First Taste of Research

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Curt Richter, Professor of Physiological Psychiatry at Johns Hopkins School of Medicine, had the greatest influence on my scientific life, which began during my senior year in college at Johns Hopkins. I worked with him during the summers between my first three years as a medical student at Hopkins.

Dr. Richter, who was born in 1894, had been recruited in 1919 to Johns Hopkins from Harvard by Adolph Meyer, the first Professor of Psychiatry at Hopkins. He initially worked in the laboratory of Dr. John Watson and took over the lab when Dr. Watson left. Dr. Richter was famous for his work on self-selection of diets by rats, and the relationship between physiology and behavior.

I first learned of Dr. Richter's work when I worked as an attendant in the Henry Phipps Psychiatric Clinic at Hopkins during the summer between my third and fourth year of college. His labs were located on the third floor of Phipps, two floors above West 1, the floor that housed the most severely ill patients. He had limitless curiosity and enthusiasm, and respected the opinions of students working with him, making us all feel important. The metaphor for his professional life was walking along a shoreline, picking up interesting shells that he came across.

His most striking characteristic was his curiosity. He constantly asked questions, a habit persisting throughout his life. He never took a superior attitude in his relationships with colleagues, students, or technologists. We worked together carrying out experiments on rats, monkeys, and human beings. We developed instruments to measure motor activity in rats, the galvanic skin response in monkeys, and instruments to map the patterns of sweat gland activity in patients with a variety of diseases, including a congenital absence of sweat glands. He made it possible for us to go to scientific meetings, such as the Endocrine Society, present our scientific results and get comments on our work, even though we were medical students. There were no computers, only adding machines and machines to creat graphs of physiological data. We learned how to handle wild rats captured on the streets of Baltimore, and how to operate on the brains of wild and domestic rats, viewing the operative sites through a microscope. We became expert at removing the adrenals and other endocrine organs. Dr. Richter never characterized any of our ideas as "bad." Dr. Richter's model was Claude Bernard, the Father of Physiology, who became my model as well. His work continued to have an enormous influence on my scientific career.

At the 25th anniversary of the graduation of our Hopkins medical school class of 1952, the planning committee decided to invite to our celebration some of the faculty during our student days. At the first meeting of the committee, we decided immediately "O.K, we'll invite Curt Richter and Horsley Gantt. Now let's decide on some others." This unanimous opinion was remarkable, because neither Richter nor Gantt had ever taught us any formal courses. Their lasting impact had all been extra-curricular, which illustrates what it was like at Hopkins medical school during the 1950s.

Dr. Richter's enthusiasm and love for research made a great impact on me. He let me carry out my own experiments, published in my first three scientific papers. During my freshman year of medical school, I presented a paper at the meeting of the Endocrine Society in Atlantic City. The presentation was scheduled on a Friday, the day I was to take the final examination in Psychiatry. I went to Dr. John Whitehorn, Chairman of the Department, and said: "Dr. Whitehorn, I have a problem." He immediately offered me a chair and a cigarette, and said: "What is the problem?" I fell sure that he expected to hear of some psychiatric symptoms. When I told him my only difficulty was scheduling, he responded: "No problem. I'll just leave the examination on my desk, and you can take it before you leave." When I returned the next morning, the exam was nowhere to be found, but fortunately, Dr. Whitehorn arrived at his office, and helped me search his desk for the exam which he had left. We never found it, but again, he said: "No problem. I'll just give you an oral exam." I passed the exam.

Research was greatly encouraged at Hopkins, and the faculty was always willing to encourage students to participate. An episode that illustrates this point occurred during an oral examination that I was being given in the library by the Chairman of the Obstetrics and Gynecology Department. While Professor Eastman was questioning me about a problem patient, another student wandered into the library, and joined in our conversation. He answered some of the questions before I could. Neither the Professor nor I told him we were having an examination. After a short while, the student left the library, never realizing that he was interfering with an oral examination.

In those days before the National Institutes of Health had been founded, only 16 Hopkins medical students in the whole school carried out any research. Without any influence or participation of the faculty, we students met monthly in what we called the "Osler Society" to discuss our research results among ourselves. My chief interest (and Dr. Richter's) was in endocrinology and its influence on mental functioning and behavior. He had discovered self-selection of food intake in rats, and the effects of electric shock stress on the endocrine system of wild and domesticated rats. He had a contract with the City of Baltimore Health Department to develop an effective rat poison during the war. Among his discoveries was that rats could not taste the poison, alpha-naphthyl thiourea (ANTU), which produced acute pulmonary edema and death in rats. His findings led to its wide use as a rat poison. His observation that ANTU produced hyperpla-sia of the thyroid gland led to the idea and experiments that eventually resulted in the use of thiourea drugs to treat hyperthyroidism.

While working in Richter's lab, I was awarded a Henry Strong Denison scholarship because of my research activities. I had been the sole author of my first published scientific paper which appeared in the Archives of Ophthalmology in 1950, entitled: "Objective Testing of Vision with the use of the Galvanic Skin Response." Electrodes attached to the palms of human beings or monkeys measured the bursts of decreased electrical skin resistance that occurred with activation of the sympathetic nervous system. I administered an electric shock whenever a specific letter was projected on a screen before the subject (or monkey) but not with the projection of other letters. The galvanic skin response (the GSR, which today is part of lie detector testing) was the indication of whether the specific, conditioned letter had been seen. When the paper was submitted, I acknowledged the assistance of Anne Collins Barrett, even though she had not participated directly in the experiments. I had seen acknowledgements at the end of scientific papers that I read, and, after all, Anne had been helpful to me in general.

When we met, Anne was a student in the Bachelor of Science in medical technology program at Mount St. Agnes College. On March 11, 1948, Anne and I were attending an afternoon dance sponsored by the Newman Club, a club for Catholic students, in Levering Hall, the student activities building at Hopkins. Hopkins students often dated girls from Goucher College, Maryland College for Women, and Mount St. Agnes, all of which admitted only women in those days. Mt. St. Agnes was founded in 1867, and closed its doors in the late 1950s, transferring its academic programs to the Loyola College. The Mt. St. Agnes property was recently acquired by the Johns Hopkins University, after prior ownership by two insurance companies.

Anne, a lovely, cheerful brunette, had a smile that "looked as if all heaven had opened up." She has been responsible for all the pleasures of my life, our four wonderful children and nine grandchildren. Beyond question, Anne is the "best thing that ever happened to me." The first weekend after we met, we had dinner at the house of a fraternity brother who turned out to be Anne's third cousin. We went to see the opera Carmen at the Lyric Opera House, and finished the evening at a party at the Beta fraternity house. Her mother was annoyed when we arrived back at Anne's house at 5:00 AM after our first date. After 54 years of marriage, we still watch television in the living room of that same house. On our first date, as a colleague and I watched Anne descend the steps into the living room, she tripped and fell, to our uproarious laughter, she was unhurt, and we went off to an unforgettable evening.

We dated frequently throughout my senior year in college, and during my first three years at Hopkins Medical School. Upon graduation from college, Anne went to work with Dr. Paul Carliner, an internist who became famous for his discovery with Dr. Leslie Gay that the anti-histaminic drug, dramamine, was effective in preventing seasickness. This observation had extremely important military consequences. The first clinical trial of the drug to prevent seasickness was carried out on a troopship. Paul remained in private practice in his home office a quarter of a mile from our present house in Mt. Washington until his untimely death at age 46.

Anne and I occasionally met at St. Alphonsus Church in downtown Baltimore after her work and my classes, and spent a few hours in a local restaurant. During the obstetrical quarter in my third year at Hopkins, I told my father that Anne and I were going to be married the next weekend. He was shocked, convinced that getting married would keep me from becoming a doctor.

We were married in the Shrine of the Sacred Heart in Baltimore, on February 3, 1951. After a reception at the Johns Hopkins Club, our honeymoon consisted of a weekend at the New Yorker Hotel in New York City. Going up to our room, we were the only passengers in the elevator with the operator, a pleasant young man. Feeling somewhat awkward, I said to him: "It certainly is cold outside." He replied: "What do you care? You have your love to keep you warm." Only in New York! We lived for three months in Mount Washington with Anne's parents, and then moved to a second floor apartment in a row house owned by Johns Hopkins at the corner of Wolfe and Monument Streets, across the street from the Women's Clinic.

Once in our marriage, Anne left me and went home to her parents. Late one night, after I came home from the hospital, and was taking a shower, a large rat ran across the floor of our bedroom. The next morning, I called the hospital administrator, Colin Churchhill, who immediately sent over an exterminator. After a short period, the exterminator told us: "There is no problem. I have fixed it so he can't possibly get out." Anne immediately took the children to her partents' home for three weeks as we waited for the rat to die and disintegrate.

Ever since those days at Mt. St. Agnes, Anne still has cocktails and dinner once a month with the women who were with her at the dance where we met. I tell people that I married Anne and kept the other women as "controls." One of her classmates subsequently became a nun; most of the others are now widows.

At 1900 McElderry St., we were extremely happy, even though extremely poor. The office of the Dean of the School of Public Health, Dr. Alfred Sommer, is where our bedroom was in the front room of the row house that was torn down not many years after we had moved out.

While living on McElderry St. we had dinner every Saturday night with Anne's parents in Mt. Washington, and Sunday afternoon dinner with my parents. Every Saturday afternoon, Anne would do our laundry in her parents washing machine, while I was working as Teen Age Director at the Schenley Road Community Center in Roland Park. I worked from 12:00 to 4:00 PM and again from 8:00 PM to midnight. I was paid $15.00 for the 8 hours, which supplemented the $150.00/month borrowed from my father. Because I was working on Saturday afternoon, I missed all my pediatrics classes.

Hopkins rented our house on McElderry Street to Dr. Frank Williams, an Assistant Resident in Medicine and is wife. Frank was an assistant resident in medicine, and subsequently became the Director of the National Institute of Aging of the NIH. We paid Frank $32.00 per month for the second floor of the house. Once I was called by Colin Churchill, a hospital administrator, who asked why we should be allowed to sublet from Frank, rather than pay the rent directly to Hopkins. I countered his question by asking: "Who would be responsible for stoking the coal furnace in the basement?" He said no more.

We ate every evening in the Doctors' Dining Room. The doctors ate huge meals, which were free, while our wives and children had only drinks. Occasionally, some of us received letters from the Administration telling us that we were eating too much. Anne and our two children's clothes came from the "Grapevine," a consignment shop that Anne's mother ran on Roland Avenue. Most of the time, I wore the white jacket and pants of a house officer, first an intern and then assistant resident and chief resident. When we picked up the pants from the hospital laundry room, they were so heavily starched that it was impossible to get one's legs in them without first fighting your way with your fist from the waist to the ankles.

In the summer between my third and fourth year of medical school, I was not able to continue to work in Curt Richter's Laboratory because we were short of money, even though Anne still worked for Dr. Carliner. I learned that the pharmaceutical company, Charles Pfizer & Co., was going to hire medical students to act as detail men during the summer, visiting doctors to promote the use of the world's first broad spectrum antibiotic, Terramycin. Our group of 10 medical students from all over the country went to New York for orientation, before traveling over the country, speaking with physicians in their offices. It was a brilliant idea on the part of Pfizer, because nearly every physician was willing to see the "medical student in the waiting room." I still remember one lesson from our leader, the company representative: "If you were standing on a corner, handing out five dollar gold pieces, you would still have to persuade people to take them." He also taught us: "The sale begins when the customer says no." We were paid $400 per month plus expenses. Every week a bonus was awarded to the student who had managed to see the greatest number of doctors. We students decided to divide the bonus equally among ourselves, thereby eliminating the need to compete.

A major additional benefit of working for Pfizer was that, during my fourth year of medical school, I obtained a contract from Pfizer to carry out collaborative research to determine whether Terramycin was effective when administered by the intramuscular rather than the oral or intravenous route. I decided to determine its effectiveness in treating urinary tract infections. In those days, the only approval that was needed was that of the Chief Resident in Urology at Hopkins and that of Dr. George Mirick, Head of the Infectious Disease Division. There was no Institutional Review Board (IRB) in those days. This work not only provided financial aid, but led to publication of the results in the July 1952 issue of the Bulletin of the Johns Hopkins Hospital in an article entitled: "Experimental and Clinical Results with Intramuscular Terramycin."

I continued part time research work with Pfizer for the next three years, which was a financial God-send. One study was on the effectiveness of Terramycin in the treatment of experimental cholecystitis in dogs. The attitude of the faculty during my presentation of this work taught me that research was judged on its own merits, not on the academic position, or lack thereof, of the person performing the research. Increasingly, I became determined that I would go into academic medicine. In those days, internal medicine was the premier medical specialty, and most of the upper third of the graduating class entered this field. This is no longer the case, as medicine has become increasingly specialized.

Infectious diseases and endocrinology were the focus of attention in those days. I joined Dr. A.M. Fisher, who suffered from Huntington disease, and Richard Ross, Chief Resident in medicine, and subsequently, head of Cardiology and Dean of Johns Hopkins Medical School, to study of the clinical manifestations and effectiveness of antibiotic treatment of patients with staphylococcal endocarditis. This disease was prevalent then because of the occurrence of rheumatic heart disease. It is rarely seen now. HIV/AIDS did not exist, or at least was not recognized at that time.

During my last two years of medical school, we were saddened every day by news from the Korean War. There were great numbers of casualties during the advances and retreats of the United Nations forces, led by the 8th army of the United States. General Douglass MacArthur was a hero of the general public but distained by many politicians. When he returned home after being fired by President Truman in 1951, he was given a ticker tape parade in New York, and delivered a moving farewell address to the U.S. Congress. We only later learned that he had advocated the use of nuclear weapons during the war when the United Nations forces were in full retreat from North Korea. Paradoxically, it was the first demonstration of a nuclear weapon fired as an artillery shell in 1953 that convinced the North Koreans that they should seek a truce. By the time President Eisenhower went to Korea two weeks after he became president, an armistice was signed. Unfortunately, over 157,000 American casualties had been sustained by then, with 400,000 casualties among the other United Nations and South Korean forces. Although the exact number remains unknown, the number of North Korean casualties was in the hundreds of thousands.

Except for momentous news related to the Korean War, we on the Osler house staff had little contact with the world outside of the hospital. I was hospitalized for minor surgery during my second year of assistant residency and had the opportunity to watch the 1954 hearings in Congress in which Senator Joseph McCarthy defended a close friend of Roy Cohn of McCarthy's staff. Joseph Welch was the lawyer for the Army who, during an attack by the Senator on a young member of Welch's staff, named Fisher, made the famous remarks: "Let us not assassinate this lad further, Senator. Have you no sense of decency, sir, at long last? Have you left no sense of decency?" This hearing marked the end of the McCarthy era, marked by a national hysteria, the response to an unholy alliance between the American Communist Party and Soviet spies in the United States during the 1930s and 1940s, which ended in the early 1950s, after some of them had stolen the secrets of how to design an atomic bomb.

My second scientific publication was six months after my first. James W. Woods, a friend and co-worker who was a student working with Drs. Phillip Bard and Vernon Mountcastle in the Department of Physiology, and I published a paper in the Archives of Neurology and Psychiatry, entitled: "Interruption of Bulbocapnine Catalepsy in Rats by Environmental Stress."

Jim slept in the Physiology Department, setting an alarm clock to wake him up every hour during the night to adjust a heating lamp placed over experimental cats or monkeys who had had parts of their brain removed that interfered with their ability to maintain the proper body temperature. Jim was eventually replaced by a thermocouple, and had to resort to driving an oil tanker truck from Baltimore to Washington and back twice a night to get sufficient income to support his life as a graduate student.

The drug, bulbocapnine, was of great interest, because it could produce immobility that resembled patients with catatonic schizophrenia. We discovered that immobility induced by the drug could be interrupted by placing the rats in a pool of water where they would have to swim. Even when immobilized by bulbocapnine, they would begin to fight with each other in response to electrical shocks administered through bars in the bottom of their cages. This showed the difference between the effects of bulbocap-nine and anesthetic drugs. We also found that the catalepsy could be interrupted by having the cataleptic rats breath high concentrations of carbon dioxide. The same effect was observed with the administration of scopolamine, a drug which blocks the para-sympathetic nervous system, or cocaine. Audiogenic seizures, that could be produced in rats by loud noise, was not abolished by bulbocapnine. Thus, from the beginning, my research has been oriented toward the study of the biochemistry of mental functioning, an interest created by working with Curt Richter in Phipps Clinic. How wonderful it would have been in those early studies of wild and domesticated rats, if we had had techniques, such as positron emission tomography, to relate brain chemistry, mental activity and behavior. These new "tracer" techniques for "molecular imaging" would not be developed until decades later.

We mapped out the patterns of sweat gland activity in human beings heated in a heated enclosure. The third of my first three papers was the study of a mother and daughter with "hereditary ectodermal dysplasia of the anhidrotic type." These patients were intolerant of heat, because of the absence of sweat glands. We observed that the patients did manifest axillary and facial sweating, as well as on the palms and soles of their feet. I wanted to find out whether they had a congenital absence of epocrine, but not apocrine sweat glands, such as those in the axillae. After we showed that their axillae would indeed sweat, I wanted to get a biopsy specimen to confirm the hypothesis that this was due to functioning apocrine sweat glands. I went to the Chief Resident in surgery and asked if it would be possible to obtain a skin biopsy. Of course, we would obtain informed consent.

The Chief Resident asked: "How many biopsy specimens do you want?" Somewhat surprised at the question, I responded: "How many can I get?" He replied: "The knife is sharp." I said: "One will be enough." I published the results in the Archives of Dermatology and Syphilology in 1952, the year I graduated from medical school, and began my internship in internal medicine on the Osler Service at Hopkins Hospital.

Throughtout my entire professional life, I have been interested in the autonomic nervous system, which controls sweat glands as well as other autonomic functions. This interest was also stimulated subsequently by the study of three patients with orthostatic hypotension (their blood pressure fell dramatically whenever they stood up). We found that they could not regulate their blood pressure when given vasoactive drugs that either raised or lowered their blood pressure. They were able to excrete enormous amounts of urine when their extracellular fluid was expanded by administration of normal saline solution. Studies of these patients resulted in my receiving the Francis F. Schwentker award given to a member of the Johns Hopkins House staff for excellence in research.

Most diseases are characterized by a deficiency in one or more physiologic or biochemical processes. At other times, disease can be the result of normal processes being increased. For example, persons can exhibit deficient or excessive sweating. Hyperand hypo-thyroidism are classic examples of an increased or decreased physiologic process, respectively. Patients with orthostatic hypotension have a generalized decrease in sympathetic nervous system activity affecting both their blood vessels and sweat glands. Persons with tumors of the adrenal glands manifest abnormally high secretion of nor-adrenaline. Hyperactivity of the sympathetic nervous system can result in coronary artery disease or essential hypertension. Diseases of the autonomic nervous system are now considered "molecular" as well as "physiological" diseases.

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