Vaccinated (16 page)

Dr. Michael Traister (left) inoculates Kirsten Hilleman's ten-day-old daughter, Anneliese, with the recombinant hepatitis B vaccine, 1999. Maurice Hilleman looks on.

But Boyer's and Cohen's studies also precipitated fears among scientists and the public that genetic engineering was an invasion of humanity into the realm of God. A
Time
magazine cover in the 1980s titled “Tinkering with Life” showed a DNA molecule surrounded by several white-coated scientists with hammers and rulers. At the head of the DNA was a fanged snake.

 

M
ERCK SCIENTISTS REALIZED THAT
B
OYER
'
S AND COHEN
'
S DISCOVERY
could be used to make a hepatitis B vaccine without using human blood. They recruited a molecular biologist working at the University of California in San Francisco, William Rutter. Using Boyer's DNA-cutting enzyme, Rutter removed the surface protein gene from the virus and inserted it into one of Stanley Cohen's bacterial plasmids. When the bacteria reproduced, they made large quantities of hepatitis B surface protein. But Rutter and Merck found, much to their dismay, that the surface protein made by the bacteria didn't induce an immune response in animals. So they decided to try something else, soliciting the help of Ben Hall at the University of Washington. Hall used common baker's yeast instead of bacteria. Hilleman found that the hepatitis B surface protein made in yeast induced protective antibodies in chimps and, later, in people, so he used this system to make the next hepatitis B vaccine.

On July 23, 1986, the FDA licensed Merck's yeast-derived recombinant hepatitis B vaccine. The vaccine is still used today.

 

B
Y THE LATE
1980
S, THE HEPATITIS
B
VACCINE HAD BEEN USED BY LESS
than 1 percent of the world's population. But between 1990 and 2000, hepatitis B vaccine usage increased to 30 percent. By 2003, more than 150 countries used the vaccine, and the impact has been dramatic. In Taiwan, hepatitis B vaccine has caused a 99 percent decrease in the incidence of liver cancer. In the United States, the incidence of hepatitis B virus infections in children and teenagers has decreased by 95 percent. Furthermore, because hepatitis B virus infects fewer people, the hepatitis B vaccine has dramatically increased the number of potential liver donors. “Hilleman's heroic role in controlling the hepatitis B virus scourge ranks as one of the most outstanding contributions to human health of the twentieth century or any century,” recalls Thomas Starzl, a pioneer of liver transplantation. “From my parochial point of view, Maurice removed one of the most important obstacles to the field of organ transplantation.”

Hilleman ranked the hepatitis B vaccine as his company's greatest single achievement: “We made the world's first hepatitis vaccine, the world's first anticancer vaccine, the world's first recombinant vaccine, and the world's first vaccine made from a single protein.” If the worldwide use of hepatitis B vaccine continues, chronic infection with the virus will be virtually eliminated, and in thirty to forty years, so will consequent cirrhosis and liver cancer.

O
n Sunday morning, February 7, 1886, George Walker and George Harrison were strolling across the flat untouched savannah of South Africa. Walker was building a cottage for two brothers, the Stubens, and Harrison was building one for a widow, Petronella Oosthuizen. Idly kicking at the ground, Harrison stubbed his foot on an outcrop of rock. He picked it up, examined it carefully, pulled out his prospector's pickax, and struck off smaller pieces. Before coming to South Africa, Harrison had been a gold miner in Australia. Oosthuizen's nephew, George Overbay, remembered what happened next: “[Harrison] borrowed my aunt's frying pan in the kitchen, crushed the conglomerate to a coarse powder on an old ploughshare, and went to a nearby [water pump] where he panned the stuff. It showed a clear streak of gold.”

On July 24, 1886, George Harrison wrote to the president of the South African Republic, Johannes Krüger, asking for a prospector's license. As news of Harrison's find spread, hundreds of miners rushed to the area, also hoping to get licenses. At nine o'clock on the morning of September 20, 1886, they got their answer. A government official stood beside his wagon and read Krüger's proclamation to the men: “I, Stephanus Johannes Paulus Krüger, advised by and with the consent of the executive council, proclaim [this district] as a public digging.” Within a few months thousands of men had pitched tents in a town soon to be named Johannesburg. Three years later, Johannesburg was the most heavily populated city in Africa. By 1895, almost one hundred thousand people lived there. Of them, seventy-five thousand worked in the mines; all were poor black African men taken from their rural homes, separated from their wives and children.

Krüger, for whom the gold coin Krügerrand is named, was elected president of the South African Republic for the fourth and final time in 1898. Appalled by the greed of the mining companies, Krüger thought that residents should be lamenting, not celebrating, South Africa's find. “It will cause our land to be soaked in blood,” he predicted. George Harrison, the discoverer of what was by the late 1930s the largest and richest gold mining area in the world, sold his license for £10. Several years later he was eaten by a lion.

 

B
RITISH COMPANIES THAT OWNED THE MINES HIRED RECRUITERS TO
deliver workers—derogatorily known as kaffirs—at a fixed price per head. Some became ill on the trip from their rural homes to the city. Others, crowded into small, poorly maintained barracks, suffered severe infections. Most suffered from malnutrition. If they survived, they worked for six to nine months before returning home. The constant turnover of miners meant the continuous introduction of new men into the mining compounds. Although these men suffered from dysentery and tuberculosis, no disease was more common, more severe, or more lethal than bacterial pneumonia. And every new miner was potentially susceptible.

In 1894, at a meeting of the Transvaal Medical Society of South Africa, doctors described an epidemic of a hundred cases of “purulent discharge from the nostrils and, in a large majority of cases, pneumonia.” Fifteen of those men died. Five years later, doctors described a similar epidemic: “One batch of ninety-three emaciated Kaffirs arrived in the beginning of July and some of these were ailing; altogether of this batch, eight died.” By the early 1900s, seven gold miners died of pneumonia every day. When doctors performed autopsies on men who had died and looked at sections of their lungs under the microscope, they found small round bacteria clustered in pairs. The name of the bacterium was
Streptococcus pneumoniae
, or pneumococcus. To prove that it killed the miners, researchers injected the bacteria into rabbits. Within days, all of the rabbits died.

Once they had identified the cause of this deadly pneumonia, researchers were ready to make a vaccine to prevent it.

 

T
HE FIRST VACCINE
—E
DWARD
J
ENNER
'
S SMALLPOX VACCINE—PREVENTED
a viral infection. Vaccines to prevent bacterial diseases like pneumococcal pneumonia lagged far behind, the first one appearing about a hundred years later; one of the reasons it took so much longer is that bacteria are much more complicated than viruses.

Viruses and bacteria are both made of proteins that evoke protective antibodies. But viruses don't contain many proteins; for example, measles virus contains ten proteins, and mumps virus contains nine. Bacteria are much larger; pneumococcus contains about two thousand proteins. Difficulties in determining which among these proteins evoked an immune response was among the reasons for the slower development of bacterial vaccines. Progress was also slowed by fraud.

 

I
RONICALLY, RESEARCHERS KNEW ABOUT BACTERIA LONG BEFORE THEY
knew about viruses. Martinus Beijerinck, investigating an infection of tobacco plants, was the first to figure out what viruses were and where they reproduced. But he never saw them. Not until the 1930s, with the invention of the electron microscope, did researchers finally see the viruses they were studying. Because bacteria were so much bigger than viruses, studies of bacteria had a three-hundred-year head start. In the late 1600s, Anton van Leeuwenhoek, a Dutch dry-goods dealer, produced the first microscope. While looking through his microscope at drops of rainwater or scrapings from his teeth, he noticed tiny creatures “moving in the most delightful manner.” He called them animalcules—literally “little animals.” We now know them in part as bacteria. It wasn't until the late 1800s that investigators found that bacteria weren't so delightful: some caused severe, often fatal illnesses.

The next breakthrough came when Robert Koch, a German bacteriologist, proved that specific bacteria cause specific diseases. In 1876 Koch set out to determine the cause of anthrax, a common and occasionally fatal lung disease in cattle but rarely in man. Living in the farmlands that housed his crude laboratory, Koch took pieces of spleens from cows that had died of anthrax and, using tiny wooden slivers, injected them into mice, all of which died. When he looked at the cow spleens through a microscope, they were teeming with bacteria. Koch reasoned that bacteria had killed the mice. Now he had to prove it. So he inoculated small pieces of spleens from infected cows into gelatinous fluid scooped from the center of an ox's eye, hoping that it would provide the nutrient substances necessary for the bacteria to grow. (Many early scientific studies sound like a witch's incantation from
Macbeth
.) During the next few weeks Koch watched the bacteria reproduce. He then injected his culture of anthrax bacteria into mice and found that again they all got sick; their lungs were loaded with anthrax bacteria. Koch had made an important observation. Until that time, scientists had believed that only bacteria taken from someone who was sick could make you sick. Koch proved that bacteria grown in his laboratory could also cause disease. Robert Koch was a father of the germ theory of disease.

During the next ten years Koch found that he could grow bacteria on nutrient media made from potatoes and gelatin. He placed his media in special flat glass dishes invented by a young researcher working in his laboratory, Julius Petri. Later, Koch discovered the bacteria that cause tuberculosis and cholera. By 1900, researchers had found twenty-one different bacteria that cause diseases. “As soon as the right method was found,” said Koch, “discoveries came as easily as ripe apples from a tree.”

Koch's observation that bacteria could be grown in the laboratory led to a series of important discoveries and three vaccines.

The first breakthrough occurred in the late 1800s, when two French researchers, Emile Roux and Alexandre Yersin, isolated the bacterium that causes diphtheria, then a common cause of death. Diphtheria causes a thick gray membrane to collect in the windpipe and breathing tubes, often suffocating its victims. In the United States alone, diphtheria infected two hundred thousand people every year, mostly teenagers, and killed fifteen thousand. Roux and Yersin, like Koch, found that they could reproduce the disease by injecting bacteria into experimental animals. But they also found that when they grew bacteria in liquid culture, the liquid alone caused severe and fatal disease; bacteria themselves weren't necessary. Apparently, diphtheria bacteria were making a toxin.

The second breakthrough resulted in the first Nobel Prize in medicine. Working in Marburg, Germany, Emil von Behring found that animals injected with diphtheria toxin made antibodies to the toxin, called antitoxin, and that antitoxin prevented disease. Scientists later extended Behring's discovery to make antitoxins to several bacteria. Behring's discovery was also the inspiration for the Iditarod dogsled race, which re-creates the life-saving emergency transport in 1925 of diphtheria antitoxin from Nenana to Nome, Alaska—a distance of 674 miles—during an outbreak of diphtheria. Although two children died during the outbreak, Behring's antisera saved the lives of many others.

Another French researcher, Gaston Ramon, made the third breakthrough in the late 1920s when he found that toxin that had been inactivated by formaldehyde could protect people against diphtheria. Now researchers no longer had to rely solely on antitoxins to fight bacterial infections. People injected with formaldehyde-treated toxin, known as toxoid, could be protected against diphtheria for the rest of their lives by making their own antibodies. This observation also led to vaccines against tetanus and, in part, whooping cough. Because of these three vaccines, the number of people killed every year in the United States by diphtheria decreased from fifteen thousand to five; by tetanus, from two hundred to fifteen; and by whooping cough, from eight thousand to ten.

Production of new bacterial vaccines exploded in the early 1900s. Pharmaceutical companies in the United States made vaccines by growing bacteria in pure culture, killing them with chemicals, and putting dead bacteria in a tablet. They called these vaccines bacterins. Bacterins were sold to prevent strep throat, acne, gonorrhea, skin infections, pneumonia, scarlet fever, meningitis, and intestinal and bladder infections. Bacterins were easily ingested, readily available, simple to make, and highly lucrative. There was only one problem: they didn't work. Nor did they have to. Pharmaceutical companies weren't required to prove that their products worked until the early 1960s. Change came later, but only when prompted by disaster.

 

I
N
1954
CHEMISTS AT
C
HEMIE
G
RÜNENTHAL, A
W
EST
G
ERMAN COMPANY,
tried to make an antibiotic by heating a chemical called phthaloylisoglutamine. (Don't try to pronounce this word in your head.) The resultant drug didn't kill bacteria. So they tried something completely different: they tested animals to see whether the drug had an antitumor effect. Again, no luck. Finally, in a small test in people, researchers at Grünenthal found that the drug put patients into a natural, all-night sleep. On October 1, 1957, they advertised the drug as a sleeping pill and claimed that it was completely safe. They also claimed that pregnant women could use it to treat morning sickness, although they never specifically tested the drug for this use. They called the drug thalidomide. By 1960, hundreds of babies had been born with their hands and feet directly stuck to their bodies. Thalidomide damaged twenty-four thousand embryos; half died before birth. Today, about five thousand people live with birth defects caused by thalidomide.

The thalidomide disaster caused a reevaluation of the U. S. Food, Drug, and Cosmetic Act, passed in 1938. Congress amended it in 1962 to compel pharmaceutical companies to show that their products actually worked before selling them.

 

T
HE FIRST PERSON TO TRY TO MAKE A
vaccine
TO PROTECT
S
OUTH
African gold miners from pneumococcal pneumonia was Sir Almroth Wright. In February 1911, Julius Werhner, chairman of the Central Mining Investment Corporation in London, called upon Wright, a famous British researcher. A tough, opinionated man who actively opposed women's suffrage, Wright was the inspiration for the character of Sir Colenso Ridgeon in George Bernard Shaw's
The Doctor's Dilemma
. (The dilemma in Shaw's play is that Ridgeon, with enough antiserum to save one person from tuberculosis, must choose between a physician colleague and a talented artist. Smitten by the artist's wife, Ridgeon chooses the doctor, hoping that the artist will die as a consequence. Wright is said to have stormed out of an early performance of the play.) Werhner chose Wright to develop a vaccine against pneumococcus because he knew that several years earlier Wright had developed a successful vaccine against typhoid fever, caused by the bacterium
Salmonella typhi
. Wright had made his vaccine by growing
Salmonella
in pure culture and killing it with heat. Before his discovery, typhoid had been a common and fatal infection, especially among soldiers. During the Spanish-American War, about two hundred Americans died of their wounds, while typhoid killed two thousand. After Wright found that his vaccine worked, the British military gave it to all of its soldiers during the First World War. (The Second World War was the first in which more soldiers actually died in battle than of infection.)

Wright assumed that he could make a vaccine to prevent pneumococcal infection the same way that he had made his typhoid vaccine. So he took a strain of pneumococcus, grew it in culture, and killed it with a chemical. On October 4, 1911, Almroth Wright inoculated the first of fifty thousand South African gold miners with his vaccine. In January 1914 he published his results: “The comparative statistics that have been set forth above testify in every case to a reduction in the incidence rate and death rate of pneumonia in the inoculated.” But Wright was wrong. One year later a statistician working for the South African Institute for Medical Research reanalyzed Wright's data and found that his vaccine didn't work at all. The reason for his failure would soon become evident.