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.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.
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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 information is sometimes updated with an addendum submitted by the Laureate. To cite this document, always state the source as shown above.
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