Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (14 page)

Shocked and embarrassed, Waksman reluctantly agreed to settle. He acknowledged in court that Schatz was “entitled to credit legally and scientifically as co-discoverer of streptomycin.” Schatz received an immediate lump sum of $125,000, a public statement by Rutgers officially acknowledging him as codiscoverer of streptomycin, and 3 percent of the royalties. Waksman shared 7 percent of his 17 percent royalty with the other laboratory workers at Rutgers. With half of the rest of the money he started the philanthropic Foundation for Micro-biology, thus reducing his own portion to 5 percent. Waksman took pains to include twelve laboratory assistants, clerks, and even the man who washed out the laboratory glassware. The settlement was broadcast on page one of the
New York Times
and in
Time
magazine.

Schatz felt vindicated and hoped to use the money to continue in microbiology research. But, following the notoriety, the doors of top-grade laboratories were closed to him. No other department head wanted to hire an aggrieved “whistle-blower,” as such a contentious, publicly aired episode had been hitherto virtually unknown within the scientific community. The establishment closed ranks. He was, in effect, blacklisted.

In 1952, two years after the settlement, Waksman became the sole recipient of the Nobel Prize in Physiology or Medicine, even though Nobel regulations allow up to three people to share it. Schatz waged an unsuccessful campaign to obtain a share of the Nobel Prize. Burton Feldman, a historian of Nobel awards, uncharitably refers to Waksman as getting the Nobel “for not discovering streptomycin.”
¹²

The public dispute was tragic for both men. Waksman, heartbroken, regarded the year 1950 as “the darkest one in my whole life” because of the perceived betrayal by Schatz and the horrible publicity brought about by the whole affair.
¹³
Schatz, a penniless student, was at
least financially recompensed but was deprived of what he felt to be his rightful share of the Nobel Prize and of career possibilities. Years later, Waksman would quote Dubos: “In science the credit goes to the man who convinces the world, not to the man to whom the idea first occurs.”
¹⁴

Schatz had to wait fifty years to be awarded Rutgers’ highest honor, the Rutgers Medal, in 1994 as codiscoverer of streptomycin.

Meanwhile, in the same year that Waksman received the Nobel Prize, 1952, his discovery was eclipsed by the introduction of the chemical isoniazid (often called INH), a significantly more effective treatment for tuberculosis, which could be taken orally. With the further discovery that drugs given in combination increased efficacy, the annual death rate from TB per 100,000 population in the United States fell from 50 to 7.1 by 1958.

Serendipity and Cyclosporin

The search for new antibiotics and the microbes that produce them led to the serendipitous discovery of another breakthrough drug in 1978. The Sandoz laboratory in Basel, Switzerland, tested a fungus found in a soil sample from Norway for antibiotic activity. None was found. But one of their enterprising biochemists, Dr. Jean-François Borel, found that it could suppress immunity in cell cultures. An immunosuppresant, a drug that interferes with the body's rejection of foreign tissues, had been unearthed: cyclosporin. This led to the explosive development of human-organ transplant surgery, initially in kidney transplantation, and then in more difficult surgery, such as liver, heart-lung, pancreas, and bone marrow transplants.

The problem with antibiotics is that bacteria reproduce at an astonishing speed and, like all organisms, mutate. As a result, new strains emerge that are resistant to the drugs. The more frequently antibiotics are used, the more quickly bacteria seem to outwit them. In the United States by the year 2005, physicians in practice wrote 130
million prescriptions per year for antibiotics, as many as half of which were unnecessary. Beyond this, at least 30 percent of all hospitalized patients received one or more courses of therapy with antibiotics. One result of this widespread use is the continuous emergence of antibiotic-resistant pathogens, which in turn fuels an ever-increasing need for new drugs.

In 1993 the World Health Organization (WHO) declared tuberculosis, which claimed about 2 million lives each year, a global emergency. WHO estimates that by 2020, one billion people will be newly infected.

7

The Mysterious Protein from Down Under

Hepatitis was the farthest thing from Baruch Blumberg's mind as he pursued his research. Armed with an M.D. from Columbia University and a Ph.D. in biochemistry from Oxford University, he decided to study how and why people of different backgrounds react differently to disease. How do genetically determined biochemical and immunological variants among different populations determine differences in susceptibility and resistance to disease? This concept, known as polymorphism, became the focus of his work at the National Institutes of Health in Bethesda, Maryland.

In the 1950s his field trips over a seven-year period, which focused on drawing blood from diverse peoples, took him all over the world: West and East Africa, Spain, Scandinavia, India, China, Taiwan, the Philippines, Australia, Micronesia, Canada, South America. In high boots and a broad-brimmed hat, Blumberg looked more like Indiana Jones than a genetic researcher. In the search for genetically determined proteins, he assembled an increasingly diverse collection of blood samples.

“B
Y THE
M
IRACLE OF
C
HANCE
…”

In 1960 a leap in his thinking occurred. His premise was straightforward and based on the classic antigen-antibody response. If the blood
of one individual—say, a blood donor—contains a protein that is not natural to another individual, the foreign protein (antigen) may excite an immune response and elicit a defensive globulin (antibody) in the recipient. As he put it, “We decided to test the hypothesis that patients who received large numbers of transfusions might develop antibodies against one or more of the… serum proteins (either known or unknown) which they themselves had not inherited but which the blood donors had.”
¹

Transfused patients are exposed to blood from many different donors and therefore to whatever varying substances exist in that blood. Their immune system reacts to these foreign substances and makes antibodies, which are stored. Blumberg's aim was to use this store of antibodies to find hitherto unknown blood proteins.

He developed a simple technique that could readily identify antigen-antibody reactions. In a central depression in a thin sheet of gel, Blumberg would place the blood of, say, a multiply transfused hemophiliac patient. Presumably exposed many times over to proteins in donors’ blood not common to his own, it would contain a host of antibodies. Blumberg then placed blood samples from various subjects in several other punched holes arrayed around the central well. If any of these contained antigens recognized by antibodies in the central well sample, the resulting chemical reaction would form a dark line in the region of diffusion between them.

In 1963 he came across a surprising finding. Of twenty-four different tests in the panel from individuals all over the world, the blood of a multiply transfused American hemophiliac had an antibody that reacted with only one. That specimen was from a decidedly unlikely source, an Australian aborigine. It had been sent to Blumberg by a colleague from the University of Western Australia in Perth. Blumberg dubbed the mysterious protein “Australia antigen.” What could possibly have been the connection between a hemophiliac patient from New York and an aborigine from Australia?

The following year Blumberg joined the staff of the Fox Chase Cancer Center in Philadelphia and, with colleagues there, tested the unusual New York blood sample against thousands of other samples, trying to find out why the precipitating antibody had occurred. They
observed a similar biochemical fingerprint in some patients with Down's syndrome and certain kinds of leukemia. The presence or absence of the Australia antigen seemed to be a constant feature of an individual.

But then fortune smiled, and a single exception turned the course of the investigation. In 1966 a patient with Down's syndrome, originally negative for the Australian antigen, turned positive. Laboratory tests and liver biopsy confirmed that he had developed hepatitis, without jaundice, in the interval. Blumberg had a true “Eureka!” moment as he came to suspect a link between the Australia antigen and acute viral hepatitis. The following year, another fortuitous event elated the researchers in Blumberg's laboratory. A technician who had previously tested negative for Australia antigen developed symptoms of hepatitis and tested her own serum for liver enzymes and the antigen. Both proved positive, enabling Blumberg to truly connect the dots for the first time.
²

In the previous two centuries, epidemics of what was termed “infectious jaundice” had swept through military troops in many countries. Transmission studies by Japanese and German researchers in 1941–42 established the viral origin of the disease, which came to be known as hepatitis. Then, based on other experiences during World War II, with the advent of transfusions of blood and blood products in 1943, the terms “infectious hepatitis” and “serum hepatitis” appeared, later designated more simply as hepatitis A and hepatitis B. Researchers had not yet identified the actual viruses and didn't know where to look for them.

Hepatitis B attacks liver function. In its more severe form, the viral liver infection produces a loss of appetite, vomiting, and fatigue, but the most characteristic clinical sign is the vivid yellow color—jaundice—it imparts to the whites of the eyes and, often, the entire body. It is transmitted through sex or through contact with blood, via transfusions or dirty needles. About 1.5 million Americans are chronic carriers who may show no signs of the disease but can transmit the virus to others. Far more infectious than the virus that causes AIDS, the hepatitis B virus can live for a week outside the body on a dry surface. Most cases of hepatitis are acute and self-limiting, but many progress to a chronic form that can be deadly. Over 350 million
people worldwide are chronically infected with this virus. It kills more than 1.5 million people a year and is the leading cause of liver cancer.

Blumberg conducted clinical and laboratory studies that tested and supported the hypothesis that the Australia antigen was a hepatitis virus or was located on it. Blumberg then briefly encountered hostility from what he characterized as “the establishment” when his report was rejected for publication. He tried to understand the dynamics of the resistance: “We found the hepatitis virus while we were looking at quite different things. We were outsiders not known to the main body of hepatitis investigators, some of whom had been pursuing their field of interest for decades.”
³
We have seen in several other medical discoveries that the basis of a conceptual reformulation is often ignored initially or faces delayed consideration and acceptance. Only after other groups corroborated Blumberg's unexpected finding was his initial paper published two years later.
⁴

Within a few years, intensive investigations would identify the Australia antigen as the protein that envelops the hepatitis B virus. The connection between the American hemophiliac and the aborigine eventually became clear. Subjected to multiple blood transfusions, the hemophiliac had, at some point, been exposed to blood that contained the hepatitis B virus and had developed antibodies against it. These reacted against the virus's protein in the blood of the aborigine, who happened to be a virus carrier. The inclusion of the aborigine's sample had been a most fortunate happenstance. If Blumberg had examined only the blood of Americans, he might not have stumbled upon his discovery, as fewer than half a percent of Americans are carriers and would yield a positive reaction. In contrast, 20 percent of Australian aborigines have a positive reaction. Even so, Blumberg was lucky to get the reaction at all, but his odds were much improved by the Australian sample. It represented a turning point that, in Blumberg's words, “by the miracle of chance, led us directly to the hepatitis B virus.”
⁵

By 1970 a group of British scientists visualized the whole virus itself by electron microscopy. By the mid-1970s, infection with hepatitis after transfusions essentially disappeared from the United States and the other countries where compulsory testing in blood banks was instituted.

Baruch Blumberg, with his colleague Irving Millman, next turned his attention to developing a vaccine using the sera of patients with the antigen, to elicit antibody production and prevent hepatitis B infection. What was needed was a carefully controlled trial on a population at high risk for hepatitis B. He filed his patent application at the end of 1969.

The perfect individual to conduct such a trial was Wolf Szmuness, an epidemiologist at the New York Blood Center. Szmuness had himself once been part of a population “at high risk”: in the 1960s he had fled with his family to the United States from a series of pogroms in his native Poland against the remaining Jews that had survived World War II. Under his direction, the vaccine was tested on more than a thousand volunteers from the city's gay male community, representing a population at particularly high risk for hepatitis B because of their sexual practices. Almost 70 percent were carriers, and as many as a third of those previously uninfected would become so in a year.

The vaccine was proved highly effective and safe and has been in general use since 1982 when the Fox Chase Cancer Center licensed it to the Merck pharmaceutical firm. More than a billion doses of vaccine have been administered, mainly via national campaigns in Africa, Asia, and the Pacific to reduce the risk of primary liver cancer. New infections in the United States dropped to 80,000 a year in 2006 from more than 200,000 in 1982 when the vaccine was first used, according to the Centers for Disease Control and Prevention in Atlanta. However, the disease is still fairly common among drug abusers who inject themselves.