The Eureka Moments

Dec 16, 2012

A trio of dedicated 19th century scientists helped create a vaccine to fight a brutal killer.

The Eureka Moments

For centuries, maternal and neonatal tetanus had no opponent as it tortured and killed newborn babies and mothers in every village, city and nation. But the war against the disease took a dramatic turn in a 19th-century German laboratory, which soon was followed by other successes. Today MNT no longer threatens lives in much of the world. With this issue, Kiwanis magazine begins a series of articles that will revisit the key victories that have pushed MNT to the brink of elimination.

While fighting in the Napoleonic Wars’ Peninsular War, British soldiers in Spain fell to more than battle wounds:  during that conflict, which ran from 1808 to 1814, 12.5 of every 1,000 casualties contracted tetanus.

The deadly disease is caused by the bacterium Clostridium tetani, spores of which are widespread in the environment, including in soil, animal feces and the human intestine. Tetanus spores enter the body through an open wound—a battle injury, for example, or in an umbilical cord cut by an unsterile instrument—and develop in environments absent of oxygen. Those facing the devastating disease experience increasingly violent and painful muscle spasms, some capable of ripping muscles and fracturing the spine.

The 19th-century soldiers fell ill to a disease all too common—both then and now—in remote regions of the world. While war wounds made the men vulnerable, women and infants in Southern and East Asia, Africa and other developing nations fell ill to maternal and neonatal tetanus through unhygienic birth practices. Two hundred years later, community mortality surveys—studies of infant deaths and their causes in randomly selected villages/communities—show that tetanus kills nearly 60,000 infants and a significant number of mothers annually.

“The disease is particularly common and serious in newborn babies. Most infants who get the disease die,” says Dr. Abdo Konur of the Institute of Molecular Biology and Tumor Research of Marburg’s Philipps University and a member of the Kiwanis club currently being organized in Marburg. “Neonatal tetanus is particularly common in rural areas where most deliveries are at home without adequate sterile procedures. Tetanus is indeed closely correlated to the development status of a country.”

That’s why Kiwanis International and UNICEF have joined forces to create The Eliminate Project, a partnership to eliminate maternal and neonatal tetanus from the globe by 2015 by immunizing more than 100 million women and their future babies at a cost of US$110 million. The vaccine that makes this possible came about through a series of events that unfolded decades after the Peninsular War’s end. By World War I, the medical landscape for treating tetanus had changed, thanks to the work of two men, Baron Kitasato Shibasaburo and Emil von Behring.

The two brilliant medical minds—the former a native of Kumamoto, Japan, and the latter born in Hansdorf, West Prussia (now part of Poland)—followed separate career paths that eventually brought them to Berlin’s Institute of Hygiene under Robert Koch, a famed German physician considered to be the founder of modern bacteriology.

Kitasato began his work with Koch in 1886; von Behring arrived in 1888. By 1890, von Behring—who had a special interest in diphtheria and tuberculosis—had worked with colleague Erich Wernicke to develop an effective therapeutic serum against diphtheria. At the same time, von Behring and Kitasato developed a similar serum to fight tetanus.

Serum therapy was not a vaccine; rather, it treated people who had existing cases of diphtheria and tetanus.

While working with diphtheria, von Behring was able to inoculate animals—first sheep, later horses—with a relatively pure form of the bacterial toxin that caused it, Konur explains. “These toxins, which are released by the bacterium, are proteins, and proteins are well-recognized by the immune system, mainly by the so-called B cells. Upon recognition of a foreign protein, these cells start to produce proteins themselves, which bind to the foreign protein (the bacterial toxin) and neutralize them.”

Von Behring called those neutralizing proteins—the active ingredient of the diphtheria serum therapy—“anti-toxins”; we know them today as antibodies. He further showed that these antitoxic qualities were located not within blood cells themselves, but within the cell-free serum. Animals already infected with diphtheria could be cured by receiving a dose of the serum.

Conflicting stories exist as to when the first human diphtheria patient was successfully treated with a blood serum. One widely cited version has von Behring successfully treating an ill little girl in Germany on Christmas Day 1891. The College Physicians of Philadelphia, Pennsylvania, self-described as the “oldest professional society in the United States,” claims that systematic use of the serum to treat diphtheria did not occur until late 1892.

Konur, however, cites an original letter of von Behring’s, kept at Philipps University’s Emil von Behring Library, which is headed by Dr. Ulrike Enke. In the letter dated December 30, 1891, von Behring wrote to a friend, Richard Muttray, that he had finished the scientific work regarding tetanus and diphtheria therapy and that he planned to begin treating humans in the middle of January 1892.

“I think this is the best source documenting when the first human therapy has taken place,” Konur says.

At the same time, von Behring was working with diphtheria, Kitasato was concentrating on tetanus. Kitasato’s grandson, Dr. Ichiro Kitasato, senior advisor, The Kitasato Institute, believes the drive behind his grandfather’s dedication to the project derived from his work with Koch, who was a mentor to the Japan native.

Koch had developed his famous three postulates for establishing proof of the cause of disease: the presence of a particular parasite in all lesions, the parasite’s isolation in a pure culture and the parasite’s ability to reproduce the disease in laboratory animals. At the time that Kitasato began concentrating on tetanus, the established theory about the disease was that the tetanus bacillus could not be purely cultivated. “It is Symbiosis,” reported Professor Flügge of Germany’s University of Göttingen in 1885.

Kitasato, however, asserted that if Flügge’s theory was true, Koch’s three postulates would dissolve. To prove the prevailing logic wrong—and thus preserve his mentor’s postulates—Kitasato began working on the pure cultivation of the tetanus bacillus. He developed new equipment that used a special petri dish, began experimenting and, in 1889, became the first person to successfully grow the tetanus bacillus.

“I believe the hidden drive of Kitasato at this time was the conviction that his mentor Koch’s three postulates are right—and the enthusiasm to find a way to save people from deadly tetanus,” Ichiro Kitasato says. “He was devoted to his study in high aspiration to help humankind.”

The following year, Kitasato discovered an antitoxin for the disease, setting up an opportunity to apply von Behring’s blood serum therapy to tetanus. As with diphtheria, animals such as rats, guinea pigs and rabbits could be cured with existing forms of tetanus when injected with the appropriate blood serum.

“This kind of therapy is known today to be a passive immunization,” Konur explains. “That means that the patient doesn’t produce the toxin-specific antibodies by himself; the antitoxin (neutralizing antibody) is administered to him.”

Von Behring and Kitasato’s work also demonstrated that the antibodies were specific to the diseases from which they originated—tetanus antitoxin could not neutralize the diphtheria toxin, and vice versa.

Both men would be honored for their breakthroughs in blood serums and passive immunization. Von Behring received the 1901 Nobel Prize for Physiology and Medicine for his work with serum therapies. Kitasato formed Kitasato Institute (later Kitasato University) in 1914 and was the first dean of medicine at Keio University and the first president of the Japan Medical Association. In 1924, he was ennobled with the title of danshaku (baron) in the kazoku peerage system of the Empire of Japan.

The serum and passive immunization discoveries laid the foundation for the development of an actual tetanus vaccine. In 1920, a French biologist and veterinarian, Gaston Ramon, opened a small lab near his house. It was there that he would make a groundbreaking contribution to modern medicine.

In 1923, while working with the diphtheria toxin, he used formalin (a solution containing 40 percent formaldehyde) to weaken it. The result: The toxin would be too weak to produce diphtheria when injected into a subject, but still strong enough to stimulate an immune response. In short, he had discovered an active immunization, one that could be given directly to a human to prevent a disease, rather than first be cultivated in an animal’s serum and then transferred to a human to treat an already established case.

“This is called toxoid, a more advanced method,” Kitasato explains.

Ramon correctly concluded that his work with the diphtheria toxin could be applied in a similar manner to the tetanus toxin and developed a tetanus toxoid as well.

The tetanus vaccine was born—and today, a version of that vaccine is at the heart of The Eliminate Project. It’s a mission that Baron Kitasato Shibasaburo would have embraced, his grandson believes.

“Shibasaburo preached how it is important to prevent, rather than treat, in order to eliminate an infectious disease, and laid the foundation of public hygiene,” Dr. Ichiro Kitasato says. “In the developing countries where hygiene management is inadequate, tetanus such as maternal and neonatal tetanus is still prevailing. To deliver vaccines (and/or antiserum) to these countries and to eliminate tetanus is what Shibasaburo, who fought with tetanus bacillus for the public welfare, hoped for.”

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