A Fascinating World of Biology
As told by Marcus E. Raichle
I was born on March 15, 1937, in Hoquiam—one of three small towns (Aberdeen, Hoquiam, and Cosmopolis) nestled in the port of Grays Harbor on the coast of Washington State. My parents resided in the neighboring town of Aberdeen where my father, Marcus Simpson Raichle, was a practicing attorney (he later entered the savings and loan business where he worked until retirement). The only hospital in the area was the Hoquiam General Hospital; hence, that is my official birthplace.
My parents were the children of immigrants. My paternal grandfather, John George Raichle, was sent by his parents to the United States at age six with his sister Barbara, age 11, to live with relatives in the Midwest. They were from a family of 13 children residing in Dettingen, Germany, where the Raichle family and its descendants have resided since the 14th century.
The reception of the Raichle children, John and Barbara, was inhospitable, and they were eventually taken in by the Marcus Simpson family of Burlington, Iowa, who raised them; hence my father’s given name of Marcus Simpson. My grandfather Raichle married the daughter of another German immigrant family, Sarah Buhrmaster, and moved with his new wife to Yakima, Washington, where he built his own home, which stands to this day. He bought land, started a fruit orchard, and worked as an accountant for one of the large fruit companies in Yakima. The Raichle family of Yakima ultimately consisted of seven children, all of whom attended the University of Washington. My father then attended the University of Washington Law School, graduating at the peak of the Great Depression. He luckily found work upon graduation in a small law firm in Aberdeen, Washington.
My mother’s father, Lawrence Hopkinson, emigrated from Leeds, England, where he was a linotype operator. He settled in Milwaukee, Wisconsin, and through his work as a linotype operator was able to raise enough money to bring his bride, Ada Hayward, his father and mother, brothers and sisters, and eventually some of his wife’s relatives to this country. Having accomplished this, he then decided to become a physician. He ultimately graduated from the Milwaukee Medical College and School of Dentistry in the class of 1897. He remained in Milwaukee, where he practiced medicine and continued to participate in the academic affairs of the Milwaukee Medical College. Eventually, he rose to the rank of professor of anatomy and lecturer on rectal diseases. My mother, Dorothy Margaret Hopkinson, was born in Milwaukee, the youngest of four children. She attended Milwaukee Downer College.
Although the Hopkinson family seemed to be thriving in Milwaukee, the climate was a problem for my grandfather (bitterly cold in the winter and hot and humid in the summer) and was in stark contrast to that of England. He ultimately decided to leave Milwaukee and settle in, of all places, Aberdeen, Washington, which at the time was a rough and tumble logging town. Little data exist on the reasons behind this decision other than climate. It is noteworthy, perhaps, that he was a member in good standing of the International Order of Foresters, an organization originating in England but active in North America promoting issues of importance to middle-class families and underserved populations. Likely, in the early 1900s, Aberdeen, Washington, represented an opportunity for someone with these interests.
My parents met and married in Aberdeen where they raised my sister, four years my junior, and me. In those days, Aberdeen, along with its sister communities of Hoquiam and Cosmopolis, was a vibrant place with thriving timber and fishing industries. The local school system, all public except for the local Catholic grade school, was excellent. College attendance rates were high. Extracurricular programs were varied and excellent. I was a mediocre athlete but competed in swimming through graduation.
Among the great strengths of the school system and the community in general were its music programs. Not only were the school programs above average, but this small community even had a respectable symphony orchestra in which I ultimately played. Both of my parents were musical. My mother had a lovely singing voice and, while growing up, regularly accompanied her father, a violinist, on the piano. My father was a gifted piano player who would relax in the evening by sitting down and playing popular music. All he needed was the tune, he could supply the chords! In this environment, I was required to take piano lessons, which I did from kindergarten through high school. In junior high school I fell in love with the oboe, a beautiful instrument when played well, which is something not easily done! I had a masterful teacher, Eugene Stensager, who was part of the high school music program. I had great success as an oboe player in high school and briefly considered a career in music. I have remained an active oboe (and English horn) player to this day as a member of a community symphony orchestra in St. Louis.
The Path to Science
As a reader of this essay, you might be wondering from where the seed of my scientific career came. Although my grandfather was a doctor, I did not enter kindergarten announcing that I wanted to be a physician. I did not own a chemistry set, and I did not collect bugs or other objects of scientific interest. In school, I took all of the science and math courses offered more because it was expected than for any other reason. I did well in these courses but was certainly not the class genius. My parents were told by my high school chemistry teacher, after the first quarter, that I was a daydreamer and needed to be more focused on the class work. (I was receiving a grade of C at the time but managed to pull it up to an A by the end of the year.) I did enjoy my geometry class, particularly working through the “proofs.” Solving problems and figuring out how things worked always fascinated me. But the classes in which I did equally well if not better were English, history, and current affairs. These were interests that I shared with my father. We often discussed the political issues of the day. He was a moderate Republican and was very distressed when John Dewey was defeated by that “failed haberdasher” from Missouri. My father would, I suspect, be surprised to know that Harry Truman has become one of my most admired public figures, although given the thoughtful way in which my father approached problems, he too might have become a convert.
My reading (a lifetime habit) during the transition from high school to college was rather wide ranging and foretold, in retrospect, a lifelong array of interests. A few examples may be of interest. The book Religions of Man by Houston Smith fueled an interest in the role of religion in society and in my own life, something that I continue to ponder. Winston Churchill’s Triumph and Tragedy, the final volume in his six-volume series on World War II was a marvelous read, stimulating an interest in history and political science that endures to this day. And, finally, the marvelous little book by George Gamow, One, Two, Three Infinity, was a spell-binding read fueling the latent scientist in me that I was only to discover much later.
Reinforcing my interest in the social sciences and in public affairs was my participation in an American Legion program known as Boys State (there was a separate Girls State in those days!). We spent several weeks on a college campus constructing a state government, which I enjoyed. Emerging from this was my election as a senator from the state of Washington and my subsequent participation in Boys Nation in Washington, D.C., where two from each state came together to operate as a United States Senate. This was a heady experience including sessions in the old Senate chambers of the U.S. Capitol and a meeting with President Eisenhower in the Rose Garden of the White House. After this, I was set to enter the University of Washington in Seattle in the fall of 1955 as a history and political science major with the ultimate goal of law.
I enjoyed college, both the academics and the extracurricular activities. I became a regular member of the University Symphony as an oboe player, president of my fraternity and also rowed with the University of Washington crew. (I was not a great oarsman but I had fun.) By the time I reached my junior year, I was made aware of the fact that I had to take some science courses in order to receive a bachelor’s degree from the college of arts and sciences. I had taken some math courses (through calculus) for reasons that escape me after these many years, but these did not qualify. My father suggested that I take zoology as he had when he was at the University of Washington. He even had some of his class notes and drawings, which I deeply regret were subsequently lost or discarded. So, I signed up for the beginning course in zoology, which was the turning point in my career.
In 1959, the introductory course in zoology was taught by a marine biologist named Dixie Lee Ray. She received her PhD from Stanford in marine biology, studying the peripheral nervous system of the fish Lampanyctus leucopsasus. The class was attended by several hundred undergraduates, so there was no direct contact with Professor Ray, only with her teaching assistants. Regardless, through her lectures, her effect on the class—and particularly me—was electric. It suddenly made me realize that there was a world of biology out there that had completely escaped my notice. To give you a sense of the impact of Professor Ray on a group of undergraduates, consider the fact that because of her interest in the peaceful use of nuclear energy she was appointed president of the U.S. Atomic Energy Commission by President Richard Nixon in 1973, the only woman ever to serve in this position. She returned to Washington State in 1976 and was elected governor, a post she held until 1981. On learning of her death in 1994, I was saddened by the fact that I had never had the chance to thank her for a career-changing experience, something that I suspect others had undergone as well.
Following my experience in Professor Ray’s class, I decided to plunge headfirst into a science curriculum with the aim of going to medical school. Although neither my mother nor my father had ever pressured me in my career decisions, I believe that my mother was quietly pleased when the possibility of my entering medicine emerged. The road ahead was far more challenging for me than I had expected. No class was ever as engaging as the one taught by Professor Ray. But it was not all biology; I essentially had to start over in my junior year taking freshman chemistry and physics. Then, of course, was the dreaded course of organic chemistry, the graveyard for many dreams of attending medical school. At the University of Washington, it was taught by a terrifying figure, Professor Shaw, who had introduced the course to decades of undergraduates by saying, “Look to your right, look to your left, they won’t be here by the end of the quarter.” I was still there at the end of the quarter but only barely so!
By the time I was approaching the midpoint of my senior year; I had most of the basic requirements for medical school but was still wondering whether I was ready. When I was home for Christmas break, my mother urged me to apply, “What have you got to lose?” (I still have a vivid memory of our conversation.) So, I hastily prepared the application for the University of Washington Medical School and mailed it. Several months passed before I received a letter from the school informing me that I had been rejected. I was disappointed but also eager to know why and what, if anything, it would take to improve my chances for the following year. So, I set up an appointment with the director of admissions.
At my meeting with the medical school director of admissions, I was informed that the reason for my rejection was that I had failed to show up for my interview! I was stunned and even more so when he showed me my application. In my haste to prepare my application I had made an error in my return mailing address (1616 East 47th Street instead of the correct 1617 East 47th street). One incorrect digit and I was faced with a decision: Do I do another year in pre-med or do I return to my original goal of law school? I finally decided that I was going to prove to myself that I could do this. I immediately applied for early admission and scheduled classes for the year that included advanced chemistry and biology. Early in the year, I received an invitation to interview at the University of Washington and shortly thereafter was offered early admission to the class of 1960.
Entering medical school was an exciting experience. A shirt and tie and white coats were required from day one in those more formal times. It was also, for me at least, a somewhat terrifying experience. I was surrounded by classmates most of whom had sought careers in medicine all of their life. Many had parents who were doctors. During our first quarter of classes some even complained that what we were studying was disappointingly similar to what they had already studied in college. To me everything was frighteningly new. Biochemistry was by far the worst. (I failed my first test!) I was clearly off to a rocky start; but fortunately, things changed in the second half of the first year when we headed into the neuroanatomy/neurophysiology course. This conjoint course was taught by a truly distinguished faculty. At the time, the standard textbook in the field of neurophysiology for medical and graduate students was that edited by Ruch and Patton. They were our professors along with a group of other excellent faculty who seemed to enjoy teaching as much as I enjoyed learning.
A weekly highlight of the neurophysiology/neuroanatomy course was an hour the freshman class spent with the head of neurology, Fred Plum, discussing clinical-pathological correlations. Dr. Plum was the youngest chair of neurology in the country and an articulate but intimidating presence. I will never forget my first exchange with him that occurred during one of these hours. He asked the class what sensory modality was related to itch. I raised my hand, something I rarely did as one of the shyest members of the class, and responded, when he called on me, with “pain.” It was the answer he wanted, and he was very complimentary. It was the ego boost of the year!
By the second year of medical school, the playing field had become much more level. The materials were new to all of us making the whole experience for me, in particular, much more enjoyable. It was in my third year of medical school, however, that my career trajectory moved even more in the direction of the neurosciences. Although I enjoyed and did well on my clinical rotations (I loved sewing up wounds, surgical and traumatic; delivering babies; ferreting out the diagnostic significance of heart sounds; as well as talking to patients), my rotation on the neurology service was particularly relevant to my emerging career goals. Once again, Fred Plum played a critical role.
The neurology service was at King County Hospital in downtown Seattle. Each week, Fred Plum would make rounds with the students and house staff on the service. This was a high stress event for all concerned. The two patients to be presented were carefully selected by the chief resident. A separate student was chosen to present each case, and the students were carefully rehearsed by the chief resident prior to rounds with Dr. Plum. The students could not use notes or refer to the patient’s chart, which had to be handed to Dr. Plum at the beginning of the presentation. The student stood on the patient’s left—across the bed from Dr. Plum. The setting and its preamble were seemingly designed to heighten anxiety in everyone, which they did quite effectively. To add to the drama, on this particular occasion, I was not rehearsed! The reason for this escapes me, but I have the vague recollection it had something to do with a disagreement I had with the chief resident!
The case I presented to Dr. Plum at King County that day in 1963 had symptoms most likely of hysterical origin. I presented the case succinctly and indicated as such. This, my second encounter with Fred Plum, went even better than the first! He seemed especially pleased with my summary of the case. I was clearly on my way to becoming a neurologist.
Later, in my junior year in medical school, Fred Plum was offered the job of chairman of neurology at the New York Hospital–Cornell Medical Center in New York City on the death of his mentor Harold Wolf. I asked him if I could spend my senior elective time with him on the neurology service at the New York Hospital. He agreed. It was a wonderful experience. In addition to my time on the neurology service, I needed to spend some elective time on a surgery rotation. Bronson Ray was then chief of neurosurgery at the New York Hospital. He had been the last resident of Harvey Cushing (the father of American neurosurgery) at the Peter Bent Brigham Hospital in Boston. Although Dr. Ray rarely took students on his service, he agreed to take me for an experience that I treasure to this day. He was a revered man of great dignity in and out of the operating room. There was never any shouting or instrument throwing. I had the distinct honor of holding the sucker on several occasions as he delicately operated on the pituitary gland through a large craniotomy. When I returned to Cornell as a neurology resident, I believe that he was disappointed I did not choose neurosurgery, but a research career was looming ever larger for me and I felt that neurology was a better venue for that (more on that later).
The Medical Scientist Training Program (MSTP) tract that exists in many, if not most, medical schools today, awarding to those lucky enough to be accepted to these programs a joint MD/PhD degree, did not exist when I was in medical school. But the University of Washington, being one of the most academically oriented state medical schools in the country, offered an extra year of training and a master’s degree to qualified medical students. I, of course, was not “qualified” as the lone social scientist in our class, and I have to admit that I was very envious of those selected.
During college, with the exception of one summer as a carpenter’s apprentice and during the first summers while a medical student, I was a lifeguard for the state of Washington at one of its parks on Puget Sound. It was not until the summer between my junior and senior year that I was able to get a laboratory rotation in the department of orthopedic surgery working with a team of surgeons studying spinal cord development. Although the work in which I was engaged was never published, I loved the experience, which was focused on the microscopic anatomy of the developing rat spinal cord.
A tremendous added plus to that summer’s laboratory experience was an early morning class on human neuroanatomy taught by the famous neuropathologist Ellsworth (Buster) Alvord. Each morning at 7 a.m., a small group of us gathered to listen to his lectures on neuroanatomy, and in parallel, we built models of the human using colored clays and wire. It was the first time that I achieved a clear three-dimensional (3-D) sense of the organization of the human brain. The model I built sits just outside my office to this day.
Graduating from medical school in the spring of 1994, I married my long-time sweetheart, Mary Elizabeth Rupert, also from Aberdeen, who received her undergraduate degree at the same time I received my MD. We had dated on and off for many years and also worked together as lifeguards for the state of Washington. I am writing this in our 50th year together with four grown children (a lawyer, an obstetrician, an economist, and a psychology professor—and 12 grandchildren).
Having spent nine years at the University of Washington, I thought it time to go elsewhere for training. Although I fully intended to become a neurologist and train with Fred Plum at Cornell, his program and many others required a minimum of two years of internal medicine, which I did in Baltimore at Johns Hopkins. In Baltimore, I divided my time between the Baltimore City hospitals and the Johns Hopkins hospital. In those days, a house officer’s schedule was 24/7 and all night every other day and every other weekend. It was stimulating and exhausting. But somehow the research bug had taken hold, and I found myself pursuing a number of things in the context of my clinical work.
An example of the type of research I did as a medical intern and resident was the analysis of spinal fluid in patients with intracranial bleeding. At the time, the breakdown of hemoglobin in spinal fluid, its chemistry and temporal dynamics, was reasonably well characterized but using it to estimate the onset of bleeding in individual patients had not been actively pursued. The instrumentation necessary to characterize the breakdown products of hemoglobin in cerebrospinal fluid existed in the laboratory of the National Institute of Aging situated on the campus of the Baltimore City hospitals. The laboratory was under the direction of Rubin Andrus. He was most agreeable to my coming to his laboratory at any hour of the day or night to analyze my specimens on his instruments. I had great fun doing this work through two years in the Hopkins system, and although I never published my results, which would have been difficult under the circumstances, I derived great satisfaction in collecting and analyzing data. I even organized a “research day” with other house officers where we presented our work to the attending medical staff that included Julius Krevans, who later became dean of medicine at the University of California, San Francisco, and Charley Carpenter, a world expert on cholera who subsequently became head of medicine at Case-Western Reserve School of Medicine.
In the summer of 1966, we moved to New York City to begin my neurology residency. Clinical duties dominated my time particularly in the first year of my residency. However, Plum made it clear that we were in a program that not only expected excellence in the clinic but also an acknowledgment of the importance of research. Emphasis was placed on how we thought about a problem, not whether we had the answer. At the time, Plum and his long-time collaborator Jerry Posner were pioneering a new, systematic approach to the problems of stupor and coma that placed special emphasis on the recognition and remediation of reversible causes, largely metabolic. As residents, we were learning a new approach to these problems with the galley proofs of the first edition of their classic monograph Stupor and Coma.
My first serious foray into research as a resident again began during my second year when I was the consult resident for the New York Hospital. This was a maturing experience where you operated largely on your own as a consultant to all of the services of the hospital. Of course, you had a backup, usually Plum, but you were expected to take charge. A year or two before I began this rotation, investigators at the Massachusetts General Hospital had introduced the use of massive doses of intravenous penicillin as a treatment for deadly, gram-negative bacterial infections. Although the therapy was effective in treating the infection, it had unexpected and unintended side effects. These manifest as the sudden onset of confusion and random jerking movements of the large muscle groups of the body (i.e., so-called multifocal myoclonus) that were aggravated by any attempt on the part of the patient to move. In some patients, the syndrome progressed to frank seizures and coma. All of this was typical of a metabolic encephalopathy. I realized that I was seeing increasing numbers of these patients. Although they presented with a variety of medical problems, the common denominator was the fact that they were all on high doses of penicillin.
From a neuroscience perspective, it had been known for some time that penicillin was epileptogenic when applied directly to the cortex of experimental animals. The idea that it could behave in a similar fashion when given systemically in large doses was less well appreciated and, prior to the use of massive does, was probably never encountered. When it was encountered, the clinical situation was often complicated with other conditions such as kidney failure, which could also cause a similar encephalopathy.
Clearly, there needed to be a carefully controlled study of the problem in the laboratory. To explore this association in more detail, I sought the assistance of Sidney Lewis, Henn Kutt, and Fletcher McDowell, members of the neurology faculty at Cornell with a research interest in epilepsy and with a laboratory fully equipped for small animal research of the type needed for this type of study. Working nights and weekends in the Lewis/ Kutt/McDowell laboratory, I was able to sort this out with studies in 13 cats and 36 rats. Our most noteworthy finding was that intravenously administered penicillin produced an encephalopathy in animals that was similar in all respects to that observed in humans except that the effective dose was species specific—with cats most susceptible and humans least. Also, the toxic effect of penicillin on the brain was directly related to its antibacterial activity. This study led to my first published scientific paper, which appeared in the Archives of Neurology in 1971 (Raichle, Kutt, Louis, and McDowell, 1971). I had finally gone from bedside to bench, casting light on an important clinical problem and learning in the process how to do well-controlled experiments, analyze data, and write a publishable manuscript (probably the most challenging part of all). But doing this on nights and weekends was not ideal for preparing me in the ways of scientific research such that I could eventually operate on my own. Thus, I sought time off from my residency to work full time in the laboratory with Fred Plum and Jerry Posner.
As mentioned earlier, Fred and Jerry were deeply committed to an understanding of the metabolic causes of coma, and in the course of their research, quantitative measurements of brain blood flow and metabolism became increasingly important to their objectives. Fortunately, Seymour Kety and Carl Schmidt of the University of Pennsylvania had laid the groundwork for these measurements in the late 1940s (Kety and Schmidt, 1948). The majority of the work of Kety, Schmidt, and their colleagues focused on making measurements in humans. As a result, they were the first to provide us with quantitative measurements of human whole brain blood flow and oxygen consumption. To this day, their technique remains the “gold standard” of such measurements.
It is worth noting what was involved in the Kety/Schmidt technique as applied to humans. The technique was based on the Fick principle that, in essence, says that by measuring the blood concentration of what is presented to an organ minus what is leaving, combined with the rate of blood flowing to the organ, one can compute the rate at which, in their case, oxygen was used. The trick was how to measure, quantitatively, the blood flow. They devised an ingenious technique using the inert diffusible gas nitrous oxide and measuring the concentrations of the gas in arterial and in venous blood across the brain. This they did by placing a catheter in the femoral artery in the groin and a second catheter in the jugular bulb. From these data, it was possible to compute the blood flow to the brain. In the Plum and Posner implementation of the Kety-Schmidt technique, the radioactive inert gas Krypton 85 was substituted for nitrous oxide, making measurements of its concentration history in arterial and venous blood much easier.
The experimental question I inherited on entry into the Plum-Posner lab was determining whether the hydrogen ion was important in the matching of brain circulation to its metabolic needs. The logic behind the question emerged from two observations. First, the normal fuel for brain energy metabolism is glucose, and the metabolic extraction of its potential energy produces carbon dioxide and water. Thus, as glucose is consumed, carbon dioxide increases. Second, acute changes in arterial blood and, concomitantly,
brain carbon dioxide tension have immediate and profound effects on brain blood flow (i.e., increases in carbon dioxide tension by inhaling low concentrations of carbon dioxide cause increases in blood flow, and hyperventilation causes a decrease). The answer seemed obvious—carbon dioxide was acting on brain blood vessels to change blood flow. Unfortunately, the situation was a bit more complicated. Changing the amount of dissolved carbon dioxide in the brain has a direct effect on brain pH because the brain is buffered by bicarbonate.
The key to separating the roles of carbon dioxide and pH is the fact that the brain appears to normalize its pH during sustained periods of hyperventilation, suggesting to us that, if we hyperventilated anesthetized laboratory animals for several hours, we would see an initial drop in blood flow that returned to control levels despite significantly reduced arterial carbon dioxide tensions. However, despite carefully controlled ventilation and levels of anesthesia, we failed to observe the predicted change. In fact, blood flow not only dropped initially with the onset of hyperventilation but continued to fall during the five hours of the experiment. In a control experiment with arterial carbon dioxide tension maintained at a normal level, blood flow again fell across the five hours of observation. We could not explain this declining blood flow other than to surmise that it represented an unstable experimental preparation. The alternative we arrived at was to use ourselves as the experimental subjects. After all, the high altitude experiments leading to our work were done in humans, and the techniques we were using to measure brain blood flow and metabolism had been validated in humans by Kety, Schmidt, and their colleagues.
Not knowing for sure just how this was going to play out, I volunteered to go first. Gordon Potts, newly head of neuroradiology at the New York Hospital and later to become one of the leading neuroradiologists in the world, placed the catheters in my jugular bulb and femoral artery while I lay in a hospital bed in the same laboratory in which we had conducted our animal experiments. I was fitted with a face mask for the inhalation of the radioactive gas to measure blood flow and also for the monitoring of my end-tidal CO2 . An end-tidal CO2 meter was placed in front of me so that I could monitor my respirations. My brain blood flow and metabolism were measured at the beginning of the experiment while I relaxed, breathing at a normal rate.
Then the ordeal began—hyperventilating sufficiently vigorously to reduce my arterial carbon dioxide tension to half its normal value and holding it there by continuing to hyperventilate for five hours. Fred and Jerry took turns cheering me on while repeatedly measuring my brain blood flow and metabolism. Once in the routine, it was somewhat less difficult than I had imagined. At the end of five hours, I had to suddenly stop my hyperventilation, forcing my arterial carbon dioxide tension back to control. This proved to be rather difficult. Jerry Posner was next and somewhat more accustomed to the experience, having done the protocol once before without measurements of blood flow. Finally, it was Fred’s turn. He soldiered through without a problem until the very end when he suddenly had a shaking chill. Although never verified, we suspected sepsis—even though an autonomic reaction to the ordeal, in retrospect, was equally likely. For Jerry and me, the relief in getting through this was enormous (something like boot camp in the world of cerebral blood flow and metabolism). The relief was shortlived. The morning following Fred’s experiment he announced that we all needed to do it again to boost the “n”! Fortunately, the vote was two to one against, and Fred clearly had no alternative subjects waiting in the wings.
The data arising from this study proved to be exceptional (three measurements of blood flow, oxygen consumption, glucose utilization and lactate production before, during, and after sustained hyperventilation plus an additional subject, Jerry Posner, with arteriovenous difference measurements of all of the metabolites). The results definitely supported the hypothesis that the effect of carbon dioxide on blood flow was mediated by the hydrogen ion. In addition, the study’s comprehensive, quantitative data has proven invaluable to the present day.
Following my time in the laboratory with Fred and Jerry, I returned to my residency training, finishing in the spring of 1969 at the peak of the Vietnam War. Military service was a given for all MDs not heading to the National Institutes of Health (NIH). My service had been deferred until the completion of my residency at which time I was commissioned a major in the U.S. Air Force and assigned to the School of Aerospace Medicine. The experience there proved to be another important stepping-stone to my academic career.
The School of Aerospace Medicine had several missions. I was formally assigned to the medical evaluation unit staffed by a range of specialists, including four neurologists. Some of the physicians were career military officers, others like me were in for two years, and there were a few civilians. I was very impressed by the caliber of these individuals and by their dedication. Our job was to evaluate flying personnel in the Air Force (largely pilots and navigators) who had experienced a medical problem potentially impairing their ability to fly. We also did the medical screening of the Air Force Research Pilots (the people who would go out to Edwards Air Force Base and fly exotic new aircraft) and of the pilots who flew the U2 and SR71 planes.
In order to understand the conditions faced by the individuals we were expected to evaluate, we were strongly encouraged to attend the Air Force Flight Surgeons School as well as to attain qualifications in hyperbaric medicine (i.e., chamber certification in diving and altitude chambers). After all of this, we were placed on flying status and expected to fly on a regular basis. Given that the school did not have its own flying wing, we could pick and choose among the many aircraft at other bases. I did so liberally and enjoyed every minute of it.
Although my medical experience at the School of Aerospace Medicine was remarkable in many ways, putting the whole matter of brain function into an entirely new context, I was also exposed to a most remarkable research experience. In addition to its medical role, at that time, the School of Aerospace Medicine was very involved in understanding human adaptation to space flight. This was in part related to the intention of the air force to place a spy satellite in space and also related to the early work of NASA. In pursuit of this, the military had assembled a remarkably talented group of civilian PhDs in the area of cardiovascular and pulmonary physiology and equipped them with absolutely remarkable research laboratories for the time. Although some human research was being conducted, the primary work was performed on rhesus monkeys. The school had a colony of 1,500 monkeys attended by a core of veterinarians.
Somehow the word got out that I had done research on brain circulation and metabolism with Fred Plum and Jerry Posner, and I was recruited to work with Lowell Stone, a young PhD in cardiovascular physiology who some years later became chair of physiology at the University of Oklahoma. His technique was to chronically implant Doppler flow probes on arteries of interest and monitor changes in blood flow continuously under a variety of experimental conditions. What they proposed was that they would teach me the techniques of implanting the probes and measuring flow if I would work with them on studies of brain circulation. The veterinarians were superb surgeons, and I quickly learned how to isolate the internal carotid artery and implant the probes. We even went so far as to implant a few probes on the middle cerebral artery. In addition, we developed in implantable device in the skull of the monkey over the superior sagittal sinus that allowed chronic sampling of cerebral venous blood. I was “handed the keys” to a Grass polygraph and told to learn how to use it. Our data were recorded on FM tape and analyzed on a massive analogue computer at the school that ran on vacuum tubes and was programmed uniquely for each study using a large “circuit” board and wires. It was an exciting time and yet relaxed when compared to the rather high intensity neurology residency I had experienced under Fred Plum.
enced under Fred Plum. To my surprise, one day at the school I received a letter from the organizing committee of a meeting on brain blood flow and metabolism to be held at the Royal College of Physicians in London. Unbeknownst to me, Fred Plum had submitted an abstract of our hyperventilation experiment and, as I later learned, he expected to be asked to present our data. The organizing committee, apparently seeing my name first, sent me the acceptance letter. I was delighted and immediately began figuring out how I was going to get to London—my first trip to Europe. My commanding officer kindly agreed to give me the time off to attend the meeting.
It is customary in the air force to look for planes going your way and to ask to tag along. The best jumping off place at the time was Dover Air Force Base in Delaware, so I got on an air force plane from San Antonio to Dover and went in to base operations to see what my options were. As it turned out, the only option available was to join an Iranian air crew that was flying a brand new C141 transport plane to Tehran via London. In my flight suit sporting my flight surgeon wings, I approached the crew, and they invited me along. The only problem was, initially, they did not understand the difference between a flight surgeon and a pilot (anyone in a flight suit sporting wings must be a pilot!). They kept insisting that I take the left seat and fly the plane. Fortunately, we managed to get to London safely.
Of course, I enjoyed my first presentation at an international meeting to a group of individuals who were already legends in the field of cerebral blood flow and metabolism. Many would become close friends over subsequent years. This meeting, however, was unexpectedly important in another way. Presenting one of the most interesting papers in London in 1970 was a PhD physicist from Washington University in St Louis by the name of Michel Ter-Pogossian.
Michel Ter-Pogossian was born in Berlin and grew up in Paris. His father was a member of the French diplomatic service prior to World War II. During the war, Michel allegedly worked for the French underground. Following the war, he came to the United States and Washington University to study physics. One of the motivating factors in his decision to choose Washington University was the fact that the chancellor was Arthur Holley Compton, a Nobel laureate in physics. The other factor was that Washington University had a cyclotron that, in its day, was a fairly substantial machine.
The cyclotron was purchased at the behest of the Mallinckrodt Institute of Radiology at Washington University (i.e., the department of radiology) to produce isotopes for nuclear medicine. Shortly after the cyclotron was commissioned, the United States entered World War II and the cyclotron became a major component of the Manhattan Project. When the war was over, cyclotron-produced isotopes were no longer of interest to nuclear medicine because of the more conveniently available generator-produced isotopes. Therefore, the cyclotron became a tool for research in chemistry and physics.
Into the setting of a now-available cyclotron on the Washington University campus and a team of chemists versed in its use from their experience in the Manhattan Project, came Michel Ter-Pogossian, an eager young graduate student. In the course of his graduate work, he became interested in the potential of cyclotron-produced isotopes for research in biology and medicine, a theme that he was to pursue throughout his entire academic career at Washington University. The isotope of particular interest to Ter-Pogossian at the time was 15O (half-life two minutes). To pursue his interest and convince others of its importance, he set up a small laboratory in a house trailer just outside of the cyclotron building. Into the building, he rigged a connection directly to the beam line of the cyclotron, permitting the administration of 15O-labeled air to rodents (they simply breathed the labeled air as it came into a small container in which they were placed). He then imaged the animals immediately after the brief exposure, using a simple nuclear medicine camera of the day. The resulting “images” were sufficiently impressive that the Mallinckrodt Institute of Radiology (MIR) agreed to put a small medical cyclotron in the basement of the institute.
Once the cyclotron was up and running in the MIR, the brain became a significant focus of attention. One of the compelling reasons for the emphasis on the brain was the fact that it was a large organ nicely isolated from other organs and, in contrast to the heart, it did not move. Also, friendships mattered. The then-head of the MIR was Juan Taveras, arguably the father of American neuroradiology and whose research interests centered around measurements of brain blood flow. Without his support, the cyclotron would never have been installed in the MIR. Also, Sam Guze, head of psychiatry and vice chancellor for medical affairs and a close friend of Ter-Pogossian’s, was very interested in the possibility of using measures of brain metabolism to study patients with psychiatric disease.
Two additional factors propelled brain studies with cyclotron-produced isotopes forward. First, Michael Welch, a young radiochemist who received his PhD at University College London and a postdoc at the Brookhaven National Laboratory, joined the Ter-Pogossian laboratory and immediately made the synthesis of 15O-labeled water, oxygen, and carbon monoxide routine. 15O-labeled water was selected as the inert, diffusible tracer for the measurement of brain blood flow. 15O-carbon monoxide was the tracer for the measurement of brain blood volume because of its irreversible binding to hemoglobin. And, 15O-labeled oxygen was, in combination with the other two tracers, the key to measuring brain oxygen consumption. Second, a radiation detector system was constructed that was capable of assessing the concentration of these 15O-labeled radiopharmaceuticals in the human brain. The detectors, three on each side of the head, had to be shielded in substantial quantities of lead in order to capture the regional distribution of these high energy isotopes. With appropriate radiopharmaceuticals in hand and a detector system suitable for detecting them in the brain, research began to determine whether regional oxygen consumption could be measured in the human brain. It was the result of these very earliest experiments (Ter-Pogossian, Eichling, Davis, and Welch, 1970) that Michel Ter-Pogossian presented at the meeting in London in 1970 that I attended. At the meeting, he approached me and asked if I would be interested in joining his group in St. Louis to pursue studies of brain circulation and metabolism with cyclotron-produced radiopharmaceuticals. The prospect of being able to measure brain oxygen consumption regionally in humans for the first time was an opportunity too attractive to pass up. I joined the faculty of Washington University School of Medicine in the summer of 1971 and have been a member of the faculty ever since. In retrospect, the appointment was unique in several ways. I was a clinically trained neurologist with a background in measurements of brain circulation and metabolism, recruited by a physicist (Michel Ter-Pogossian) to work in a radiology department laboratory populated by physicists, chemists, engineers, applied mathematicians, and computer scientists along with talented cyclotron operators, machinists, and technicians. At the time I was the only neuroscientist in the lab. Such an environment today would be considered typical of an interdisciplinary research operation, but, at the time, no one spoke of us in those terms. The other important feature of the Ter-Pogossian lab was the fact that most of us resided in rather cramped quarters on the sixth floor of the MIR with the cyclotron in the basement, the neuroradiology suite with some of our research equipment on the third floor, and animal quarters, labs, and surgery on the floors above us. Interactions were inescapable and incredibly valuable.
Initially, I had a joint appointment in radiology and neurology, which has expanded over the years to include neurobiology, psychology, and biomedical engineering. My laboratory has always resided in the MIR. Initially, I was a member of the Ter-Pogossian laboratory but eventually acquired my own laboratory known as the Neuroimaging Laboratory, which presently consists of 23 faculty members from five departments in the university (radiology, neurology, psychiatry, psychology, and pediatrics) and 100 staff, students, and postdocs. My introduction to the use of the 15O-labeled radiopharmaceuticals involved experiments in monkeys and humans. At the time, these radiopharmaceuticals were administered directly into the internal carotid artery by way of a catheter introduced into the femoral artery and threaded there under fluoroscopic control, a technique I mastered with the help of the MIR neuroradiologists. All human studies were performed on patients undergoing carotid angiography as part of the clinical evaluation. Data were collected on a classic Laboratory Instrument Computer (LINC) but analyzed by hand because of the limited computational capability of the LINC. Our initial objective was to validate the Ter-Pogossian method for the measurement of regional brain oxygen consumption, a technique he developed with his graduate student John Eichling. Having been schooled in the gold standard for such measurements in the Plum/Posner laboratory, it was a straightforward problem. The technique came through with flying colors (Raichle, Grubb, Eichling, and Ter-Pogossian, 1976).
In the early experiments in the Ter-Pogossian lab we discovered that 15O-labeled water was not, as advertised, a freely diffusible tracer. Although this was not an impediment in our use of the tracer for the measurement of blood flow, it opened up a line of investigation that remains incomplete to this day. The tantalizing insight that this discovery provided was the fact that the blood brain barrier was a flexible membrane that, with respect to water, mirrored many of the features and functions of the distal tubule of the kidney. We were having great fun pursuing this and other novel and unexpected findings when an event occurred that not only changed the practice of medicine but also opened up the prospect of safely obtaining true 3-D images of the anatomy and the function of the human brain. It was the invention of X-ray computed tomography by Godfrey Hounsfield, a self-taught engineering genius working for EMI Limited in England.
It has now been 55 years since I entered the classroom of Dr. Dixie Lee Ray at the University of Washington. I was a junior majoring in history and political science envisioning a career in law like my father. I suddenly realized that there was a fascinating world of biology to be explored that I had never considered. The abrupt change in my career trajectory was a challenge, at times a bit frightening, but one that I have never regretted. The opportunities afforded me over the years have been extraordinary. The thrill of discovery remains undiminished.