Maurice Hilleman played a key role in the development of many vaccines, including the Mumps vaccine and the vaccine for Pandemic Flu. Both of these vaccines are grown in chicken embryos as a weakened strain of the live virus. Hilleman was a researcher at Merck & Co. until 1984.
This article is a profile of his life and work from the Philadelphia Enquirer (August 30th, 1999, reprinted with permission).
In the middle of a night in March 1963, a feverish 5-year-old named Jeryl Lynn wandered into her father's bedroom in Lafayette Hill and woke him up, complaining about a sore throat.
Her father, Maurice R. Hilleman, a microbiologist, took one look at his daughter's swollen glands and realized she had the mumps.
Back then, mumps was one of the most common diseases of childhood - approximately 200,000 children in the United States came down with it every year. The disease, caused by a virus that grows in the salivary glands and in the back of the throat, is usually benign. About half the children with mumps develop a mild case of meningitis, an infection of the brain. In a fraction of those cases, that could lead to permanent deafness, even death. Forty years ago, between 20 and 30 children died each year from complications of mumps.
Hilleman, who was conducting research on the infectious diseases of childhood at what is now Merck & Co., comforted Jeryl Lynn the best he could. Then he seized the opportunity to learn from her misfortune.
Even though it was past midnight, Hilleman drove to his laboratory at Merck's research facility near Lansdale, where he picked up cotton swabs and beef broth. Back home, he took the swabs and gently wiped the back of his daughter's throat, collecting the mumps virus growing there. Then he immersed the swabs in the broth, drove back to Merck and put the exposed broth in a freezer. He worked quickly, because in the morning he had to leave for a business trip to South America, and by the time he returned Jeryl Lynn's infection might have cleared.
The swabs taken by Hilleman that night more than three decades ago had a far-reaching impact.
When he returned to his lab, Hilleman used the frozen specimens to isolate the mumps virus. By growing the virus in the cells of chicken embryos, he was able to produce what is known as an attenuated form of the virus: It was too weak to cause disease but still strong enough to trigger the body's natural defenses and make a person immune.
By 1967, Hilleman had turned his daughter's virus, dubbed the Jeryl Lynn strain of mumps, into the world's first live vaccine against mumps. Soon, mumps became a disease of the past in the United States.The names Jenner, Pasteur, Salk and Sabin are likely to register with people. Not Hilleman. Even though he is the godfather of the modern vaccine era. Even though he has, in a career that has spanned six decades, developed nearly three dozen vaccines - more than any other scientist.
Even though it is no exaggeration to assert, as many leading scientists do, that Maurice Hilleman has saved more lives than any other living scientist.
His credits include not only the preventive vaccine for mumps, but also vaccines for measles, rubella (German measles), chickenpox, bacterial meningitis, flu and hepatitis B. Every time an American mother takes her child to the doctor for a well-baby checkup, she likely encounters the fruits of Hilleman's labor - vaccines that have put an end to longtime scourges of American childhood.
Many of the diseases that Hilleman's vaccines helped bring under control have been all but forgotten by a well-immunized generation of Americans. But not that long ago in this country, these diseases not only kept children home from school, they also sent them to the hospital and even the cemetery. Today Hilleman's measles vaccine alone prevents an estimated one million deaths around the globe every year.
Hilleman, who holds a Ph.D. in microbiology from the Univesity of Chicago, has also made notable discoveries in basic science. He figured out the pattern of genetic changes in the flu virus, enabling epidemiologists to give people advance warning of pandemic flu, and his discovery of an unknown monkey virus in the early 1960s eventually led scientists to find the most common genetic mutation involved in human cancers.
"Dr. Hilleman is one of the true giants of science, medicine and public health in the 20th century," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, during an awards dinner for Hilleman last year. Given Hilleman's work, ranging from immunology to cancer research, Fauci said, "One can say without hyperbole that Maurice has changed the world."
Hilleman himself is embarrassed by all the accolades heaped on him by other scientists. "Colleagues," he said, "make things happen."
At 79, Maurice Hilleman is a lean man with thinning hair, deep-set eyes and reading glasses that slip down to the end of his nose. When he thinks, he frequently buries his face in his hands and falls silent, as if communing with the muses. Then he jolts you with the first words out of his mouth, which are often profanity.
"Goddamnit," he told me as he broke one of these private seances, "science has to produce something useful. That's the payback to society for support of the enterprise."
I met Hilleman a year ago when I arrived in his office at Merck to tap his memory about the early quest for a polio vaccine. He sat at a long work table and recounted, in exacting detail, the scientific challenges of conquering a virus that brought terror to virtually every American home with children during the height of the polio epidemics in the 1950s.
Although Hilleman wasn't centrally involved, he knew the key scientists who were - Jonas Salk, Albert Sabin and Hilary Koprowski among them. Their pioneering work has now put the world on the threshold of a landmark achievement: the eradication of polio virus everywhere on the planet, possibly by the end of next year.
For Hilleman, the successful international effort to immunize the world's children against polio illustrates the ultimate power of vaccines. Not only can vaccines control infectious diseases, they can also eliminate them in their natural state. That's what happened with smallpox in 1979 and that's what is about to happen with polio.
"The wave of the future," Hilleman told me, "is to get rid of disease."
Although he officially retired from Merck in 1984, Hilleman still keeps regular office hours, culls through stacks of medical journals every week and is a consultant to myriad national and international vaccine advisory committees and public-health organizations. On his many international trips, he is often accompanied by his wife, Lorraine, a retired nurse. Besides Jeryl Lynn, now an executive with a California research firm, he has another daughter, Kirsten, and four grandchildren.
Ever since 1944, when he received his doctorate in microbiology, Hilleman has been an advocate of science in the public interest. Science, he insists, must serve society, not the reverse.
His bedrock belief in the responsibility of scientists to make the world a better place to live may be the only thing to survive his upbringing in the ultraconservative Missouri Synod Lutheran Church, which his German-immigrant ancestors helped found.
Though Hilleman professes to have rebelled against their fundamentalist teachings early on ("When I was 4 years old, I decided it was all mythology"), the Lutheran church left him with an enduring belief in the importance of being his brother's keeper. "It is always back there in your computer when you are first putting together pieces of information in your head," he says.
Much to the chagrin of his mentors at the University of Chicago, who wanted him to pursue an academic career after graduation, Hilleman took a research job at E.R. Squibb & Sons, the big pharmaceutical company. "I wanted to do something useful," Hilleman explains. Within a year, he had developed a vaccine to protect American troops in the Pacific from Japanese encephalitis, an often fatal infection of the brain.
Apart from a nine-year stint at Walter Reed Army Institute of Research - the epicenter of infectious disease research during World War II - Hilleman has spent his career in industry, most of it at Merck, which hired him in 1957 to head a newly created department of virus and cell biology.
The 1950s were an exciting time in infectious disease research, particularly the effort to combat viral infections. The electron microscope had been refined to the point that biologists could finally study viruses, the smallest of organisms, directly.
But the development of effective vaccines against viruses had been greatly hampered because researchers were not able to grow them in the laboratory.
Unlike bacteria, viruses can't survive outside a living cell. To produce large quantities of viral-based vaccines, scientists first had to figure out a way to get viruses to reproduce in large numbers in laboratory cell culture.
In 1948, a scientific team at Harvard University met the challenge by successfully growing polio virus in the lab. The feat, which won the 1954 Nobel Prize in medicine and led to Jonas Salk's polio vaccine, opened up a new era in which scientists could, for the first time, develop live-virus vaccines against a wide range of diseases.
Well into the 1950s, Merck had largely staked its future on the development of medicines to treat diseases, not vaccines to prevent them. But by 1957 the company's directors knew that vaccines against viral diseases, particularly the diseases of childhood, would soon become important. To enter the vaccine field, the firm needed not only a world-class scientist, but also a proven leader, and it began courting Hilleman.
At first, Hilleman wasn't sure he wanted the job. He wanted to do science, not get bogged down in administration. The longer he held out, the higher Merck went with the salary offer. When it hit the mark he needed to ensure a private school education for Jeryl Lynn, Hilleman accepted. In the end, Hilleman got not only the ability to send Jeryl Lynn to Plymouth Meeting Friends School, but free rein to run his lab as he saw fit.
His first project, an improved version of Salk's polio vaccine, proved problematic for Merck. Even after the new vaccine had been developed and introduced, Hilleman continued research and discovered that macaque kidney cells, used to produce the vaccine, carried a previously unknown monkey virus. The virus, he found, could cause cancer in hamsters. Although he was certain it posed no danger to humans, Merck removed the vaccine rather than take the risk.
Soon, however, Merck's investment in Hilleman began to pay off. All through the 1960s, he developed one vaccine after the other. First measles, then mumps, then rubella, then various two-vaccine combinations. Then, in 1971, came his crowning achievement - the so-called MMR vaccine, one shot, followed by a booster, that protects children against three different diseases - measles, mumps and rubella. It is now the cornerstone of pediatric health in the United States.
Hilleman's hepatitis B vaccine, originally developed in 1981 and now recommended for all infants in the United States, not only protects children from a debilitating blood-borne virus but it is also the first vaccine to prevent a human cancer - cancer of the liver.
"Since Pasteur," says Dale C. Smith, the chief medical historian at the Uniformed Services University of the Health Sciences in Bethesda, Md., "he's done more for preventive medicine than anyone else."
Were it not for serendipity, however, Hilleman might have ended up as the manager of a J.C. Penney store in a forgotten corner of Montana.
He was born in Miles City, a former frontier town on the high plains of southeastern Montana. His mother died during his birth, along with his twin sister. Maurice had seven older siblings and was raised by relatives on a farm at the confluence of the Yellowstone and Tongue Rivers, not far from where Custer had made his last stand against the Sioux four decades earlier.
By Hilleman's time, the Indian wars were over, the Northern Pacific Railroad had been built and most of the buffalo eliminated. But Miles City, named after another famous Indian fighter, Gen. Nelson A. Miles, was still a dusty cow town. On the family's farm, Maurice and his siblings tended cattle and chickens, cut hay, raised vegetables, made horseradish and fashioned brooms that they sold in town.
"In Montana, things got done," Hilleman says. "You put up a barn, a fence, a gate. These were project events. Then everybody would go out, get a fresh bucket of water, sit on a log and pass around a cup to celebrate. It's the same feeling you have when you get a vaccine licensed."
With farm life all around him, Hilleman took an early interest in biology. He befriended the chickens, even talked to them, and figured out how to hypnotize the roosters.
In the eighth grade, Hilleman discovered Darwin. One Sunday, he was caught reading The Origin of the Species in church. "I told the minister that the book belonged to the public library and I was going to turn him in if he took it from me," Hilleman recalls.
Besides books, Hilleman's link to a world beyond Miles City was the radio. On a good day, when the weather conditions were right, he could get weak signals from station KFYR in Bismarck, N.D. On Sunday afternoons, he listened to Meet the Scientists, a program produced at the University of Chicago. The squawk box could also pick up the Chicago Theater of the Air and the Metropolitan Opera. "To me," Hilleman says, "this was intellect."
But in 1937, when Hilleman graduated from Custer County High, he had no plans to attend college. The family didn't see the need for it and, besides, there was no money to pay the $45 a semester it would take to send him to a state school.
Instead, Hilleman took a job as a stock boy at the local Penney's store, which hired one Custer High grad every year for a management trainee position. A few weeks into his new job, Hilleman was rescued. His oldest brother, who had gone to seminary, came home for the summer. "When is Maurice going to college?" the brother demanded.
That fall, Hilleman entered Montana State University in Bozeman on a scholarship. After graduation, he won a fellowship to Chicago, where he wrote a prize-winning Ph.D. dissertation on chlamydia, a family of microbes including those that cause the most common type of venereal disease.
Little was known about the biology of chlamydia back then. But Hilleman was able to develop an antibody system to distinguish different subtypes of the bug - something nobody thought could be done. He accomplished the feat by infecting chickens with a type of chlamydia found in parrots. If he gave the chickens 20 injections of the parrot chlamydia, he could get them to produce chlamydia antibodies.
"Coming from a farm," Hilleman explains, "I always had a good friend called the chicken."
On April 17, 1957, Maurice Hilleman was sitting in his basement laboratory at the Walter Reed Army Institute of Research in Washington when his eyes lit on a small item in that day's New York Times. A flu outbreak in Hong Kong had stricken an estimated 250,000 people.
"Throughout the day," the Times reported, "thousands of sick persons have stood in long lines awaiting treatment in clinics. Many women carried glassy-eyed children tied to their backs."
It was the glassy eyes that caught Hilleman's attention. That suggested high fevers. "I said, `Son of a bitch. This is pandemic flu.'"
When the so-called Asian flu reached the United States six months later, I was 11 years old. My mother was one of its victims. I remember arriving home from school and finding her, day after day, laid out in bed with high fevers. It was scary - she didn't even have the energy to make dinner. Eventually, she recovered, but the flu cost her three months of work. Even so, she considered herself lucky.
Pandemic flu - an epidemic afflicting entire continents if not the entire inhabited world - was known to have occurred only once before, in 1918. It killed more than 20 million people, including 600,000 Americans. And then it abated, with infection and death from flu returning to typical levels.
Fear that a repeat of the 1918 pandemic would hobble the American military made flu a high priority at Walter Reed, where Hilleman was heading research on respiratory viruses.
In his early research, Hilleman made an important discovery. Each year, he found, the flu virus underwent small changes in its surface proteins. Because the changes were so minuscule, people exposed to earlier versions of the flu virus typically had natural immunity to the current year's virus. Though they might get sick, the illness wouldn't be very severe or last too long.
But every once in a while, Hilleman found, the flu virus underwent a major genetic change. Since it was so different from what had preceded it, people carried no natural immunity. If the virus turned out to be particularly virulent, millions would be at risk of illness and death. This, Hilleman reasoned, was what happened in the 1918 pandemic.
And it was what he thought was going on in Hong Kong in the spring of 1957. The implications were enormous. A simple extrapolation of the 1918 death rate would have meant more than one million American deaths in a single flu season.
Acting on intuition after reading the Times' article, Hilleman ordered the Army to get throat swabs from some of the Hong Kong victims. The specimens reached his lab on May 13, several weeks after the outbreak was reported.
Working nine 14-hour days, Hilleman and his colleagues at Walter Reed were able to culture the virus and isolate what appeared to be a new strain of flu. Blood samples taken from different populations showed that nobody had any antibodies to the virus, indicating that it was, in fact, an entirely new bug with potential to kill millions of people because they had no natural defenses against it.
Hilleman immediately notified the Armed Forces Epidemiological Board, the U.S. Centers for Disease Control, the World Health Organization and the country's six vaccine manufacturers. He also put out a press release to warn the American public to expect pandemic flu in the fall, just as school was starting.
To give the vaccine manufacturers an early start on making a protective vaccine, Hilleman sent them samples of the newly isolated virus. The labs would have to weaken it, passing it from one chicken embryo to another, so it wouldn't cause disease. Merck alone went through 150,000 eggs every day.
By fall, when the full force of the flu hit the United States, 40 million doses of vaccine had been prepared. Across the country, people lined up for shots. Those who got them did not have to face the illness my mother experienced, and tens if not hundreds of thousands of lives were spared.
Although between 30 and 40 percent of American families had a case of the flu, the death toll was held to about 69,000. The country was then in the midst of the postwar expanding economy, with the Cold War at full tilt; had the proper vaccine not been widely available, the societal effects of pandemic flu can only be imagined.
Today, Hilleman's findings about changes in the flu virus - known as "drift" (a minor change in surface proteins) and "shift" (a major change, which can trigger pandemic flu) - are used by public-health agencies to track the new flu viruses that emerge every year and to fashion vaccines to combat them.
While the system is far from perfect (in 1968, the third pandemic flu of the century claimed more than 34,000 American lives), Hilleman's work has given scientists the weapons they need to significantly reduce the potential casualties if they act quickly enough.
The special genius that leads one individual to develop three dozen vaccines is of course impossible to quantify or articulate. But a degree of insight into the Hilleman intellect can be gleaned from a series of pithy imperatives he delivered as part of his acceptance speech when he received the 1997 Albert Sabin Gold Medal. "Get the facts," he said. "Create a committee of one. You're it, so dig it out yourself. . . . Get the big picture. Minutiae clutter the head. . . . Hang in for the seven-day week. Interruptions are deadly."
For most of us born before the early 1960s, measles was an inevitable - and mostly innocuous - disease of American childhood. In my case, measles sent me home from Mrs. Dietrich's nursery school in Klamath Falls, Ore., for two weeks. All I remember are the little red spots that covered my body from head to toe, the white Naugahyde couch in my godparents' living room where I spent my days stretched out under a hand-crocheted afghan, and the chocolate milkshakes that magically appeared every night, courtesy of kindly friends and relatives.
Not everybody, however, was so lucky. In those years, measles was the leading cause of death due to infectious disease among children in the United States. Although most survived, some were left with lifelong disabilities, including permanent hearing loss and brain damage. No wonder, then, that public health officials wanted children with measles to be quarantined until they passed the contagious stage.
"Measles, you know, is somewhat like AIDS," Hilleman tells me as he sits in his office at Merck, scribbling notes on a yellow legal pad.
Measles and AIDS? The comparison seems preposterous. But science supports the analogy.
The measles virus, which lives only in humans, invades the body through the mouth, grows in the lungs and lymph nodes, and eventually spills into the bloodstream. By infecting the blood cells that combat infectious disease, measles knocks out natural defenses for several days, leaving a person prey to other life-threatening illnesses such as pneumonia. That's exactly what happens with AIDS, in a slow, progressive process that cannot be reversed. With measles, however, the immune system manages to bounce back. But not soon enough for some.
When the Spanish conquistadors brought measles to the Americas, the disease wiped out entire villages of Aztecs and Incas. It decimated some Native American tribes and wreaked havoc on the colonists as well. During the Civil War, measles struck large numbers of rural recruits who had never been exposed to the virus. On the Union side, 67,000 soldiers got sick and 4,000 died.
With the advent of the germ theory at the end of the 19th century, people knew enough to isolate those who came down with measles, easing the crisis. But even by the 1950s, when I got measles, the illness afflicted four million children a year in the United States and more than 100 million elsewhere in the world. Every year, measles sent nearly 50,000 American children to the hospital and killed 3,000. The death toll in other countries exceeded six million a year. With no preventive vaccine and no treatment available, about all doctors could do was hold the hands of the dying.
Hopes rose in 1961 when a Harvard researcher developed the first measles vaccine, which was made with live measles virus. But the new vaccine proved too toxic to use - vaccinated children came down with rashes, fevers and sometimes convulsions.
At Merck, Hilleman set out to solve the problem. In what would become a long-term relationship in the development of childhood vaccines, Hilleman turned to Joseph Stokes, chief of medicine at Children's Hospital of Philadelphia, which saw hundreds of measles cases every year. Stokes had a practical solution: Give a measles shot in one arm and a shot of gamma globulin - which carried measles antibodies - in the other. In effect, the gamma globulin prevented the measles-like symptoms caused by the live virus in the vaccine.
Hilleman had to overcome another problem. The chicken embryos in which the measles virus was grown for large-scale vaccine manufacturing proved to be contaminated with a bird virus that caused leukemia in chickens. While there was no evidence the virus caused cancer in people, Merck, which had just entered the vaccine arena, didn't want to take any chances.
In search of virus-free chickens, Hilleman turned to Kimber Farms, a poultry operation in Northern California that was breeding leukemia-free chickens from hens that had developed antibodies to the chicken leukemia virus. At first, the farm didn't want to part with its prize poultry. But Hilleman discovered that the farm's research director shared his Montana roots. Soon, he had a deal. "Montana blood runs very thick," Hilleman says, "and chicken blood runs even thicker with me."
An entire generation of American children has been protected from measles because of the work done in Hilleman's lab in the early 1960s. Last year, the United States reported just 100 cases of measles, a smattering compared to the millions in the pre-vaccine era.
Mini-outbreaks among the unvaccinated still occur. In 1990-91 in Philadelphia, 1,500 children came down with measles, nine of whom died. Only one of the nine had been vaccinated, but he turned out to have an immune system disorder that made the vaccine ineffective.
And in Africa, where some countries are too poor to immunize all their children, 500,000 children die every year from measles.
But in the Western Hemisphere, measles is so much on the wane that the Pan American Health Organization has begun a campaign to eradicate the virus throughout the Americas. That means making sure 95 percent of all children in every country get vaccinated against measles.
On May 17, Hilleman helped launch the final push to drive measles out of Honduras. Standing under a big yellow-and-white striped tent in Tegucigalpa, he gave one of the first doses of the measles vaccine to a screaming toddler. Merck donated 320,000 doses of the vaccine to carry out the initiative - a contribution worth about $5.4 million, according to company officials.
Later, Mary Flores, the wife of Honduran President Carlos Flores, offered thanks. Since Hurricane Mitch, she said, the country had been visited by many heads of state and received many contributions. But Hilleman's gift, she said, meant more than material things: It was a gift of health and long life for the children of Honduras.
For all his work toward the betterment of human health, Hilleman didn't overlook another species that played a large role in the development of almost all his vaccines.
In 1971, he developed a vaccine for Marek's disease, a viral infection that leads to lymphoma in chickens. Known as range paralysis by poultrymen, the disease used to cause millions of dollars' worth of losses every year. Among those hardest hit were the large poultry farms in Delaware, Maryland and parts of Pennsylvania.
But Hilleman's vaccine - made with a related herpes virus found in turkeys - took care of the problem, revolutionizing the economics of the poultry industry in the process.
"I figured I owed it to the chickens," Hilleman says.
Tomorrow, Maurice Hilleman turns 80. The reticent scientist who never fails to credit teamwork will himself be the center of attention. More than 1,000 of the world's leading infectious-disease experts and other scientists will gather for a day-long symposium in Hilleman's honor at the University of Maryland's Institute of Human Virology.
The guest list for the party reads like a who's who in public health in the last half of the 20th century, with a fair number of Nobel laureates expected. The celebration, which will include a keynote address by Supreme Court Justice Anthony Scalia, will be hosted by Dr. Robert Gallo, institute director and codiscoverer of the AIDS virus.
Though Hilleman is unlikely to win a Nobel - an award that tends to favor achievements in basic science over practical applications - the list of honors he has received is long, including a lifetime achievement award from the World Health Organization in 1996, the 1983 Albert Lasker Medical Research Award, and a 1988 National Medal of Science, the United States' highest scientific honor.
Gallo, who is sparing in his use of superlatives, can't say enough about the achievements of the former cowpoke from Montana: "If I had to name a person who has done more for the benefit of human health, with less recognition than anyone else, it would be Maurice Hilleman. Maurice should be recognized as the most successful vaccinologist in history."
It's been more than a decade since Hilleman worked in the laboratory, and he is painfully aware of the unfinished agenda there. The most pressing need, he says, is to develop vaccines for three global killers - malaria, tuberculosis and AIDS.
Hilleman would like to see a crash AIDS vaccine program, centrally coordinated, with teams of researchers pursuing different aspects of the unprecedented scientific challenge - not unlike the way polio was conquered in the 1950s.
"That," says the scientist who set out "to do something useful" a half-century ago, "is what you need for the difficult problems."
Article © 1999 PHILADELPHIA NEWSPAPERS INC.
Reprinted with permission.