Midwest, East, West
Stanley Ben Prusiner was born on 28 May 1942 in Des Moines, Iowa. “My history is not atypical of many Americans” he later wrote: born in the Midwest, educated in the East, living in the West. He was named for his father’s younger brother, who had died of Hodgkin’s disease at twenty-four. Soon after his birth his father, Lawrence, an architect, was drafted into the U.S. Navy and served as a communications officer in the Pacific, while Stanley and his mother, Miriam, lived with her mother in Cincinnati.
The family was Jewish, part of the wave of Russian-Jewish immigration to the American heartland. His paternal grandfather, Ben, had come to the United States from Moscow as a boy in 1896 and grew up in Sioux City, Iowa, among many other Russian Jews. After the war the Prusiners returned to Des Moines, where Stanley’s brother Paul was born, and in 1952 moved back to Cincinnati, where his father practised architecture for twenty-five years.
An education in research
At Walnut Hills High School in Cincinnati Prusiner studied Latin for five years, invaluable, he said later, for writing scientific papers, but found school dull. At the University of Pennsylvania, where he majored in chemistry and rowed on the heavyweight crew, he came alive. In the summer of 1963 he began research on hypothermia in the department of surgery, and the experience persuaded him to stay at Penn for medical school. There he studied the brown fat that warms hibernating hamsters, work that took him to the Wenner-Gren Institute in Stockholm for much of his final year.
After an internship at the University of California, San Francisco, where he met his wife, Sandy Turk, a high-school mathematics teacher, he spent three years in the U.S. Public Health Service at the National Institutes of Health, studying bacterial enzymes in the laboratory of Earl Stadtman. There, he wrote, he learned how research is really done: developing assays, purifying molecules, documenting a discovery by many approaches and writing clearly about what is and is not known.
A patient and a puzzle
In July 1972 Prusiner began a neurology residency at UCSF. Two months later he admitted a woman who was steadily losing her memory and her ability to perform everyday tasks. She was dying of Creutzfeldt–Jakob disease (CJD), a rare and invariably fatal brain disorder then attributed to a mysterious “slow virus.” The infectious agent behaved strangely: it provoked no immune response, survived treatments that destroyed ordinary viruses, and took years to cause disease. Related illnesses included kuru among the Fore people of New Guinea and scrapie in sheep.
These diseases had already produced one Nobel Prize. In the 1950s and 1960s the American physician D. Carleton Gajdusek had studied kuru, a fatal neurological illness spread among the Fore through funeral rites, and shown that it could be transmitted to chimpanzees; he shared the 1976 Nobel Prize for the work. But what kind of agent caused kuru, CJD and scrapie remained a mystery, and many assumed it would prove to be an unusual virus.
Prusiner was captivated. He read everything he could find on these diseases and decided to identify the molecular nature of the agent. Colleagues warned him that the work was risky: experiments with scrapie depended on injecting extracts into mice and hamsters and waiting many months to see whether they fell ill. In July 1974 he set up his own laboratory at UCSF to study scrapie, initially funding it with dull but fundable grants on brain chemistry while he collaborated with William Hadlow and Carl Eklund at the Rocky Mountain Laboratory in Montana.
A heretical protein
Prusiner had expected the scrapie agent to turn out to be a small virus. Instead, as his purifications improved, the data kept telling him that the infectious material contained protein but no detectable nucleic acid, no DNA or RNA, the genetic molecules every known infectious agent needed to reproduce. The idea that a protein alone might be infectious had been floated before, notably by the radiobiologist Tikvah Alper and the mathematician J. S. Griffith in the 1960s, but it ran against the central assumptions of biology.
In 1982 he published his conclusions in Science and introduced a new word, “prion” from “proteinaceous infectious particle.” The paper, he recalled, set off a firestorm. Virologists were incredulous; some researchers working on scrapie and CJD were furious. The criticism spilled into the press and at times became personal and vicious. Meanwhile, at a low point, the Howard Hughes Medical Institute declined to renew his funding and UCSF initially refused him tenure, a decision later reversed. Private funders, including programmes supported by R. J. Reynolds and the Sherman Fairchild Foundation, helped pay for the thousands of animals his experiments required.
Building the case
Over the next fifteen years Prusiner and a growing circle of collaborators assembled the evidence. His lab isolated the prion protein, PrP, and with Leroy Hood determined part of its sequence. With Charles Weissmann they cloned the gene that encodes it, and discovered that the gene is a normal part of the host’s own DNA. Antibodies revealed that healthy brains contain a normal form of PrP; disease occurs when the protein folds into an abnormal shape that can, in turn, induce normal copies to misfold, in a self-propagating chain reaction. Karen Hsiao found a PrP mutation that causes inherited prion disease and reproduced the illness in transgenic mice.
Prions thus explained a puzzle that no virus could: the same diseases could be infectious, inherited or apparently spontaneous. Prusiner and his colleagues looked harder than anyone for a hidden nucleic acid, had one been found, he noted, the word prion would have disappeared, and none was. By the early 1990s the prion concept was becoming accepted, though a minority of scientists continued to argue for an undiscovered virus.
The work also explained a cruel feature of these diseases: the abnormal form of PrP is extraordinarily stable, resisting heat, radiation and the chemicals that destroy viruses, which is why prions could survive ordinary sterilisation and why surgical instruments and medical products could transmit CJD from patient to patient.
Mad cows and a Nobel Prize
The stakes became painfully public with the epidemic of bovine spongiform encephalopathy, “mad cow disease”, in British cattle in the late 1980s and 1990s, and the 1996 recognition of a new variant of CJD in people who had eaten infected beef. Prusiner’s work provided the framework for understanding how a protein could pass from cattle to humans, and it shaped the safety measures for food, blood and surgical instruments that followed.
In 1997 Prusiner was awarded the Nobel Prize in Physiology or Medicine, unshared, “for his discovery of Prions, a new biological principle of infection.” He had already received the Albert Lasker Award for Basic Medical Research in 1994 and the Wolf Prize in Medicine in 1996, and later received the National Medal of Science in 2010. The idea once dismissed as heresy had become textbook biology.
Beyond mad cow disease
Prusiner argued early that prions might illuminate far more common disorders. In 1999 he founded the Institute for Neurodegenerative Diseases at UCSF to study illnesses caused by misfolded proteins. Research by many groups has since shown that the proteins that accumulate in Alzheimer’s disease, Parkinson’s disease and related conditions can spread through the brain by a prion-like process of templated misfolding, and Prusiner’s laboratory has reported that the protein behind multiple system atrophy behaves as a prion. How far the prion model extends remains an active scientific debate, but it has opened new routes toward diagnosis and treatment.
In 2014 he told the story of his career, including the battles over his ideas, in a memoir, Madness and Memory: The Discovery of Prions, A New Biological Principle of Disease.
Family, faith and character
Prusiner has credited his family with sustaining him through the years of ridicule. The personal attacks, he wrote, caused his wife Sandy considerable distress, but she and their daughters, Helen and Leah, gave him a loving refuge from the torrent of criticism. After a skiing injury and back surgery in 1983 he took up swimming, which brought him quiet amid the controversy.
His Jewish roots lie in the Russian-Jewish immigrant communities of Iowa and Ohio, and he is counted among the many American Jewish laureates of the Nobel Prize in medicine. His persistence through more than a decade of scepticism, pursuing an idea that threatened his funding and his job, is the defining trait of his career, and it is hard to imagine the prion concept surviving without it.
Legacy
Prusiner’s discovery added a new category to the list of infectious agents, alongside bacteria, viruses, fungi and parasites, and showed that the shape of a protein, not just its sequence, can carry biological information. Few scientists have had to defend an idea against such sustained hostility for so long, and fewer still have been vindicated so completely.
His career has become a classic illustration of how science is supposed to work: careful data that refuse to fit the accepted picture, a long and bruising argument, and in the end a changed understanding of life itself. As he wrote in his Nobel autobiography, it is reasonable for scientists to be sceptical of ideas that do not fit, yet the best science often comes from exactly those results.
Sources & further reading
Stanley B. Prusiner, Biographical, NobelPrize.org · The Nobel Prize in Physiology or Medicine 1997, Press release, NobelPrize.org · Stanley B. Prusiner, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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