As evidenced by the Koplik spots, the rash is not restricted to the outer skin surfaces, as the infection can spread to internal tissues in the lining of the mouth, lung, eye, ear, and other body surfaces. An infected patient may begin to cough up blood and experience chest pains as the heart and lung recoil from the viral assault. The resulting damage can trigger complications such as pneumonia, diarrhea, and corneal damage. As the virus wends its way through the body, the liver, spinal cord, and brain can become involved. Complications can include permanent neurological damage and blindness, particularly in adults. As indicated above, these symptoms can progress to death directly caused by the virus, or they can render the body severely susceptible to secondary infections (usually bacterial in origin) that finish the job.
Despite considerable human experience with measles since Rhazes’s reports, both in terms of its public health devastation and symptoms, the discovery of the measles virus did not occur until the middle of the 20th century. The virus arose from a most interesting source.
Enders Game
Virtually every photograph publically available of John Enders portrays a dignified man, almost invariably in a tweed jacket, who looks every bit an Ivy League patrician. Although stereotypes are frequently dangerous, they are surprisingly accurate in this case. John Franklin Enders was born on February 10, 1897, in West Hartford, Connecticut.15 John’s father, John Ostrom Enders, was a wealthy Hartford banker, and his grandfather had founded the Aetna Life Insurance Company.
Although better known today as the center of the insurance business (including Aetna, Travelers, and, of course, The Hartford), Hartford was also a mecca for the intelligentsia in turn-of-the-century America. The local newspaper, the Connecticut (later Hartford) Courant is the longest-serving newspaper in the United States, while the number of publishing houses calling Hartford home at the beginning of the 20th century eclipsed even nearby New York City. Indeed, the list of prominent authors, who lived here included Harriet Beecher Stowe and Samuel Clemens (Mark Twain), both of whose finances were managed by Enders’ father. Clemens made a strong impression on John during the writer’s frequent visits to the Enders home in the early years of the 20th century. Given his pedigree and interest in erudition, John Enders, like his brother after him and many other members of his blue-blooded family, attended Yale University. Whereas his brother Ostrom joined the family business after graduating from Yale, John’s experience took a different route.
John Enders enrolled at Yale University in the autumn of 1915, a halcyon time in America despite the fact Europe had already lost millions to a year-long war. John was soon captured by the new fad of flying aircraft. In the handful of years after controlled flight had first been demonstrated by Wilbur and Orville Wright on the dunes of Kitty Hawk beach on December 17, 1903, access to flying machines had remained quite rare—limited to an affluent few who could afford such diversions. As detailed in Marc Wortman’s outstanding 2007 book, The Millionaire’s Unit, Yale hosted an elite group of flyers, many of whom volunteered to fly in France once the United States entered the First World War in the spring of 1917.16 Although Enders did not see battle, he did join the fledgling Army Air Corps as an ensign and played an equally important role as an early military flight instructor in Pensacola, Florida. The dangers associated with aviation, particularly in those early days, clearly left an impression on Enders, who tended to avoid flying as a means of transportation for the rest of his life thereafter.17
At war’s end, Enders finished his studies at Yale. Upon graduation in 1920, he returned to Hartford and tried for a year to make his name in the real estate business, but his heart was simply not in it.18 Instead, he enrolled at Harvard as an English major, where he focused upon Celtic and early English literature. As Enders was completing his master’s degree, he happened to share a boardinghouse in Brookline, Massachusetts, with an Australian by the name of Hugh Kingsley Ward.19 Ward was the youngest of eight children from an aristocratic Sydney family (his father had served as a scout in the Maori wars and later became editor of the Sydney Mail and the Daily Telegraph). After graduating from the University of Sydney, he was awarded a Rhodes Scholarship to Oxford. As one sign of his assimilation into English society, he took up the sport of rowing, participating in the 1912 Olympic Games. Conveniently, the games were held in London that year, and while this might seem to have presented a certain advantage for a member of the Australian team already acclimated to the time and location, his Australian teammates denigrated Ward as a foreigner inserting himself into an established team and not being “an Australian rower.”20 Ward was therefore largely excluded by the team from most events in the 1912 London Olympics.
After completion of the games, Ward finished degrees at Oxford in anthropology and public health in 1913. Ward was enamored with the emerging field of microbiology, but his studies were interrupted by the outbreak of the Great War. He served in France as part of the Royal Army Medical Corps Special Reserve. Despite being wounded and gassed multiple times, Ward survived the war and was embraced upon his return to Australia as a hero, receiving the Military Cross with two bars. After the war, he returned to Oxford and continued his work on microbiology.21 Ward desired to perform research in America and was awarded a one-year Rockefeller Foundation fellowship to work with Hans Zinsser at Harvard. Zinsser was an American bacteriologist who had discovered the pathogen responsible for typhus.
As we have already seen, the Harvard roommate of the Aussie Ward was the Connecticut Yankee John Enders. As Enders was completing his master’s thesis on Middle English and was preparing to embark on a PhD on the subject, the two struck up a lasting friendship. Enders would frequently accompany Ward to his laboratory, where the latter would often be engaged in long experiments.
This initial exposure to bacteriology fascinated the American, and Enders was soon infected by the rapidly spreading field. Enders was particularly intrigued by Zinsser and his work. Enders switched majors in 1927, and three years later, he successfully defended a doctoral dissertation on tuberculin and endotoxins.22 Although a Yale man by family tradition and early training, Enders accepted an offer to remain in Cambridge, and he would remain at Harvard for the rest of his professional career (though he did ultimately donate his papers to his alma mater).
As a junior professor, Enders’s first breakthrough occurred in experiments performed just as the Second World War was taking hold in Europe. Enders and two colleagues, Alto E. Feller and Thomas H. Weller, grew vaccinia virus in tissues derived from chicken embryos.23 This may sound rather banal, but the study was a landmark that introduced the world to opportunities arising from the new science of cell culture. The fundamental breakthrough came from Enders’s findings that viruses could be propagated in the laboratory using eggs or even small dishes of cells rather than relying upon more laborious, expensive, and slower techniques that required producing viruses in chickens, cows, monkeys, or other animals. The field of cell culture would soon change the scientific and medical worlds, but a series of tragic events slowed its adoption for a time.
The slide towards war drained both the resources and personnel needed to follow up on the work. In addition, Enders’s boss and inspiration, Hans Zinsser, was slowly dying of leukemia, to which he would succumb in 1940. This loss was not just a personal blow for Enders; he also inherited the responsibility and burden of running Zinsser’s laboratory studies of typhus, as well as Zinsser’s entire department at Harvard.24 Worse still, Enders’s wife of sixteen years, Sarah, died from acute myocarditis in 1943, a tragedy that led Enders to surrender his responsibilities as department head to a colleague.
Freed from the administrative burden and perhaps needing to put his mind elsewhere to overcome his grief, Enders focused on his work. In 1946, he was recruited by Drs. Charles Janeway (whom we met in an earlier chapter) and Sydney Farber (for whom the Harvard Cancer Center is named) to Children’s Hospital, also in Boston. Around this time, Enders began to study mumps, a disease that captures the secon
d letter of MMR and whose viral pathogen had been discovered in 1934 by the Vanderbilt University investigator Dr. Ernest Goodpasture.25
Although mumps is not one of the deadlier viruses known (roughly one in ten thousand infected people dies), it is one of the most infectious, being easily spread among individuals in confined settings such as nurseries or military barracks. Mumps could temporarily incapacitate a group of soldiers and thus had become a high priority for the United States military. Using an approach similar to the one Enders used with vaccinia virus, the NIH scientist Karl Habel demonstrated that mumps virus could be cultured in chicken embryo cells (specifically, fibroblasts) isolated from eggs.26
Inaugurating his new laboratory at Children’s Hospital, Enders appointed Thomas Weller and his new pediatric resident, Dr. Frederick Chapman Robbins, to optimize his own approaches using chicken embryo cells to create a vaccine. Starting in 1948, Robbins began the process of propagating mumps virus. Weakening the virus through repetitive passages through eggs, he soon adapted an attenuated form of the mumps virus, a subject to which we will soon return after a short interlude.
This important work with mumps was a mere footnote relative to Enders’s impact on polio. Over a remarkably short time, the team of Weller, Robbins, and Enders likewise developed the ability to culture poliovirus in eggs—itself a key achievement that would be needed to mass-produce future vaccines—and to use this system to evaluate the ability of antisera and vaccines to block polio. These accomplishments would earn each member of the team the 1954 Nobel Prize for Physiology or Medicine.
Having made key contributions to the development of both mumps and polio vaccines, Enders turned his sights upon two forms of measles in 1954. This work briefly led to a side project on rubella, also known as German measles (and the third letter depicted in the acronym MMR). The virus responsible for rubella and the discovery of its vaccine has recently been detailed at length in the outstanding book The Vaccine Race.27 While rubella is relatively innocuous in children, viral infection in pregnant women can be devastating. Infection of the mother can spread to the fetus, where rubella causes massive damage. Consequently, the pregnancy often suffers from spontaneous abortions, or, for those fetuses that survive, debilitating injury.
The fame and fate of rubella were strongly influenced by a tragic incident involving a Hollywood superstar, Gene Tierney, whose child was severely injured by an infection with rubella in utero.28 A stunning actress best known for her starring role in the 1944 film Laura, Tierney married Oleg Cassini, the famous fashion designer, in 1941. The couple became pregnant in 1943, but Tierney was exposed to German measles during a performance at the Hollywood Canteen. She gave birth to a severely disabled daughter, Antoinette Daria Cassini, who suffered from severe neurological symptoms, including profound mental deficiencies, blinding cataracts, and deafness. Tierney entered a long depression that shortened her career and broke up her marriage. She then fell in love with John Fitzgerald Kennedy (the future president) and had a series of high-profile and soon-to-be-divorced beaus, including Charles Feldman (who was divorcing Jean Howard), Prince Aly Khan (as he was divorcing Rita Hayworth), and a Texas oil baron (as he was divorcing Hedy Lamarr).
Despite this string of high-profile affairs, Tierney is perhaps best remembered in popular culture for her connection with German measles. Years after giving birth to Antoinette Daria Cassini, Tierney was approached by a woman who told her that she had snuck away from quarantine and had gone to the Hollywood Canteen. According to an article in the New Yorker, “Everyone told me I shouldn’t go,” the starstruck woman told Tierney years later at a tennis match, not realizing what she was responsible for, “but I just had to go. You were my favorite.”29
This experience later served as a plot vehicle for one of Agatha Christie’s most famous novels, The Mirror Crack’d From Side to Side, which became a best seller and spawned multiple adaptations for the large and small screens.30 In part driven by the publicity generated by the highly publicized experience of Gene Tierney, many resources were dedicated to propel a race for a vaccine. Enders’s primary contribution was to provide the key techniques utilized by Dr. Leonard Hayflick—the primary subject of The Vaccine Race—to propagate the virus in cultured cells.31
Although rubella (German measles) and rubeola (measles) share considerable similarities in their names and symptoms, the viruses are quite distinct. Another key contribution of Enders was the definitive discovery of the measles virus. Based on the cell culture techniques developed in his laboratory, a new team consisting of Thomas C. Peebles and Kevin McCarthy was able to propagate a virus isolated from an eleven-year-old boy from the Fay Boarding School in Southborough (Massachusetts), facilitating its identification in 1954.32 Indeed, the viral isolate from young David Edmonston (who is still alive and well as of press time) would go on to provide the material that would be developed into a vaccine to prevent measles.33 The aforementioned www.scienceheroes.com website estimates that John Enders has contributed to the saving of more than 120,000,000 lives as of early 2017 (twice as many as Gaston Ramon and three times more than Paul Ehrlich or Shibasaburo Kitasato).34
Shrunken heads & Big Impacts
Joining John Enders in the pantheon of vaccine innovators is a figure born into tragedy but who would survive to save countless numbers of children. Maurice Hilleman was born on August 30, 1919 in Custer County, a cattle ranch and dirt farming region of almost four thousand square miles in Wyoming that has been populated by no more than five thousand houses holding no more than thirteen thousand people at any time for more than a century.35 The county received its name and raison d’etre in the days following the disastrous Battle of the Little Bighorn, which occurred about 130 miles to the southwest. Led by a flamboyant, controversial, and reckless General George Armstrong Custer, the 7th Cavalry Regiment was utterly decimated by the Sioux chief Sitting Bull in June 1876. A panicked federal government threw up a series of forts throughout the Montana Territory to help contain the victorious Native Americans. One of these forts, really a mere outpost, was known as the Tongue River Cantonment. Given its proximity to the Little Bighorn battlefield, the garrison grew for a time, and the site was formally named for one of Custer’s fallen officers, Myles Keough (whose horse was the sole American survivor of the battle).36 In the early days after its creation, Fort Keough was commanded by General Nelson Appleton Miles, a Civil War veteran who had gained a reputation as an Indian hunter (controversially claiming the solo capture of the famous Nez Perce chieftain Chief Joseph). Miles would later capture Puerto Rico from the Spanish in a war for primacy in the Caribbean and become a popular author based on his many experiences.37 An eponymous civilian village near the fort served as the birthplace of Maurice Hilleman.
In the middle of the Spanish flu outbreak (a subject to which we will return in the final chapter), the very Christian Anna Hillemann (née Uelsmann) performed one of her last acts on earth, giving birth to Maurice and a stillborn twin sister, named Maureen.38, 39 Within a few hours of birthing, Anna began to suffer from seizures, symptoms of eclampsia, and would be dead within hours. Just prior to her death, she instructed her husband about the future disposition of her six older sons and daughter, relating that the newborn Maurice was to be raised by Maurice’s uncle. According to Paul Offitt’s outstanding account of Hilleman’s life, Vaccinated, Maurice was raised in the rough-and-tumble environment of the Montana farmlands, almost succumbing to a particularly virulent case of diphtheria as a child.40
Perhaps reflecting the wild and primitive natural beauty surrounding him, Maurice grew into a rebellious and independent thinker. As a child, he was raised under the strict fundamentalist view of the Missouri Synod Lutheran Church, a conservative German-language denomination that rejected humanism and strongly advocated creationism. For this reason, a childhood confrontation with church elders is particularly instructive to gain a view of Maurice’s developing personality. It seems that the young Maurice was caught in the act of reading a library
book during a Sunday sermon.41 This was not just any book but Darwin’s Origin of Species, and an outraged minister attempted to grab the book away from the child. Maurice fought back, indicating the library book was checked out under his name and that the confiscation of the book, as public property of the library, would be a violation of the law. The minister reeled back from this response, and the satisfied Hilleman would never again conform to the teachings of the Synod. Such rebelliousness continued to characterize Hilleman throughout his career, during which he was known as a brilliant but brutal taskmaster. He proudly and prominently displayed a cabinet full of shrunken heads, one symbolically placed for each employee he had fired.42
Perhaps motivated by a combination of self-imposed brilliance, strong work ethic, and a fear of becoming a shrunken head in someone else’s cabinet, Hilleman became the most prolific discoverer of new vaccines who has ever lived. Hilleman’s specialty was the efficient creation of attenuated forms of viruses that could be used as vaccines. As an employee at E.R. Squibb and later as head of vaccinology at Merck & Company, Hilleman and his team developed a series of vaccines that continue to save the lives of millions each year, including those for measles, mumps, rubella (all three components of MMR), as well as Japanese encephalitis, hepatitis B, and chickenpox viruses (the latter of which was later reformulated and approved as a shingles vaccine months after Hilleman’s death).43, 44
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