My history is not atypical of many Americans: born in the midwest, educated in the East, and now living in the West. My early years were shared between Des Moines, Iowa and Cincinnati, Ohio. Shortly after I was born on May 28, 1942 in Des Moines, my father, Lawrence, was drafted into the United States Navy. I was named for my father’s younger brother who died of Hodgkin’s disease at the age of 24. We moved to Boston briefly where my father enrolled in Naval officer training school before being sent to the south Pacific. He served as a communications officer for the remainder of World War II on an island called Eniwetok where the first hydrogen bomb was detonated a decade later.
During my father’s absence, my mother, Miriam, and I lived in Cincinnati where her mother, Mollie Spigel, also lived. Prior to moving to Cincinnati, Mollie had lived in Norfolk, Virginia, where she raised three children after her husband Benjamin was killed at age 50 in a traffic accident. Besides many special memories of my maternal grandmother, I have many fond reminiscences of my paternal grandfather, Ben, who emigrated to the United States in 1896 as a young boy from Moscow. He grew up in Sioux City, Iowa, as did my father with many other Russian Jews. Shortly after the end of World War II, we returned to Des Moines where I attended primary school and my brother, Paul, was born. In 1952, we moved back to Cincinnati with the hope that my father would be able to find a much better job as an architect. In Cincinnati, he practiced architecture for the next 25 years, which enabled him to provide a very comfortable home for his family.
During my time at Walnut Hills High School, I studied Latin for five years, which was to help me immensely later in the writing of scientific papers. But I found high school rather uninteresting and was most fortunate to be accepted by the University of Pennsylvania where I majored in Chemistry.
The intellectual environment of the University of Pennsylvania was extraordinary – there were so many internationally renowned scholars who were invariably receptive to the intrusions of undergraduate students even before the days of student evaluations of the faculty. The small size of the undergraduate student body undoubtedly contributed to the accessibility of the faculty. Besides numerous science courses, I had the opportunity to study philosophy, the history of architecture, economics, and Russian history in courses taught by extraordinarily knowledgeable professors. Although I was among the smallest of the heavyweight crew team members and thus had no chance of rowing in the varsity boat, I greatly enjoyed the many hours that I spent at this wonderful sport.
During the summer of 1963 between my junior and senior years, I began a research project on hypothermia in the Department of Surgery with Sidney Wolfson. I quickly became fascinated by the project and continued working on it throughout my senior year. I decided to remain at Penn for Medical School largely because of the wonderful experience of doing research with Sidney Wolfson. During the second year of medical school, I decided to ask Britton Chance if he would allow me to study the surface fluorescence of brown adipose tissue in Syrian golden hamsters as they arose from hibernation. Chance had reported that the surface fluorescence of other organs reflected the oxidation-reduction state of those tissues. As anticipated, large changes in the fluorescence of brown fat were found during non-shivering thermogenesis.
My research on brown fat allowed me to spend much of the fourth year of medical school at the Wenner-Gren Institute in Stockholm working with Olov Lindberg on the metabolism of isolated brown adipocytes. This was an exciting time and I began to consider seriously a career in biomedical research. Early in 1968, I returned to Philadelphia to complete my medical studies and to contemplate my options. The previous spring, I had been given a position at the NIH once I completed an internship in medicine. It was the height of the Vietnam war with 500,000 young Americans trying to control the spread of Communism in southeast Asia. But I was facing an internship at the University of California San Francisco (UCSF) that would require me to work every other night for an entire year, a prospect about which I was not enthusiastic. The privilege of serving in the US Public Health Service at the NIH clearly outweighed the unpleasant prospects of an internship. Although the workload was awesome, I managed to survive because San Francisco was such a nice place to live. During that year, I met my wife, Sandy Turk, who was teaching mathematics to high school students.
At the NIH, I worked in Earl Stadtman’s laboratory where I studied glutaminases in E. coli. My three years at the NIH were critical in my scientific education. I learned an immense amount about the research process: developing assays, purifying macromolecules, documenting a discovery by many approaches, and writing clear manuscripts describing what is known and what remains to be investigated. As the end of my time at the NIH began to near, I examined postdoctoral fellowships in neurobiology but decided a residency in Neurology was a better route to developing a rewarding career in research. The residency offered me an opportunity to learn about both the normal and abnormal nervous system.
In July 1972, I began a residency at the University of California San Francisco in the Department of Neurology. Two months later, I admitted a female patient who was exhibiting progressive loss of memory and difficulty performing some routine tasks. I was surprised to learn that she was dying of a “slow virus” infection called Creutzfeldt-Jakob disease (CJD) which evoked no response from the body’s defenses. Next, I learned that scientists were unsure if a virus was really the cause of CJD since the causative infectious agent had some unusual properties. The amazing properties of the presumed causative “slow virus” captivated my imagination and I began to think that defining the molecular structure of this elusive agent might be a wonderful research project. The more that I read about CJD and the seemingly related diseases – kuru of the Fore people of New Guinea and scrapie of sheep – the more captivated I became.
Over the next two years I completed an abbreviated residency while reading every paper that I could find about slow virus diseases. In time, I developed a passion for working on these disorders. As I plotted out a course of action, the task became more and more daunting. The tedious, slow, and very expensive assays in mice for the scrapie agent had restricted progress and I had no clever idea about how to circumvent the problem. I did think that after working with the scrapie agent for some time that I might eventually be able to develop such an assay.
Since both Sandy and I liked living in San Francisco, I accepted the offer of an assistant professor position from Robert Fishman, the Chair of Neurology, and began to set up a laboratory to study scrapie in July 1974. Although many people cautioned me about the high risk of studies on scrapie due to the assay problems, such warnings did not dull my enthusiasm. To gain a base of research support from the NIH, I initially wrote grant proposals on glutamate metabolism in the choroid plexus. Such proposals were dull but were readily funded because I had worked on glutaminases earlier. Eventually, I managed to gain modest NIH support for my scrapie studies but this was not without considerable difficulty. To rebut the disapproval of my first NIH application on scrapie, I set up a collaboration with William Hadlow and Carl Eklund who were working at the Rocky Mountain Laboratory in Hamilton, Montana. They taught me an immense amount about scrapie and helped me initiate studies on the sedimentation behavior of the scrapie agent.
I had anticipated that the purified scrapie agent would turn out to be a small virus and was puzzled when the data kept telling me that our preparations contained protein but not nucleic acid. About this time, I was informed by the Howard Hughes Medical Institute (HHMI) that they would not renew their support and by UCSF that I would not be promoted to tenure. When everything seemed to be going wrong, including the conclusions of my research studies, it was the unwavering, enthusiastic support of a few of my closest colleagues that carried me through this very trying and difficult period. Fortunately, the tenure decision was reversed and I was able to continue my work. Although my work was never supported by HHMI again, I was extremely fortunate to receive much larger funding from the R. J. Reynolds Company through a program administered by Fred Seitz and Macyln McCarty and shortly thereafter from the Sherman Fairchild Foundation under the direction of Walter Burke. While the vast majority of my funding always came from the NIH, these private sources were crucial in providing funds for the infrastructure which was the thousands of mice and hamsters that were mandatory.
As the data for a protein and the absence of a nucleic acid in the scrapie agent accumulated, I grew more confident that my findings were not artifacts and decided to summarize that work in an article that was eventually published in the spring of 1982. Publication of this manuscript, in which I introduced the term “prion”, set off a firestorm. Virologists were generally incredulous and some investigators working on scrapie and CJD were irate. The term prion derived from protein and infectious provided a challenge to find the nucleic acid of the putative “scrapie virus.” Should such a nucleic acid be found, then the word prion would disappear! Despite the strong convictions of many, no nucleic acid was found; in fact, it is probably fair to state that Detlev Riesner and I looked more vigorously for the nucleic acid than anyone else.
While it is quite reasonable for scientists to be skeptical of new ideas that do not fit within the accepted realm of scientific knowledge, the best science often emerges from situations where results carefully obtained do not fit within the accepted paradigms. At times the press became involved since the media provided the naysayers with a means to vent their frustration at not being able to find the cherished nucleic acid that they were so sure must exist. Since the press was usually unable to understand the scientific arguments and they are usually keen to write about any controversy, the personal attacks of the naysayers at times became very vicious. While such scorn caused Sandy considerable distress, she and my two daughters, Helen and Leah, provided a loving and warm respite from the torrent of criticism that the prion hypothesis engendered. During the winter of 1983, I herniated a disc in my lumbar spine while skiing and this slowed the pace of my work for much of the year. After a laminectomy, I began swimming regularly, which brought relaxation and a much needed quiet time to my life.
Just prior to my back problem, the protein of the prion was found in my laboratory and the following year, a portion of the amino acid sequence was determined by Leroy Hood. With that knowledge, molecular biological studies of the prions ensued and an explosion of new information followed. I collaborated with Charles Weissmann on the molecular cloning of the gene encoding the prion protein (PrP) and with George Carlson and David Kingsbury on linking the PrP gene to the control of scrapie incubation time in mice. About the same time, we succeeded in producing antibodies that provided an extremely valuable tool that allowed us to discover the normal form of PrP. In a very important series of studies, the antibodies were used by Stephen DeArmond to study the pathogenesis of prion disease in transgenic mice. Steve brought the much needed talents of an outstanding neuropathologist to these studies. As more data accumulated, an expanding edifice in support of the prion concept was constructed. Ruth Gabizon dispersed prions into liposomes and purified scrapie infectivity on columns with PrP antibodies. Karen Hsiao discovered a mutation in the PrP gene that caused familial disease and reproduced the disease in transgenic mice while Michael Scott produced transgenic mice abrogating the prion species barrier and later artificial prions from chimeric PrP transgenes. Indeed, no experimental findings that might overturn the prion concept were reported from any laboratory. By the early 1990s, the existence of prions was coming to be accepted in many quarters of the scientific community, but the mechanism by which normal PrP was converted into the disease-causing form was still obscure. When Fred Cohen and I began to collaborate on PrP structural studies, I was again extremely fortunate. Fred brought an extraordinary set of skills in protein chemistry and computational biology to investigations of PrP structures.
As prions gained wider acceptance among scientists, I received many scientific prizes. The first major recognition of my work was accorded by neurologists with many other awards coming soon thereafter. But the most rewarding aspect of my work has been the numerous wonderful friends that I have made during an extensive series of collaborative studies. It has been a special privilege to work with so many talented scientists including numerous postdoctoral fellows and technical associates who have taught me so much. Besides the many collaborators who have contributed their scientific skills to advancing the study of prions, I have had many colleagues who have contributed indirectly to my work by being supportive of the special needs that such a project has demanded.
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.
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