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  Beijerinck was studying tobacco mosaic disease, which stunted the growth of tobacco plants and was common in Europe and Russia. Scientists had already seen bacteria under the microscope, shown that they caused specific diseases, and figured out a method to remove them from water: filtration through unglazed porcelain. (Pots of unglazed porcelain were often kept in the home to purify drinking water.) Beijerinck assumed that bacteria caused tobacco mosaic disease. To prove it, he squeezed diseased plants through a press, collected the sap, rubbed the sap onto healthy leaves, and watched the healthy plants die. Clearly, the sap contained the organism that caused the disease. Then Beijerinck performed his seminal experiment. He passed infectious sap through a porcelain filter and, much to his surprise, found that the sap still caused disease. Beijerinck knew that bacteria should have been trapped by the filter. Something else was getting through.

  Beijerinck published his findings in a paper titled “Concerning a Contagium Vivum Fluidum as a Cause of the Spot-Disease of Tobacco Leaves.” The term contagium vivum fluidum translates as “living contagious fluid.” (Later, Beijerinck referred to the contagium as a virus.) Beijerinck said that “the contagium, in order to reproduce, must be incorporated into the living protoplasm of the cell.” Martinus Beijerinck had recognized the single most important difference between bacteria and viruses. Bacteria, capable of independent growth, can multiply on the surface of furniture, in dust, in rainwater, or on the lining of the skin, nose, or throat. But viruses, incapable of independent growth, can reproduce only within the “living protoplasm of the cell.” At the age of forty-seven, Martinus Beijerinck became the father of virology.

  JENNER NEEDED COWS TO MAKE HIS SMALLPOX VACCINE; PASTEUR needed dogs and rabbits. From Alexis Carrel, Hilleman learned that animal organs could be kept alive outside of the body, freeing researchers from using whole animals when they wanted to make their vaccines.

  On January 17, 1912—three months before the steamship Titanic sank in the Atlantic Ocean—Carrel, a French surgeon working at the Rockefeller Institute in New York City, removed a small piece of heart from an unhatched chick embryo and placed it in the bottom of a flask. Every two days he added nutrient fluid that contained chicken plasma and a crude extract made from a chicken embryo. He wanted to see how long he could keep the piece of chicken heart alive. Obsessed that the heart might be inadvertently contaminated with bacteria, Carrel created a cult around its maintenance, insisting that the walls be painted black and that his technicians wear long black gowns with hoods when they entered the room in which it was kept. To celebrate their success, every January doctors and nurses at the Rockefeller Institute lined up outside the research laboratory, locked hands, and joined Carrel in lustily singing ”Happy Birthday” to the small piece of heart. Carrel and his colleagues maintained the chicken heart fragment until his death in 1944.

  FROM ERNEST GOODPASTURE, WHO WORKED IN THE EARLY 1930s, HILLEMAN learned that viruses could be grown in eggs, a discovery that forged a permanent bond between virologists and chicken farmers.

  Born on a farm near Clarksville, Tennessee, Goodpasture, a quiet, unassuming pathologist, was interested in fowlpox, a virus similar to smallpox. Because fowlpox infected chickens, he decided to try to grow the virus in hens’ eggs, reasoning that eggs were sterile (antibiotics hadn’t been invented yet) and inexpensive. Working at Vanderbilt University in Nashville, Goodpasture took an incubating hen’s egg, bathed it in alcohol, and, to sterilize the shell, set it on fire. Then, using an eggcup as an operating table, he cut a small window in the shell and injected the egg with fowlpox. The virus grew readily in the membrane surrounding the chick embryo. Hilleman used Goodpasture’s technique to make his pandemic influenza and mumps vaccines.

  FROM MAX THEILER, HILLEMAN LEARNED THAT HUMAN VIRUSES COULD be weakened and made into vaccines by growing them in animal cells. (Remember, Hilleman weakened his daughter’s mumps virus by growing it in chick cells.)

  Theiler, a South African émigré also working at the Rockefeller Institute, wanted to make a vaccine to prevent yellow fever, a tropical viral disease that caused bleeding, the unmistakable symptom of black vomit, jaundice—a yellowing of the eyes and skin that gave the virus its name—and death. Because yellow fever virus caused severe internal bleeding, it was called a viral hemorrhagic fever. Yellow fever was common in the United States; an outbreak in Philadelphia in the late 1700s killed 10 percent of the city’s residents, and an outbreak in New Orleans in the mid-1800s killed 30 percent. The terror once caused by yellow fever is associated today with another viral hemorrhagic fever: Ebola virus.

  In the mid-1930s, Max Theiler performed a series of experiments that determined how researchers would make viral vaccines for the next seventy years. Using Carrel’s technique of growing chopped-up animal organs in laboratory flasks, Theiler found that yellow fever virus grew in mouse embryos. So he passed the virus from one mouse embryo to another and eventually from one chicken embryo to another. Theiler reasoned that as yellow fever virus got better and better at growing in cells from different species—like mice and chickens—it would become less and less capable of causing disease in humans. (Today we know that human viruses forced to grow in animal cells undergo a series of genetic changes that make them less capable of reproducing and causing disease in people.) To test his theory, Theiler injected a thousand Brazilians with what he hoped was a weakened form of yellow fever virus. He found that most people developed antibodies to the virus and that no one got the disease. By the end of the 1930s, Theiler had inoculated more than half a million Brazilians, and epidemics of yellow fever in Brazil abated. The yellow fever vaccine made in mouse embryos by Max Theiler in the mid-1930s is still used today.

  Theiler’s technique of weakening human viruses by growing them in cells from other species remains the single most important method for making live weakened viral vaccines. His method has been used to make vaccines against measles, mumps, rubella, chickenpox, and polio. In 1951, “for his discoveries concerning yellow fever and how to contain it,” Max Theiler won the Nobel Prize in medicine. When asked what he planned to do with the $36,000 in prize money, he said “Buy a case of Scotch and watch the [Brooklyn] Dodgers.”

  Like Jenner and Pasteur before him, Theiler also saw tragedy follow his vaccine. In the early 1940s, scientists made Theiler’s vaccine using human serum obtained from several volunteers, to stabilize the virus. Unfortunately, unnoticed at the time, at least one of these volunteers was jaundiced, infected with hepatitis B virus. As a consequence, more than three hundred thousand American servicemen injected with contaminated yellow fever vaccine got hepatitis, and sixty died. Human serum was never again used to stabilize vaccines.

  FROM THE RESEARCH TEAM OF JOHN ENDERS, THOMAS WELLER, AND Frederick Robbins, working at Boston Children’s Hospital (part of Harvard’s Medical School) in the late 1940s, Hilleman learned how to grow animal and human cells in the laboratory. Alexis Carrel’s technique, using chopped up animal organs, was called tissue culture; the Enders group’s technique, using single layers of animal or human cells grown in laboratory flasks, was called cell culture. Now when researchers want to grow viruses, they simply take a vial of cells out of the freezer, thaw them out, place them into laboratory flasks, watch them reproduce until a single layer neatly covers the bottom of the flask, and inoculate them with viruses. The days of growing viruses in whole animals or chopped-up animal organs were over. The Enders group’s technique is still used to make viral vaccines today.

  One of the Boston group’s first cell cultures was made from a human fetus. On March 30, 1948, at 8:30 a.m., Thomas Weller walked across the street in front of Boston Children’s Hospital and into the office of Duncan Reid, an obstetrician working at the Boston Lying-In Hospital who had just aborted a twelve-week pregnancy. The mother had chosen to end her pregnancy because she had been infected with rubella, a virus known to cause birth defects. Reid handed Weller the fetus. After coaxing fetal cells to reproduce on the bottom of laboratory fl
asks, Weller found that polio virus grew in the cells. Weller, Robbins, and Enders found later that polio virus also grew in a variety of different animal and human cells. Prior to these experiments, polio virus could be grown only in cells from brains and spinal cords. Researchers feared using a polio vaccine made from nervous tissue for the same reason that they feared Pasteur’s vaccine: the dangerous side effect of autoimmunity.

  John Enders (left) and Thomas Weller in their laboratory at Boston Children’s Hospital, November 1954 (courtesy of the March of Dimes Birth Defects Foundation).

  In 1954 Enders, Weller, and Robbins won the Nobel Prize in medicine for “their discovery of the ability of polio viruses to grow in cultures of various types of tissue.” These studies allowed Jonas Salk and Albert Sabin to make polio vaccines that eventually eliminated polio from most of the world.

  FROM JONAS SALK, THE SCIENTIST WHO FIRST FOUND A WAY TO prevent polio, Hilleman learned that vaccines could win the heart of the American public.

  Born and raised in New York City, the son of Russian immigrants, Salk was driven, obstinate, and self-assured. Working at the University of Pittsburgh in the early 1950s, Salk used the Enders group’s technique to grow polio virus in monkey kidney cells. Then he purified the virus, killed it with formaldehyde, and injected it into seven hundred children in and around Pittsburgh. Salk reasoned that killed polio virus would induce polio antibodies but wouldn’t cause polio. In 1954, funded by the March of Dimes, doctors and nurses injected four hundred thousand children with Salk’s vaccine and two hundred thousand with an inert liquid that looked like vaccine, called placebo. The program was then and remains today the largest test of a medical product ever performed. Following the announcement that the vaccine worked, Americans named hospitals, schools, streets, and babies after Salk and sent him money, clothes, and cars. Universities offered him honorary degrees, and countries issued proclamations in his honor. Salk started the day as a scientist at the University of Pittsburgh and ended it as one of the most revered men on the face of the earth. When people hear the word vaccine today, the first person they think of is Jonas Salk.

  But like Jenner, Pasteur, and Theiler before him, Salk watched tragedy follow his vaccine. When Salk found that polio vaccine could be made by inactivating polio virus with formaldehyde, five companies stepped forward to make it. On April 12, 1955, each of those companies was permitted to sell its vaccine to the public. One company, Cutter Laboratories of Berkeley, California, made it badly. Researchers and executives at Cutter were confident that they had made their polio vaccine exactly as Jonas Salk had prescribed, giving it to the children of four hundred and fifty of their employees. But, because Cutter researchers hadn’t properly filtered out the cells in which they grew polio virus, some virus particles had effectively escaped the killing effects of formaldehyde. As a consequence, more than one hundred thousand children were inadvertently injected with live, dangerous polio virus. Worse, children injected with Cutter’s vaccine spread polio to others, starting the first and only man-made polio epidemic. When the dust settled, live polio virus contained in Cutter’s vaccine had infected two hundred thousand people; caused about seventy thousand to have mild cases of polio; permanently and severely paralyzed two hundred people, mostly children; and killed ten. It was one of the worst biological disasters in American history. Federal regulators quickly identified the problem with Cutter’s vaccine and established better standards for vaccine manufacture and safety testing. Cutter Laboratories never again made another polio vaccine. And Salk’s polio vaccine helped to dramatically reduce—and in some countries eliminate—one of the world’s most crippling infections.

  HILLEMAN HAD LEARNED FROM WHAT HAD GONE RIGHT AND WHAT had gone wrong before him. By the time he made his mumps vaccine, an enormous path had been cleared through the thicket. “It was an age of genius,” he said. “I was able to do what I did because of what they did.”

  CHAPTER 4

  The Destroying Angel

  “That fatal and never to be forgotten year, 1759, when the Lord sent the destroying Angel to pass through this place, and removed many of our friends into eternity in a short space of time; and not a house exempt, not a family spared from the calamity. So dreadful was it that it made every ear tingle, and every heart bleed; in which time I and my family were exercised with that dreadful disorder, the measles. But by blessed God our lives were spared.”

  EPHRAIM HARRIS, COLONIST AND FARMER, FAIRFIELD, NEW JERSEY

  While Maurice Hilleman was making his mumps vaccine, he was also making a measles vaccine.

  Measles infection starts innocently enough, with fever, cough, a runny nose, pinkeye, and rash. But measles virus also can infect the lungs, causing fatal pneumonia, and the brain, causing seizures, deafness, and permanent brain damage. And it can infect the liver, kidneys, heart, and eyes, blinding many survivors. Furthermore, measles virus causes one of the most insidious, unrelenting diseases of childhood—subacute sclerosing panencephalitis (SSPE), a rare but uniformly fatal disorder. Symptoms of SSPE usually begin about seven years after measles infection. At first children undergo subtle personality changes, their handwriting deteriorates, and they seem to forget things. Later, when the horror of the disease fully emerges, children are progressively less able to walk, stand, or talk; then they become combative, have seizures, lapse into a coma, and die. Despite decades of study, a parade of drugs, and heroic supportive measures, no child has ever survived SSPE.

  In the early 1960s, when Maurice Hilleman wanted to make his vaccine, measles virus was killing eight million children in the world every year. Doctors and public health officials were desperate to find a way to prevent it.

  THE ROAD TO A MEASLES VACCINE STARTED IN BOSTON.

  In 1954, Thomas Peebles was working in the laboratory of John Enders at Boston Children’s Hospital. The team, which had just won the Nobel Prize in medicine for its work on polio, also included Sam Katz, a brilliant infectious diseases specialist and pediatrician from New Hampshire, and Milan Milovanovic, a scientist from Belgrade, Yugoslavia. Peebles, fresh from his internship at Massachusetts General Hospital, had gotten a late start in his career, spending four years in the navy during the Second World War. Enders assigned Peebles the task of capturing measles virus. Although researchers were sure that a virus caused measles, no one had ever coaxed it to reproduce inside a test tube.

  In January 1954, Peebles got the break he was looking for. Dr. Theodore Ingalls called Peebles and told him about an outbreak of measles at the Fay School, an exclusive all-boys private school in Southborough, a suburb west of Boston. (The school, founded in 1866, was one of the oldest boarding schools in the United States.) Peebles got into his car, drove thirty miles, and convinced the school’s principal, Harrison Reinke, to allow him to collect blood from the boys. Then he went to each student and said, “Young man, you are standing on the frontiers of science. We are trying to grow this virus for the first time. If we do, your name will go into our scientific report of the discovery. Now this will hurt a little. Are you game?”

  For the next few weeks Peebles tried unsuccessfully to capture measles virus. But on February 8, 1954, his luck changed. David Edmonston, a thirteen-year-old student at Fay, had stomach cramps, nausea, fever, and a faint red rash that started on his face and spread to his chest, abdomen, and back. When David’s temperature rose to 104 degrees, large quantities of measles virus coursed through his veins. Thomas Peebles was about to do something that no one had dared to do before: make a vaccine using human organs.

  In the early 1950s, doctors subjected children to a medical procedure, now abandoned, for a condition called hydrocephalus—literally, “water on the brain.” In the center of the brain, specialized cells make fluid that bathes the spinal cord; the fluid must travel through a series of narrow canals. Sometimes, because of infection or birth defects, those canals are blocked and spinal fluid is trapped, compressing the brain. To relieve the blockage, surgeons would drill a small hole into the center
of the brain, insert a plastic catheter, and create a tunnel under the skin that ended in the ureter, a tube that connects the kidneys to the bladder. In order to connect the catheter to the ureter, surgeons needed to remove a kidney—one perfectly healthy, fully functioning human kidney. Now, instead of spinal fluid getting trapped in the brain, it was carried to the bladder and urinated out of the body.

  Enders couldn’t bear to see healthy kidneys wasted. “He was the typical penurious Yankee,” recalled Sam Katz. “He just hated to see things wasted. And his thriftiness extended to [laboratory] materials.” So Enders sent Thomas Peebles to collect the kidneys before they were thrown away and asked him to try to grow measles virus in them. First, Peebles treated the kidneys with a powerful enzyme to make sure the kidney cells didn’t clump together. Then he put the cells into sterile flasks, watched them reproduce until they covered the bottom of each flask, and added David Edmonston’s blood. After a few days, the kidney cells shriveled up and died. Edmonston’s measles virus was apparently reproducing inside the cells, killing them in the process.

  Now that the Boston researchers could grow measles virus in laboratory cells, they could weaken it to make a vaccine. Peebles, Katz, and Milovanovic grew the virus serially in twenty-four cultures of human kidneys, twenty-eight cultures of human placentas (Enders apparently couldn’t stand to watch placentas getting thrown away either), six hens’ eggs, and six minced chick embryos. They hoped that by forcing David Edmonston’s measles virus to grow in this hodgepodge of human and animal cells, the virus would weaken sufficiently to be a vaccine. There was, however, no formula, no recipe, for how to do this.