Vaccinated Page 7

  What would have happened if Maurice Hilleman had made his measles vaccine using eggs contaminated with chicken leukemia virus? Would the vaccine have caused leukemia or other cancers? The answer came in 1972, ten years after Hilleman had licensed his first measles vaccine. Researchers studied about three thousand veterans of the Second World War who had died of cancer to see whether they were likely to have received a yellow fever vaccine made in eggs contaminated with chicken leukemia virus. The answer was no. Although chicken leukemia virus caused cancer in chickens, it didn’t cause cancer in humans. But when Maurice Hilleman made his measles vaccines, he didn’t know that. “I just couldn’t take that chance,” he recalled.

  CHAPTER 5

  Coughs, Colds, Cancers, and Chickens

  “This blender is going to revolutionize American drinks.”

  FRED WARING

  Between 1944, when he left the University of Chicago to work at E. R. Squibb, and 1968, when he made his own measles vaccine at Merck, Maurice Hilleman made or tried to make several unusual vaccines.

  One prevented cancer.

  Hilleman’s vaccines to prevent measles, mumps, and pandemic influenza all had one thing in common: they were made in chickens. “Chickens were my best friend,” he said. “I could hypnotize them. All you had to do was lay them on their side and let them stare at a white feather. They were transfixed by that feather. They helped me so much. Maybe I could do something for them.” When Hilleman finally paid his debt to chickens, he also fulfilled a promise that was made, but never kept, by Herbert Hoover.

  During the 1928 campaign for the presidency of the United States, newspaper advertisements by the Republican National Committee proclaimed that Warren Harding and Calvin Coolidge had “reduced [work] hours and increased earning capacity, silenced discontent, put the proverbial ‘chicken in every pot,’ and a car in every backyard, to boot.” The advertisement stressed that a vote for Herbert Hoover was a vote for continued prosperity. The promise of a chicken in every pot was attractive. Chickens, like turkeys today, were expensive, served only as a delicacy for special occasions. But Herbert Hoover, who presided over the stock market crash of 1929 and the beginning of the Great Depression of the 1930s, never kept the promise.

  Hilleman remembered a strange disease that had affected chickens on his family’s farm when he was a child: “Every year we had chickens that would die or become ill from an unknown cause.” Some chickens destined for the Hillemans’ dinner table were thin and weak or had ghastly, rock-hard tumors under their skin or in their organs. “[Aunt Edith] would have a chicken killed now and then. When she saw a chicken that had lumps on the skin or had any tumors, she would say ‘We can’t eat that.’” Years later, the mysterious ailment had a name: Marek’s disease. By the early 1960s, researchers found that Marek’s disease was caused by a herpesvirus.

  Marek’s disease wasn’t a problem only on the Hilleman farm. It was a problem on many farms, affecting 20 percent of all chickens produced in the United States. The disease attacked the nerves of the legs, causing paralysis; chickens died because they couldn’t get food and water or because they were trampled by other birds. Farmers called it “range paralysis,” referring to infected chickens as being “down in the leg.” The virus also caused cancer of the skin, ovaries, liver, kidneys, heart, and spleen, killing one third of its victims. There was no treatment. Farmers simply culled infected chickens from the flock and destroyed them.

  Marek’s disease was also highly contagious. The virus hid in the fine, light dandruff that filled the air of the chicken coop. “We had these chickens dying all the time with range paralysis,” recalled Hilleman. “[In the chicken coop] there were these great festoons of chicken dandruff. We had a wire hanging down from the ceiling, and it would be just like a hive of bees swarming.” Because of its surface charge, the dandruff would cling to the wires. “Electrostatically, you would have one or two gallons of chicken dandruff hanging on there.” The light spray of dandruff hung in the air for months, easily spreading from coop to coop and farm to farm.

  Hilleman had seen Marek’s disease and remembered it. When Ben Burmester, a veterinary researcher in Michigan, found that a herpesvirus similar to Marek’s virus also caused disease in turkeys and quail, Hilleman saw his opening. “One day I get a call from Burmester from the East Lansing Regional Poultry Center,” recalled Hilleman. “[He] said, ‘Maurice, we’ve isolated a virus here from turkeys, and when we vaccinate chickens, they become resistant to Marek’s disease.’ I said ‘Ben, I’ll be out tomorrow.’ I asked him, ‘What is your interest?’ And [Ben] told me, ‘I just made an observation, I can’t do anything with it.’”

  Hilleman took Burmester’s turkey herpesvirus, grew it in the laboratory, injected it into one-day-old chicks, and found that they were protected from Marek’s disease. But before he could distribute his Marek’s vaccine, Hilleman had one more obstacle. He had to convince Merck’s board of directors to get into the chicken vaccine business. Max Tishler, Hilleman’s boss and the director of research at Merck, set up a meeting with the board. Tishler wasn’t interested in making products for animals and was certain that the board would agree. “I got hell [from Tishler] for developing the product,” recalls Hilleman. “I was asked to go to the board of directors, and the directors said, ‘That’s wonderful; go ahead.’ Max came running after me after the meeting and said, ‘Why did you do that?’ I said ‘You were the one who told me to go to the meeting.’ And [Tishler] said, ‘Yeah, but I didn’t want you to succeed. We’re not in the chicken business.’ [Marek’s disease] vaccine was such a drain on our laboratory. But it was the world’s first cancer vaccine.” Merck, like it or not, was now selling products made for chickens. Soon it would be selling the chickens too.

  Chicken farmers are in the business of converting carbohydrate (grain) into protein (meat). “There are two kinds of chicken breeders in this world,” recalled Hilleman. “There are those who breed chickens to get maximum egg production, and those who breed for maximum meat production. They all, with the exception of one company, would breed for resistance to Marek’s disease.” The one company was Hubbard Farms of Walpole, New Hampshire.

  In 1921 Oliver Hubbard, one of the first students to graduate from the University of New Hampshire with a degree in poultry farming, founded Hubbard Farms. By the early 1930s, Hubbard had developed the New Hampshire chicken, a breed unrivaled for egg and meat production. But there was one problem. The New Hampshire chicken was more susceptible to Marek’s disease than any other breed. “Hubbard Farm chickens were by far the most productive means of converting carbohydrate to protein than any other chicken in the world,” remembered Hilleman. “But if you got Marek’s into the flock, you were done.” Hilleman saw an opportunity for Merck. “Merck was out for an acquisition, and it was obvious what to do. We’ll buy Hubbard! [We’ll combine] these efficient carbohydrate-to-protein chickens with the vaccine that compensated for their genetic susceptibility to Marek’s disease.”

  In 1974, Merck bought Hubbard Farms for $70 million. Hilleman’s vaccine, the first to prevent cancer in any species, revolutionized the poultry business. Excess production caused the price of chickens to drop from $2 per broiler to forty cents and of eggs from fifty cents per dozen to five cents. Soon everyone could afford chickens, and for a while, Merck, one of the more conservative pharmaceutical companies in the United States, was the biggest chicken and egg producer in the world.

  WITH HIS MAREK’S VACCINE, MAURICE HILLEMAN BECAME THE FIRST person to make a vaccine to prevent cancer. He was also the first person to purify, characterize, and produce a drug that is now used to treat certain cancers in people.

  In the early 1900s Alexander Fleming, a Scottish biologist working in London, returned from a vacation to find something unusual in his laboratory. Fleming worked with Staphylococcus aureus, a bacterium commonly found on the skin and in the environment. He grew the bacteria in laboratory plates, where it formed small golden-yellow colonies (in Latin aureus m
eans “gold”). When Fleming returned to the laboratory after several weeks he found, much to his dismay, that the plates had been overrun with mold: fluffy green mold. But he also noticed something else. Although many colonies of bacteria were present throughout the dish, he didn’t see any in the areas immediately surrounding the mold. Fleming reasoned that a substance produced by the mold was killing the bacteria. Because the name of the mold was Penicillium notatum, Fleming called the substance penicillin. In 1929 Fleming published a paper titled “On the Antimicrobial Action of Cultures of a Penicillium with Special Reference to Their Use in the Isolation of B. Influenzae.” Fleming’s first description of penicillin is regarded as one of the most important medical papers ever written.

  For the next six years Alexander Fleming worked fitfully on his new antibiotic. But Fleming was a biologist, not a chemist; he never successfully purified penicillin. In 1935, six years after publishing his discovery, he gave up. Several years later, at the start of the Second World War, a team of researchers at Oxford University headed by Howard Florey picked up where Fleming had left off. They purified penicillin, described its physical and chemical properties, studied its effects in animals and humans, and showed how to mass-produce it, just in time to save the lives of tens of thousands of Allied soldiers.

  Ten years after abandoning his research on penicillin, Alexander Fleming won the Nobel Prize in medicine “for the discovery of penicillin and its curative effect in various infectious diseases.” Although our understanding of what penicillin is, how it works, and how it can be used to save lives couldn’t have happened without Howard Florey, few know his name. When people think of penicillin, they think of Alexander Fleming. The story of Fleming and Florey would be repeated with the discovery of the first substance to inhibit the growth of viruses and treat cancer.

  In 1957 Alick Isaacs, a Scottish virologist working on influenza virus, teamed with a Swiss biologist named Jean Lindenmann. Working in Mill Hill Laboratories just outside of London, they found, as had many researchers before them, that influenza virus destroyed cells in the membrane that surrounded chick embryos. But unlike other researchers, they found that if they first treated the chick cells with a strain of killed influenza virus, then live influenza virus didn’t destroy the cells. Isaacs and Lindenmann reasoned that chick cells exposed to killed influenza virus were making a substance that inhibited the ability of influenza virus to grow. They called this interfering substance interferon. Isaacs thought that biologists had now described their own unique element. “It is time that biologists had a fundamental particle,” he said, “for the physicists have so many: electron, neutron, proton.” Many skeptical scientists disagreed, preferring to call Isaacs and Lindenmann’s finding an “imaginon.”

  Maurice Hilleman and the interferon team at Merck, circa early 1960s.

  Unfortunately, Isaacs and Lindenmann couldn’t purify interferon, so they couldn’t study what it was or how it worked. Hilleman, by figuring out how to mass-produce it, revolutionized the field of interferon research. Where Isaacs and Lindenmann’s preparation contained seventy units of interferon per milliliter (one fifth of a teaspoon of liquid), Hilleman’s contained more than two hundred thousand. Hilleman’s final product was so pure that one unit of interferon activity was contained in only forty nanograms of protein (about one two-millionths of the weight of a grain of sand)—a potency to treat viruses that was, on a weight basis, actually greater than the potency of penicillin to treat bacteria.

  Because he was the first to purify interferon, Hilleman was the first to detail its physical, chemical, and biological properties. He found that interferon was produced not only by cells from chick embryos but also by cells from calves, hamsters, dogs, rabbits, mice, and humans. He found that interferon inhibited the growth of many human and animal viruses, including cowpox, rabies, and yellow fever. He found that interferon not only prevented infections caused by viruses but also prevented cancers caused by viruses. “Interferon was the first antiviral agent, the grandfather of them all. It was a real good inducer of resistance,” recalled Hilleman. “We could stop [cancer-causing] viruses. We could stop nearly every god-damned virus.”

  In the mid-1960s, Maurice Hilleman reasoned that interferon could be useful in treating chronic infections and cancers. And he was right. Today interferon is used in the treatment of chronic infections with hepatitis B and hepatitis C viruses, as well as cancers such as leukemia, lymphoma, and malignant melanoma.

  HILLEMAN MADE ONE OF HIS VACCINES IN A LEAKY WARING BLENDER.

  In 1944, when the United States was preparing to invade the Far East, the military became very concerned about a virus called Japanese encephalitis virus (JEV), one of the most common infections of the brain in the world. Transmitted by mosquitoes, JEV causes seizures, paralysis, coma, and death in one of every three of its victims; another third are left with permanent brain damage. Indeed, JEV is still a common infection in Southeast Asia. Every year the virus infects twenty thousand people—mostly children—and kills six thousand.

  Because American servicemen had never been exposed to JEV, they were, like the children of Asia, highly susceptible to the disease and its consequences. Military health officials asked pharmaceutical companies to submit bids for the production of JEV vaccine. Hilleman had just taken a job at E. R. Squibb. He wanted Squibb to win the contract. While at the University of Chicago, Hilleman had found that JEV could be grown in mouse brains and killed with formaldehyde. He also knew from studies performed in Russia and Japan that formaldehyde-treated JEV could prevent disease. “We [at Squibb] put out a bid for $3 a dose and said that we could have a production facility up and running in thirty days,” he said.

  Hilleman promised to make hundreds of thousands of doses of JEV vaccine for the military. But Squibb didn’t share his patriotic enthusiasm, certain that Hilleman couldn’t possibly make that much vaccine that quickly. “We had nothing on the plant site other than an old horse barn,” recalled Hilleman. “And we had to start production in thirty days. They gave me an engineer. He said to me, ‘How in the hell are we going to start production in thirty days?’ So we sat down and tried to figure out how to make a laboratory. We bulldozed all of the horse manure out of the barn and painted a concrete floor. We cleaned out the loft upstairs, where all the hay had been stored and put in a stairway. Then we put in heating and electricity.”

  To make the vaccine, Hilleman’s technicians injected JEV into mouse brains. Then they waited a few days until the virus reproduced. Hilleman remembered what happened next: “The girls would take the mice and [kill] them with ether. Then they would dip the mice in Lysol, strip the skin from the skull, and scoop out the brains with scissors.” Before treating the virus with formaldehyde, Hilleman put hundreds of tiny mouse brains into a Waring blender (named for the popular bandleader Fred Waring, who marketed it). Sometimes, when homogenized brains leaked out of the blender, Hilleman worried that technicians would catch the disease. “We put the brains into Fred Waring’s cocktail blender. And those damned blenders would leak out of the base, and sometimes brains would squirt out of the tops of the blenders. Waring didn’t give a damn about cocktail loss, but when mouse brains started to leak onto the floor, it scared the hell out of me.” (For whatever reason, television commercials for the Waring blender in the 1950s never featured its capacity to homogenize mouse brains.) Thirty women, working eight-hour shifts and processing two mice per minute, harvested about thirty thousand mouse brains a day. Because the JEV vaccine was given as a series of three doses, it took about three months to make enough of it to immunize six hundred thousand American troops. Military epidemiologists never performed studies to determine whether Hilleman’s JEV vaccine worked during the latter stages of the Second World War. But it is likely that the vaccine prevented disease in thousands of soldiers. JEV vaccine is still made in mouse brains today.

  ALTHOUGH HILLEMAN HAD A REMARKABLE RECORD OF SUCCESS IN making vaccines, he failed to make one to prevent the world’s most wi
despread and most annoying infection: the common cold. But he tried.

  The common cold has plagued humankind since the beginning of recorded history.

  Countless efforts to cure it have generally failed. In the fifth century B.C., Hippocrates noted that despite many attempts, therapeutic bleeding didn’t work. In the first century A.D., Pliny the Elder recommended “kissing the hairy muzzle of a mouse” (which also didn’t work). In the eighteenth century, Benjamin Franklin said that colds were spread from one person to another (which was true) and that people would be less likely to catch colds if they avoided damp, cold conditions (which wasn’t true). Today, people treat colds with echinacea, St. John’s wort, vitamin C, vitamin E, and zinc. But perhaps the best advice came in the nineteenth century from the renowned physician William Osler. “There is just one way to treat a cold,” he said, “and that is with contempt.”

  Colds account for half of all acute medical conditions. But despite tremendous technological advances in isolating, identifying, sequencing, and cloning cold viruses, as well as advances in understanding how the immune system responds to these viruses, scientists and researchers have done nothing to prevent the common cold.

  Most of our understanding of the common cold has been an indirect consequence of the Second World War. When the U. S. Army evacuated Britain at the end of the war, it left behind an army hospital in Salisbury, England, that had been staffed by doctors from Harvard Medical School. Christopher Andrewes, a British researcher who was the first to isolate influenza virus from people, set up the Common Cold Research Unit in the abandoned buildings. During the next four years, Andrewes persuaded two thousand adults to take “ten-day holidays” at his research unit. He wanted to see what would happen if he inoculated volunteers with nose and throat washings taken from people suffering from colds. (On its face, this doesn’t sound like much of a holiday.) Andrewes found a few things that surprised him. About half of those inoculated with cold viruses came down with colds; women were more likely to catch colds than men; antihistamines, which had just been developed, were worthless; and people who were cold were not more likely to catch colds—they were actually less likely. Andrewes figured out the last point by asking people who had been inoculated with cold viruses to stand in a draft for thirty minutes in a wet bathing suit. He also found that people inoculated with a cold virus from one person weren’t protected months later when challenged with a virus from someone else.