooned due to atherosclerotic changes. The danger from such an aneurysm was rupture of its weakened wall, with the possibility of life-threatening bleeding into abdominal tissues.

To surgically remove the diseased segment was itself a formidable undertaking, but the problem remained of how to close the gap to restore circulation. Historically, the surgical repair of large arterial defects had represented a frustrating challenge. Even in small localized injuries the successful anastomosis (surgical connection) of two segments of a blood vessel had not been accomplished until the early
1900s. The main problem in suturing vessels was injury to their interior lining, called the intima or endothelium, which could give rise to fatal blood clots.

Alexis Carrel, a French surgeon, experimented for eight years to devise a method of rejoining severed blood vessels. In 1902 he introduced an ingenious technique that involved a trio of stitches. With the use of three sutures as stays, he transformed the blood vessel's round severed end into a triangle, providing the surgeon with a flat surface. This converted the circumference into a straight line, allowing the use of a continuous suture of very fine silk. This method of “triangulation” laid the foundation for procedures that are still in use today.
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Once it was demonstrated that the rejoining of severed blood vessels was possible, the next step was to bridge large defects caused by injury or disease. Occasional brave surgeons attempted a variety of artificial grafting materials, including ivory, glass, aluminum, and silver, but such nonpermeable, nonflexible tubes invariably clotted. By the 1940s a conventional treatment for aortic aneurysms, some the size of volleyballs, involved a tedious eight- to ten-hour surgical procedure of stuffing them with hundreds of feet of fine steel wire through a needle a few inches at a time, in the hope that clotting would occur to prevent rupture. (In this condition, clotting reduces the pressure inside the weakened walls of an aneurysm to prevent rupture.) This technique undoubtedly appeared bizarre to an observer at the time, but yet another factor added a science fiction element to the scene. In an attempt to reduce the high incidence of operative infection, the procedure was performed under ultraviolet light, requiring space lab clothing to protect the operating team from sunburn.

After World War II, natural grafts from humans stored in a few medical center artery banks were used, but these were always in short supply and did not maintain circulation for long.

The patient in the ER was seen first by the senior surgical resident, Dr. Arthur Voorhees, who called his attending physician, Dr. Arthur Blakemore. The ensuing scene was vividly recalled by a participant.
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In the operating room, while awaiting a response to the urgent request for a graft phoned to the aorta bank at a major medical center across
town, Blakemore opened the patient's abdomen and placed a clamp across the abdominal aorta above the aneurysm. It was then that a nurse entered the operating room and grimly announced, “The aorta bank is empty. There isn't an aortic graft in New York City!” Arthur Blakemore was highly respected as an intrepid surgeon with an unflappable attitude that was reinforced by a deliberate manner and a soft, slow way of speaking. He was warmly referred to by his colleagues and staff as “Blake.” After a shocked silence, he quietly drawled, “Well, I guess we'll just have to make one.”

This circumstance set the scene for a dramatic confluence of dedicated research initiated by chance a few years earlier by Arthur Voorhees and the first urgent clinical application of its results. After graduating from Columbia's medical school in 1946, Voorhees was attracted to the “manual engineering” aspects of surgery and was offered a research fellowship after his surgical internship by Blakemore, who as mentor and coinvestigator encouraged and supported his self-described “flights of medical and surgical fantasy.”
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This was an era of exciting developments in cardiovascular surgery, and following the devastating battlefield wounds seen in World War II, there was a fevered drive to find a suitable blood-vessel substitute. A host of favorable conditions set the scene for an explosive development in vascular surgery. These included the availability of antibiotics, blood banks, anticoagulant therapy, and the return from the war of a large number of well-trained surgeons eager for research projects and advancement in their specialties. It was during the fellowship year that Voorhees made a simple observation regarding an inadvertent finding that would revolutionize the field of vascular surgery.

In the spring of 1947, Voorhees was experimenting on dogs, working blindly—only by touch—within the chamber of a beating heart, to develop a procedure for replacing one of the heart's valves. While sewing in the valve's replacement, he unwittingly misplaced one of the silk sutures, which ended up traversing the entire cavity of the left ventricle, the main pumping chamber of the heart. Voorhees was aware that this had occurred and made a mental note to follow up by looking for it in the autopsy on the dog.

Months later, he opened the lifeless dog's heart and was startled at what he saw: a cord stretched across the chamber, its surface glistening. Within, he could discern the three-inch-long stitch. What had caused the glistening filled Voorhees with excitement. The stitch was coated with endocardium—meaning, the lining of the heart chamber had grown over the suture!

Voorhees immediately grasped the potential significance of this serendipitous observation. In a similar way, he creatively imagined the lining of a vessel extending to line the inside of a tubelike graft. Here lay the solution to bridging a large arterial defect. In a flash he could visualize the coated single silk stitch as a component of a cylindrical structure of fabric acting as a latticework of threads that might serve as an arterial prosthesis. Lined by new intima, it would allow blood flow to be restored without inducing blood clots.

To test his idea, he fashioned a silk handkerchief on a sewing machine into a tube and used it to replace a segment of the abdominal aorta in a dog. The graft remained unobstructed for one hour before bleeding occurred.

In 1948 Voorhees was assigned to Brooke Army Medical Center in San Antonio, Texas, where he continued his work on arterial substitutes on his own time. He constructed tubes from scraps of nylon parachute cloth on sewing machines borrowed from one neighbor or another and implanted them in the aortas of six dogs. Results in one dog that survived for a month were promising.

In 1950 Voorhees returned to Columbia-Presbyterian Hospital as a surgical resident. Requirements for the cloth to be used as an arterial prosthesis were few but essential. It had to be strong, inert, stable, of the right porosity to allow endothelial growth through its lattice, supple, and yet easily traversed by a fine suture needle. The Union Carbide Company supplied a bolt of Vinyon-N material, which turned out to be the cloth used in sails. This was too inert to take a dye evenly, so it had little commercial value for the company, but it had all the physical characteristics Voorhees needed. He became adept at turning, flipping, and cutting the cloth into different sizes, shapes, and configurations. Trained as a surgeon, Voorhees needed no lessons in
stitching and suturing. His proficiency on a sewing machine would have made him a master tailor, but he put his talents instead to fashioning prosthetic tubes and implanting them in dogs’ aortas.

He reported his successes in the
Annals of Surgery
in March 1952. Typical of an initial announcement is his dry passive voice: “It was observed in this laboratory that a simple strand of silk suture… became coated in a few months throughout its length by a glistening film.”
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Voorhees planned further experiments, but did not consider using the prosthesis in humans until several months later when faced with the desperately ill man with the ruptured aneurysm and the unavailability of human aorta grafts.

Blakemore's quiet conclusion that “Well, I guess we'll just have to make one” was the signal for immediate action. Voorhees broke scrub, ran down a flight of stairs to the dog lab, hurriedly sewed a sheet of Vinyon into a tubular prosthesis, trimmed off the excess, ran back to the operating room, gave it to the nurse to sterilize in the autoclave, and scrubbed in again. Blakemore sewed in the graft and took off the clamps. The prosthesis functioned well, but the patient died from a heart attack caused by hemorrhagic shock and a diffuse clotting disorder.

Encouraged by the serviceability of the prosthesis, Blakemore placed Vinyon grafts in a succession of aneurysm patients and was thrilled to find that many were successful. A year later, he and Voorhees reported their extensive experimental and clinical work with the Vinyon graft to the National Research Council.
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The surgical world greeted these reports with tremendous excitement. The threshold of a new era in vascular surgery had been crossed.

Throughout the United States, laboratories were established to explore the use of different textiles and methods of fabrication. Steven Friedman, a vascular surgeon, described the avidity of the reception: “Surgical meetings assumed the air of textile conventions, as surgeons readily adopted a new lexicon. Terms such as crimping, needle-per-inch ratio, and tuftal rhexis were glibly bandied about by these pioneer practitioners of arterial replacement with prosthetics.”
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Surgeons quickly adopted Dacron, a polyester fiber well established in the garment industry, over Vinyon because it was easier to sew. This fabric served as the mainstay in the surgical treatment of aneurysms for decades.

Abdominal aortic aneurysm (AAA) is an abnormal widening, or ballooning, of a portion of the aortic artery, related to weakness in its wall. It is a life-threatening condition diagnosed in about 250,000 Americans every year. If detected in advance, with a CT scan or sonogram, the condition is treatable in 95 percent of cases. Undetected, such aneurysms grow and eventually rupture, killing 75 percent of the people who experience them. AAAs are very unusual in people under the age of fifty-five, but as age advances, risk increases. More than 10 percent of men eighty to eighty-five years old experience AAAs. The condition kills at least 9,000 people a year in the United States. Abdominal aortic aneurysm was the cause of death for Albert Einstein, Lucille Ball, and George C. Scott.

Einstein's Fatalism

In December 1948 Albert Einstein, then age sixty-nine, was hospitalized suffering from agonizing abdominal pains. Physicians could feel a grapefruit-sized mass in his abdomen, and surgery confirmed an abdominal aortic aneurysm. His doctors decided not to remove it, but they monitored him and prescribed pain-relieving drugs. Two years later, doctors discovered that the aneurysm had grown.

In terms of his own health, Einstein was a determined fatalist. Told that his aorta might burst unless he took care, he brusquely replied: “Let it burst.” Shortly thereafter, Einstein completed his last will and testament. In April 1955, after collapsing at home, he was taken to Princeton Hospital. The aneurysm had ruptured. He refused emergency surgery, saying, “I do not believe in artificially prolonging life.” His physician and surgical consults could not dissuade him. He died on April 18 and was cremated the same day, except for his brain, which he bequeathed for research.

In the second half of the twentieth century, thousands of patients with AAAs were successfully treated with Dacron grafts. In the 1990s metallic stents replaced Dacron prostheses. These stent-grafts are
introduced through a catheter in an artery in the groin and act as scaffolds within the aortic aneurysms no longer requiring surgical resection. They serve as a sort of artery within an artery: the aneurysm is bypassed, and blood flows through the graft instead. Open abdominal incisions are thus avoided, and some medical centers are now performing this as a one-day outpatient procedure. Former U.S. Senator Bob Dole was treated with a graft when his AAA was discovered in June 2001. (His father had died of an aortic aneurysm).

In 1985, long after being appointed professor of surgery and chief of the vascular service at Columbia-Presbyterian, Voorhees revealed, “I stumbled on the notion…. The whole development was a serendipitous outgrowth of an observation made in a related but different experiment.”
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26

The Nobel Committee Says Yes to NO

The saga of the surprising discovery of how the natural production of a gas, nitric oxide (NO), in the body can cause a wide variety of actions is replete with dramatic instances of stumbling blocks transformed into stepping-stones.

The principal investigator, Robert Furchgott, an academic researcher in pharmacology, is a gentle, soft-spoken, unassuming scientist. Small and thin, he uses a hearing aid and views the world through a thick set of lenses. In a personal interview, he was unusually candid in admitting the illuminating role of numerous “accidental discoveries” along a research trail he followed for more than half a century that revolutionized vascular biology.
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At the beginning of Furchgott's career, the innermost layer of cells lining blood vessels, the endothelium or intima, had classically been thought to serve only as a passive protective lining. The muscle in the wall of the blood vessel surrounding the endothelium, which can contract or dilate (relax), is termed smooth muscle and is not under voluntary control. The pharmacology of smooth muscle became Furchgott's major research interest.