Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (15 page)

T
HE
W
ILLOWBROOK
E
XPERIMENTS

At the same time Blumberg was doing his work, ninety-two miles away, a pediatrician interested in communicable diseases, Saul Krugman of the New York University School of Medicine, was conducting a series of experiments at the Willowbrook State School, an institution for the care of mentally handicapped children on Staten Island, New York. In the face of pitiful overcrowding, with soiled beds
jammed one next to another in the ward and in the hallways, most of the newly admitted children acquired viral hepatitis in the first six to twelve months. The ward was essentially one giant culture dish inhabited by children.

Krugman divided the children into groups to test their responses to food containing the suspected virus and the effectiveness of injections of gamma globulin (the part of the blood rich in antibodies) in protecting against hepatitis. During the course of the study, a chance observation provided an illuminating insight. Second attacks of hepatitis occurred in about 8 percent, raising the possibility that there was more than one type of hepatitis virus.

By 1967 Krugman's conclusions could not be challenged. Hepatitis is caused by at least two distinct viruses: hepatitis A, of short incubation and highly contagious, and hepatitis B, of long incubation, up to six months, and of lower contagion.
⁶
Krugman also demonstrated for the first time that hepatitis B can be transmitted not only by blood transfusions or poorly sterilized instruments but also by intimate physical contact. His studies were crucial in providing clinical evidence that the Australia antigen was a specific marker for the hepatitis B virus.
⁷

Wanted: Ethical Standards

The studies undertaken by Saul Krugman at the Willowbrook State School involved giving children food containing the live hepatitis virus. In keeping with the accepted standards of the era, Krugman received permission from the parents of the children involved as well as the approval of administrative authorities.

It is hard to believe, but at this time individual scientists and their financial backers could decide for themselves what constituted ethical research. Most of the time, their judgment was sound, but society became incensed at such appalling exceptions.
⁸
These led to the National Research Act of 1974, which required institutional review boards to approve and monitor all federally funded research.

Soon after the identification of the hepatitis B virus, the hepatitis A virus was found by electron microscopy in the waste of patients with hepatitis A and characterized as a small RNA virus. HAV is spread primarily by fecal oral contamination, contaminated water supplies, and food. It has been transmitted rarely by blood transfusion. In developing countries with substandard hygiene and sanitation, the disease is endemic.
⁹

In 1976 the Nobel Prize ceremony in Stockholm openly acknowledged the serendipitous nature of Blumberg's discovery: “Like the princes of Serendip, [he] had found something completely different from the types of substances he was looking for. The protein he had discovered was not a part of normal body constituents but instead a virus causing jaundice.”
¹⁰
In his presentation, Blumberg underscored that what he had stumbled upon was a compelling example of curiosity-driven research. Blumberg, whose friends and colleagues call him Barry, had always fondly attributed his elementary education in a yeshiva in Brooklyn, with its practice of fact-based argumentation, as conducive to modern scientific thought. It involves comparison of different interpretations, analysis of all possible and impossible aspects of the given problem, in order to arrive at an original synthesis that has never been offered before. Beyond that, Blumberg learned an invaluable lesson: “In research, it is often essential to spot the exceptions to the rule—those cases that do not fit what you perceive as the emerging picture…. Frequently the most interesting findings grow out of the ‘chance’ or unanticipated results.”
¹¹

Baruch Blumberg did not set out to discover the hepatitis B virus. As occurred in many of the greatest medical advances of the past hundred years, he stumbled upon the answer to a question he never intended to ask.
¹²
His unexpected “Eureka!” moment, which was favored, in his words, “by the miracle of chance,” illuminated a potentially devastating disease affecting millions worldwide.

8

“This Ulcer ‘Bugs’ Me!”

Nothing is so firmly believed as that which we least know.

—M
ICHEL DE
M
ONTAIGNE

“Oysters,” my grandfather, a Russian immigrant to America, called them. “Calm down, relax, or you'll get oysters in the stomach,” or “Don't eat so much spicy food—it'll give you oysters!” In the small inland town in which I grew up, oysters were an unknown delicacy, but to an immigrant's ear, the nuances of the English language often were lost. Pronunciation issues aside, my grandfather nevertheless displayed enough familiarity with the prevailing medical opinion of the time regarding the relationship between stress or spicy foods and stomach ulcers to admonish the members of his family.

“N
O
A
CID
, N
O
U
LCER
”

An ulcer is an open sore on the mucous membrane lining the stomach or the duodenum, the portion of the intestine extending immediately beyond the stomach. Since ulcers affect an estimated 5 million Americans, with about 400,000 new cases reported each year, the condition—with the complications of pain, bleeding, and perforation—is no small matter.

For many decades, Schwartz's dictum of 1910—“No acid,
noulcer”—governed treatment of peptic ulcer disease.
¹
The inside of the stomach is bathed every day in about half a gallon of gastric juice, which is composed of digestive enzymes and concentrated hydrochloric acid. Doctors typically treated ulcers by initially ordering changes in a patient's diet, in an attempt to protect the stomach walls from its acid. The Sippy diet, introduced by Chicago physician Bertram W. Sippy in 1915, was practiced well into the 1970s. Sippy called for three ounces of a milk-and-cream mixture every hour from 7:00
A.M
. until 7:00
P.M
., and one soft egg and three ounces of cereal three times a day. Cream soups of various kinds and other soft foods could be substituted now and then, as desired. Accompanied by large doses of magnesia powder and sodium bicarbonate powder, such “feedings,” as meals were known, would continue for years—if not for life.
²

Unfortunately, the intake of food brings about not only increased saliva but also the production of stomach acid in preparation for digestion. The Sippy method was thus rarely successful because, though doctors didn't realize it, the diet actually increased levels of stomach acid and therefore aggravated the symptoms of ulcers. In contemplating this well-intended but entirely inappropriate approach, one is reminded of the all-purpose huckster advertising slogan: “Successful except in intractable cases.” Physicians treating their ulcer patients with the Sippy diet must have been amazed at how many of their cases proved intractable. The fact that this falsely based approach nonetheless persisted for six decades illustrates the unfortunate fact that conventional wisdom once adopted remains stuck in place even when it flies in the face of reality.

Ulcers often progressed to the point of chronic distress with the potential of life-threatening bleeding. In such cases, the answer was surgery to remove the acid-secreting portion of the stomach.

Besides blaming stress, diet, and tobacco as factors in the development of ulcers, many physicians believed there was also a psychosomatic aspect. Building on Freud's insights and Adler's idea of “organ inferiority,” the concept of psychosomatic medicine was furthered by the experience of World War I, in which as many as 80,000 “shell-shocked” soldiers suffered from various severe somatic symptoms that seemed to have emotional origins. In his 1950 book
Psychosomatic Medicine,
Franz Alexander defined the cause of ulcers as internal conflict caused by a regressive wish to be dependent on others, the feelings stimulating increased gastric motility and secretion in anticipation of being fed by idealized parents. When the wish cannot be gratified through normal adult relationships, it was concluded, an ulcer results. In
Stress and Disease,
an influential medical textbook published in 1968, Harold G. Wolff, a well-known psychiatrist, described excess gastric secretion as a reaction to rampant “competitive striving” and other pressures of contemporary society, despite the fact that stressful life events had not been shown to be more common in patients with ulcers than in the general population.

Nevertheless, the stress-acid theory of ulcers gained further credibility when safe and effective agents to reduce gastric acid, known as H2 blockers, were introduced in the 1970s. Acid inhibitors, such as cimetidine (Tagamet) and ranitidine (Zantac), became so popular and were taken over such extended periods that they became the world's biggest-selling prescription drugs. By 1992 the worldwide market for prescription ulcer medications amounted to $6 billion a year. Ulcers affect one in ten adults in the Western world. These acid inhibitors are effective at easing symptoms, but they fail to prevent ulcers from recurring.

S
WIMMING
A
GAINST THE
T
IDE OF
“C
ERTAINTY
”

No one ever even considered a bacterial cause for ulcers. Gastroenterologists invariably thought the stomach a sterile environment. Gastric juices are so acidic, a tooth immersed in a container of the fluid overnight would have its enamel dissolved. It was taken as doctrine that bacteria could not survive and flourish in such a harsh, inhospitable environment. It is nevertheless a curious historical fact that, over the years, spiral bacteria were glimpsed in specimens of the human stomach but were dismissed as either contaminants or opportunists that had colonized the tissue near ulcers. In 1954 a widely respected gastroenterologist reported finding no spiral bacteria in more than a thousand biopsy specimens of the stomach, and this report provided what was considered “conclusive” evidence that gastric bacteria, if present, were incidental.
³

The overthrow of long-held but false concepts frequently is initiated not by those at the top of their fields but rather by those at the fringes. And technological advances in the 1970s opened a new door. Flexible fiberoptic gastroscopes enabled doctors to take targeted biopsy samples from a larger area of the stomach. In 1979 J. Robin Warren, a staff pathologist at the Royal Perth Hospital in Western Australia, was examining biopsy samples from patients with gastritis when he made a puzzling observation: there were unexpectedly large numbers of curved and spiral-shaped bacteria. He then used a special stain to make their number and shape more evident and saw that stomach cells near the bacteria were damaged.

Warren persisted in his systematic observations over the next two years. The bacteria were present in many gastric biopsies, usually in association with persistent stomach inflammation, termed chronic superficial gastritis. They were sited, often in colonies, beneath the mucus layer, indicating that they were not contaminants from the mouth, and were thriving within the mucus. Furthermore, Warren noted that the bacteria were all the same, not varied, as would be expected of secondary invaders.

Slightly Crackers

Later, reflecting on his discovery of what would be identified as
H. pylori
in the stomach, Warren commented: “It was something that came out of the blue. I happened to be there at the right time, because of the improvements in gastroenterology in the seventies…. Anyone who said there were bacteria in the stomach was thought to be slightly crackers.”
⁴

The fact that the bacteria settle particularly in the gastric antrum (the lower part of the stomach), as well as local variations in bacterial density, may explain why previous biopsies had failed to detect it. More to the point, stomach bacteria may have been overlooked simply because pathologists were not looking for it.

Despite his intriguing findings and repeated attempts to interest
his hospital's gastroenterologists in the bacteria, Warren consistently encountered indifference. At this time, an unlikely deus ex machina appeared on the scene.

Barry Marshall, a lanky twenty-nine-year-old resident in internal medicine at Warren's hospital, was assigned to gastroenterology for six months as part of his training and was looking for a research project. The eldest son of a welder and a nurse, Marshall grew up in a remote area of Western Australia where self-sufficiency and common sense were essential characteristics. His personal qualities of intelligence, tenacity, open-mindedness, and self-confidence would serve him and Warren well in bringing about a conceptual revolution. Relatively new to gastroenterology, he did not hold a set of well-entrenched beliefs. Marshall could maintain a healthy skepticism toward accepted wisdom. Indeed, the concept that bacteria caused stomach inflammation, and even ulcers, was less alien to him than to most gastroenterologists.

Is There Such a Thing as Stagnant Knowledge?