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“Breaking the back of polio”

Yale Medicine Magazine, 2005 - Autumn


In the 1940s, Yale’s Dorothy Horstmann solved a puzzle that would lead to the first polio vaccines 50 years ago this year.

Fifty years ago this year, following the largest public health trial in American history, a killed-virus polio vaccine developed by Jonas Salk, M.D., was found to be safe, potent and effective. The news set off a national celebration. Salk became an instant hero, the country’s first celebrity-scientist, a miracle worker in a starched white lab coat. But as the years passed, the essential contributions of other researchers to this lifesaving vaccine were lost to history. Dozens of men and women had been involved—at Harvard and Yale, at Johns Hopkins and the Rockefeller Institute for Medical Research, at the University of Michigan, the University of Pittsburgh and the University of Cincinnati. What follows is the story of Dorothy Millicent Horstmann, M.D., FW ’43, whose patience and intuition produced a stunning breakthrough that made polio vaccines possible.

The story begins in June 1916, with a health crisis in Pigtown, a densely populated immigrant neighborhood of Brooklyn, N.Y. Frightened Italian parents had approached local doctors and priests, according to news accounts, “complaining that their child could not hold a bottle or that the leg seemed limp.” When the first deaths followed a few days later, health department investigators rushed to Pigtown for a house-to-house inspection. All signs pointed to a disease known as infantile paralysis, or poliomyelitis (soon shortened to “polio” by the newspapers to save headline space). As it spread from Brooklyn, communities across the Northeast closed their doors to outsiders, using heavily armed policemen to patrol the train stations and the roads. The epidemic, which lasted through October 1916, claimed 6,000 lives and left 27,000 people paralyzed. New York City alone reported 8,900 cases and 2,400 deaths, 80 percent of the fatalities being children under 5. There had been minor polio outbreaks in previous years, but nothing like this.

“The menace for the future,” warned a federal health official, “is very real.”

Polio is an intestinal infection spread by contact with fecal waste. The virus enters the body through the mouth, travels down the digestive tract and is excreted in the stool. Usually the infection is slight, with minor symptoms. In a small number of cases—about one in 100—the virus invades the central nervous system, destroying the motor neurons that stimulate the muscle fibers to contract. At its worst, polio causes irreversible paralysis, most often in the legs. Most deaths occur when the breathing muscles are immobilized, a condition known as bulbar polio, in which the brain stem is badly damaged.

Though poliovirus has long been present in the environment, the disease, unlike smallpox or influenza, had triggered no major outbreaks around the world. Why it took root in Western nations, especially the United States, during the 20th century is still a matter of debate. Some researchers pointed to more careful reporting and better diagnostic techniques. Others noted the circulation of more virulent strains of poliovirus, capable of multiplying at a ferocious rate. Still others saw a correlation between the spread of polio and the ever-increasing standards of personal hygiene in the United States—people were less likely to come into contact with poliovirus early in life when the infection is milder and maternal antibodies offer temporary protection. Put simply, America’s antiseptic revolution brought risks as well as rewards.

A dread disease strikes at random

By mid-century, polio had become the nation’s most feared disease. And with good reason. It hit without warning. It killed some victims and marked others for life, leaving behind vivid reminders for all to see: wheelchairs, crutches, leg braces and deformed limbs. In 1921, it paralyzed 39-year-old Franklin Delano Roosevelt, robust and athletic, with a long pedigree and a cherished family name. If a man like Roosevelt could be stricken, then no one was immune.

Each June in America, like clockwork, came newspaper photos of jam-packed polio wards and eerily deserted beaches. Newspapers ran tallies of the victims—age, sex, type of paralysis—akin to baseball box scores. Children were warned not to jump into puddles or share a friend’s ice cream cone. Parents checked for every known symptom: a sore throat, a fever, the chills, nausea, an aching limb. Some gave their children a daily “polio test.” Did the neck swivel? Did the toes wiggle? Could the chin reach the chest?

In truth, polio was never the raging epidemic portrayed by the media, not even at its height in the late 1940s and early 1950s. Ten times as many children would be killed in accidents in these years, and three times as many would die of cancer. What had changed following World War II was the incidence of polio in the United States as well as the rising age of the victims, a quarter of whom were now older than 10. From 1940 to 1944, reported polio cases doubled to eight per 100,000, doubled again to 16 per 100,000 between 1945 and 1949, and climbed to 25 per 100,000 from 1950 to 1954, before peaking at 37 per 100,000 in 1952. “The United States had never experienced a higher crest of the epidemiological wave,” a journalist noted of the 57,000 reported cases that year, “and never would again.”

The drive to combat polio was led by the National Foundation for Infantile Paralysis, now known as the March of Dimes. The genius of this foundation lay in its ability to single out polio for special attention, making it seem more ominous, and curable, than other diseases. Its strategy would revolutionize the way charities raised money and penetrated the world of medical research. Millions of foundation dollars would be spent to set up virology programs and polio units across the country, with the first grant going to the Yale School of Medicine in 1936. Although research funding went in many directions, one point became increasingly clear: the best way to prevent polio would come through a vaccine.

This was hardly a revelation. Vaccines already had proved successful against other viruses—smallpox and rabies being notable examples. But producing a safe and effective one against polio would not be easy. Three major problems had to be solved. First, researchers would have to determine how many different types of poliovirus there were. Second, they would have to develop a safe and steady supply of each virus type for use in a vaccine. Third, they would have to discover the true pathogenesis of polio—its route to the central nervous system—in order to fix the exact time and place for the vaccine to do its work.

The first problem took the longest to solve. Dozens of strains were examined, using the stools, throat cultures and, in fatal cases, nerve tissue of polio victims. Most of this work was done by ambitious young researchers hoping to attract March of Dimes grant money. (The list included Salk at the University of Pittsburgh.) As it turned out, all of the 196 tested strains of poliovirus fit neatly into three distinct types. The poliovirus family proved remarkably, conveniently, small.

A polio vaccine, then, would have to protect against all three virus types to be successful. The next step involved the harvesting of poliovirus that was safe enough, and plentiful enough, for use in that vaccine. At Harvard, John F. Enders, Ph.D., a Yale College graduate, Frederick C. Robbins, M.D., and Thomas H. Weller, M.D., using in vitro cultivation, grew poliovirus in non-nerve tissue—a breakthrough that would win them the Nobel Prize in physiology or medicine. By cultivating these viruses in a test tube, rather than in the brain or spinal column of a monkey, researchers could get a better look at the changes occurring in polio-infected cells. Far more important, a safe reservoir of poliovirus had now been created, free from the contaminating effects of animal nerve tissue. And that, in turn, made possible the mass production of a vaccine.

But a major problem remained to be solved. Though Albert B. Sabin, M.D., and others had speculated that poliovirus entered the body through the mouth and worked its way down the digestive tract, no one had yet discovered traces of the virus in the victim’s bloodstream. How, then, did it wind up in the central nervous system? The answer would come from a research laboratory at Yale.

A girl’s impossible dream in a world of men

Horstmann had a powerful fantasy as a child: she imagined herself as a doctor. Born in Spokane, Wash., in 1911, she grew up in San Francisco, where as a teenager she accompanied a physician friend of the family as he made his rounds through the local hospital. Earning her undergraduate (1936) and medical (1940) degrees from the University of California, San Francisco, Horstmann recalled that it had “never crossed my mind that [this] was in any way unusual for a woman. … It was quite natural.”

In 1941, Horstmann applied for a residency at Vanderbilt University Hospital in Nashville, where the chief of medicine, Hugh Morgan, M.D., had a strict policy of choosing only men. “I got back a polite letter, saying no,” she recalled in an unpublished interview with historian Daniel J. Wilson, Ph.D., of Muhlenberg College in Pennsylvania. “I wasn’t exactly crushed, but I was disappointed.” Six months later, while considering an offer to enter private practice in San Francisco, she received a note from Morgan asking if “Dr. Horstmann” was still interested. She was, indeed. Somehow, Morgan had forgotten that Dr. Horstmann was a woman. Horstmann later learned from his secretary that when Morgan discovered his error, he “all but went into shock. … But we became friends, and I had a very good year there.”

When Horstmann subsequently applied for a postdoctoral fellowship at Yale, her first visit to New Haven did not go well. She had hoped to study with John R. Paul, M.D., a young pathologist who had co-founded the Yale Poliomyelitis Study Unit in 1931 with James D. Trask, M.D. As luck would have it, Paul had been called away to study a polio epidemic, leaving Horstmann to meet with Francis G. Blake, M.D., the acting dean. A giant in the field of infectious disease who was known to generations of medical students as “stuffy and remote,” Blake couldn’t quite picture Horstmann at Yale. Indeed, she recalled, he “went on to tell me how the last woman he had on the house staff did something awful.” Offended, and blissfully ignorant of the dean’s imposing reputation, she replied that “if a woman on the house staff did not live up to expectations it was remembered for the next 50 years, but if the person was a man, it was forgotten by the next year.” Horstmann was told the decision would be up to Paul. “He accepted me,” she said, “and that is how it all began.”

In 1942, with World War II under way, she arrived at Yale. As head of the Commission on Neurotropic Virus Diseases of the Army Epidemiological Board, Paul was constantly traveling to remote parts of the world. Concentrating on the spread of polio among Allied troops in North Africa, Paul confirmed the theory that adults from areas with high sanitary standards, such as Western Europe and the United States, were far more susceptible to the disease than the local population, which had built up immunity following generations of exposure.

In New Haven, Horstmann joined the Yale polio unit. Missing its two founders—Trask died of a bacterial infection in 1942 while working at an Army camp—the ranks included a handful of superb researchers, such as Joseph L. Melnick, M.D., and Robert Ward, M.D. Using an approach pioneered by Paul and known as “clinical epidemiology,” the polio unit, including Horstmann, tracked polio epidemics in Connecticut, Illinois, New Jersey, western New York state and Hickory, N.C., site of one of the worst outbreaks of the 20th century. The unit tested water and sewage, trapped flies and other insects and took blood samples from those who had the disease and those without symptoms, hoping to discover both the route of poliovirus through the body and the manner of transmission from one person to another. For Horstmann, who had come to Yale to study Streptococci, the switch to polio was inspiring. “It had a dramatic immediacy,” she said. “When you deal with an epidemic you realize it’s an urgent thing. There was so much to be learned.”

Tracking polio’s pathogenesis

Like others in the polio group, Horstmann combined her clinical studies with laboratory research. During a polio epidemic in New Haven in 1943, she collected blood specimens from every patient admitted to the hospital with symptoms of the disease—111 in all. Only one tested positive for poliovirus, a little girl with minor neck pain. Was it possible, Horstmann wondered, that poliovirus was only present in the bloodstream during the brief period before a victim took sick and the physical symptoms became apparent?

To test this theory, she began a series of experiments on monkeys, feeding them poliovirus by mouth to determine if, and when, it turned up in their blood. The results were dramatic. Poliovirus was detected within days of the feedings. Why had so many others failed to discover this? The answer was deceptively simple: they had waited too long before looking. Horstmann’s discovery, published in 1952, would pave the way for both the Salk killed-virus polio vaccine and the Sabin live-virus polio vaccine.

Working independently at Johns Hopkins, researcher David Bodian, Ph.D., M.D., later reported almost identical results. When poliovirus enters the blood, it creates the very antibodies that will soon destroy it, wiping away the signs of its existence. Horstmann had determined the time (early in the infection) and the place (the bloodstream) for the battle against polio to be waged. Her findings meant that an immunizing vaccine, packing low levels of antibody, could destroy the virus before it entered the central nervous system. In a personal letter to Horstmann in 1953, John F. Fulton, M.D., D.Phil., Yale’s distinguished historian of medicine, proclaimed: “This disclosure is as exciting as anything that has happened in the Yale Medical School since I first came here in 1930 and is a tremendous credit to your industry and scientific imagination. … It is also medical history.”

That history would continue. In 1959, the World Health Organization sent Horstmann to the Soviet Union, Czechoslovakia and Poland to evaluate the massive public health trial involving Sabin’s oral polio vaccine. Her favorable report led the way to its licensing, and widespread acceptance, in the United States and beyond. Worldwide the incidence of polio fell to 1,919 cases in 2002, a decline of 99 percent since 1988, when 350,000 cases were reported. The United States has not seen a case of wild polio since 1979.

In later years, Horstmann became the first female professor of medicine at Yale (1961), the first woman in the university to hold an endowed chair (1969) and an elected member of the National Academy of Sciences (1975).

Horstmann died in 2001. Today her portrait hangs at the School of Medicine in a gallery of luminaries from the 19th and early 20th centuries. She is the only woman honored on these walls. YM

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