The National Institutes of Health

The intramural and extramural programs of the National Institutes of Health (NIH) have been the greatest force in biomedical research anywhere in the world. Many Nobel prizes have been won by scientists working both as part of the extramural program, as well as at the site of the intramural program in Bethesda, Maryland. The Clinical Center opened in 1952, and I had the wonderful opportunity to become a Clinical Associate on July 1, 1955, after finishing the second year of Assistant Residency in Internal Medicine at Hopkins. I worked under the direction of the late renal physiologist, Dr. Robert Berliner, who subsequently became Dean of Yale Medical School.

Those were heady days. We interacted every day with the most talented and accomplished biomedical scientists in the world, as they searched for the causes of human disease. Only about 10% of the principal investigators at the NIH were really happy. Their research was successful and they won the admiration of their peers. Many of them had no thought of the relationship of their work to human disease, although they expected that sooner or later something useful would come from their research. Their main motivation was to find out how living organisms work. The other 90% of the investigators at the NIH eventually decided that they would be better off working in medical schools, where they would have the satisfaction of teaching and taking care of patients, even if they were not particularly creative or successful at research.

Before coming to the NIH, Robert Berliner had worked with the first Director of the NIH, Dr. James Shannon, whom he had known since his days at New York University in New York. In 1949, Shannon was recruited to Bethesda to head the National Heart Institute. He brought his former collegues from New York University—Bernard Brodie, Robert Berliner, Thomas Kennedy and Sidney Udenfriend—with him. I had the opportunity to meet Dr. Shannon from time to time. I recall the two of us walking back to the Hadden Hall Hotel in Atlantic City from a restaurant during the meetings of the American Society for Clinical Investigation (ASCI), the Association of American Physicians (AAP), and the American Federation for Clinical Research (AFCR). I was elected to membership in the ASCI on May 14, 1962, the AAP in 1965, and later was elected President of the AFCR. The membership of the AFCR was limited to persons under 40 years of age. We were called the "young squirts," while the members of the ASCI were called the "young Turks," a term derived from political events taking place in Turkey at the time of the founding of the ASCI. The members of the original parent organization, the Association of American Physicians (AAP), were called the "old f..ts." In those days, the annual meetings were held in the Steel Pier Theatre, which had sloping, amphitheatre seats. If you sat in the back rows, the cigarette smoke was so thick, you couldn't see the speakers at the podium.

Shannon's greatest contribution to the NIH and American biomedical research was his creation a policy where investigators submitted proposals to be evaluated by "peerreview." The reviewers had to be investigators outside one's own institution. The proposals submitted to the NIH had to be signed by the investigator's institutional director. The "peer-review"policy with reviewers from outside the institutions gave enormous freedom to the individual investigator, who no longer had to depend on his superiors in his home institution for his salary and research funds. Indirect costs were given to the institution, which provided a strong incentive to the institution to support the programs, even though the relative power of the investigator was increased greatly relative to that of administrators. Winston Churchill said that democracy has many problems, but no other system is better. The same can be said about the peer review system instituted by Shannon at the NIH over half a century ago.

The procedure is as follows: when a researcher submits an application to the NIH for a research grant, it is referred to an NIH integrated review group, or IRG. The IRG assesses the scientific merit of the proposal, and then passes the application on to a study section. Each study section consists of 20 or more scientists from the applicant's area of research. Two or three review the application in detail, assess its scientific merit, and present written critiques to the study section. After discussion, each member of the study section assigns a priority score on a score sheet. The results are tabulated, and the highest rated applications are designated to be funded, depending on the priority of the application and the availability of NIH funds. Each year about 30% of the more than 30,000 applications are funded. By 2004, there were 45,000 research-grant recipients, fellows, and trainees at American Universities.

Under the peer-review system, individual young faculty members can bypass the power structures of medical schools. With steady, annual increases in the NIH budget, there was a great increase in the size of medical school faculties who submitted increasing numbers of research projects. This resulted in a steady increase in the number of creative basic and clinical scientists throughout the United States. The United States achieved the major role in biomedical research. Essential to the success of the peer review system was the honesty of the reviewers, the objectivity and confidentiality of the proposals, and the expert opinions of peers. Their reviews were returned to the investigators, and resubmissions were commonplace if the initial application failed to be funded. Scientists worked, not to gain the favor of their academic or political leaders, but to gain the respect and approval of their peers from throughout the country. Shannon was admired by the academic faculties of all American medical schools.

We young investigators soon learned the importance of having convincing evidence that our ideas would work by obtaining and submitting preliminary results. Otherwise the proposal could be rejected if one of the reviewers stated that the basic premise was unfounded. Usually a young person beginning to carry out research would join the team of an experienced, well-funded investigator. Only later would he or she strive to become a "Principle Investigator."

With increasing clinical demands for the faculty in medical schools today, it is difficult for the clinical faculty to have time to do research. They are now required to generate income for the institution by providing patient care and are often reduced to "spending a day in the lab." More and more grants are being awarded to those with both an MD and a PhD, or with a PhD only. Some clinicians, who are basically not effective in carrying out research, do so only to be able to climb the ladder of academic medicine. Unfortunately, after they become Professors, their research activities come to an end.

Johns Hopkins has always valued research as a principal function of the University and its medical school. No other environment could have better advanced my research career than my two years at the NIH. As Clinical Associates at the Heart Institute, we were encouraged to conduct research projects, both on our own and under the leadership of our superiors, while caring for the patients of other investigators. I was surprised to observe that some research scientists hesitated to have contact with patients, to the point of conducting "rounds" of patients without even entering the patient's room.

One of my first lessons at the NIH was that the opposite of "love" is not "hate," but "to ignore." When we presented our work to our peers and leaders, their critical comments were an indication that they took the work seriously. Once, after a colleague had presented some material, Dr. Berliner, who was Research Director of the Heart Institute at the time, made no comments. On the way out of the conference room, I asked: "Do you agree with that?" I was disappointed when he told me that he didn't agree with any of what had been said, but chose not to comment. I learned then that one's best friends are those who will tell you when you are wrong as well as when you are right. While on the house staff at Hopkins, I had always taken the words of our superiors as "gospel." I was disabused of this attitude after I arrived at the NIH. Even today, I still tend to believe that what people tell me is not true. Not that they want to deceive me, but that they "don't know what they don't know." This attitude is helpful to a professional scientist. Before they made scientific presentations, I taught my colleagues and students to ask: Is what I am saying clear? Is it true? Is it new? Is it significant?

While at the NIH, I carried out experiments involving the kidneys in trained, unanes-thetized dogs. While we had technicians to help us, we had "hands on" involvement in all aspects of the studies, from injecting and examining the dogs to assaying samples of blood and urine. This training would serve me well throughout the rest of my professional life. Research depends on teamwork, with no first and second class citizens. Curt Richter had taught me that while practically everyone likes the "idea" of research, few like the hard work. My greatest incentive was an overwhelming desire to get the answer to the question that is being addressed by the experiments.

We showed that there was a balancing of the secretion of the pituitary anti-diuretic hormone and the amount of solute being excreted by the kidneys as the two determinants of the osmolality, that is, the concentration of solutes in the urine. This quantification of a physiological process taught me that diseases were not just "present" or "absent," but that there could be varying degrees of deficiencies. For example, deficiency of the antidiuretic hormone in the disease, diabetes insipidus, could be present in different degrees in different patients. This concept that there is a spectrum of deficiencies making up a given disease has been helpful to me throughout my professional life. It represnted a "physiological" approach to disease, different from the "ontological" approach which views disease is a thing that you either have or you don't. The ontological approach is expressed in the statement that you have "caught a cold." The germ theory of disease and the occurrence of genetic diseases were important factors in the acceptance of the onto-logical approach to disease, as distinct from the physiological approach.

Among the patients that I took care of while at the NIH were two older men and a teenager with a disease called "orthostatic hypotension," manifest by a dramatic fall in their blood pressure whenever they stood up. We were able to establish that the disease was a general, extensive defect in their sympathetic nervous system, which we called "Autonomic Insufficiency." I was eager to study these patients because of my familiarity with Claude Bernard, Walter Cannon, and Curt Richter.

The regulation of blood pressure is an example of one of the most fundamental principles of biology: homeostasis, a term first used by physiologist Walter Cannon to describe Claude Bernard's concept of the "constancy of the internal environment (milieu interieur)." All matter has a tendency to progress to total disorder, called an "increase in entropy." Life is maintained in a free and independent "steady state" in the face of this Second Law of Thermodynamics by the existence of mechanisms for monitoring body functions and balancing the rate of formation with the rate of breakdown of body constituents. Physiology is the characterization of these processes. Medicine today rests on a foundation of physiology. As Paul Bert wrote on February 12, 1878: "Claude Bernard is not merely a physiologist, he is physiology."

The physiological adjustments to maintain blood pressure when we stand illustrate Claude Bernard's principles. Gravitational forces have to be counteracted for primates to assume an upright posture. The activation of the sympathetic nervous system constricts blood vessels below the heart to maintain arterial pressure when we stand up, in order to maintain adequate blood flow to the heart and brain. Persons who have been in bed for a long period of time lose this ability, and become faint and lightheaded. During the Civil War and both World Wars, this condition of becoming giddy with blurring of vision with a fall in blood pressure was called "effort syndrome" or "neurocirculatory asthenia."

The three patients with autonomic insufficiency that I studied had difficulty in maintaining their blood pressure in a normal range in the face of anything that would either decrease or increase blood pressure. In normal people, administration of drugs that constrict blood vessels are counteracted by the ability of the autonomic nervous system to dilate other vessels and normalize blood pressure. This did not happen in these patients. Their blood pressure would rise when they were administered drugs, such as pitressin, that are not able to raise the blood pressure of normal persons. Removal of blood or vasodilatation by drugs in my patients resulted in a far greater fall in blood pressure than in normal persons. These patients also suffered from an absence of sweating, another process under the influence of the autonomic nervous system. The administration of drugs that constrict blood vessels or increase the volume of their extracellular fluid provided these patients great relief. I described these patients and their successful treatment was at the internal medicine meetings in Atlantic City and subsequently published the results.

Before one of these meetings, I was offered the job as Head of Nuclear Medicine at Marquette University in Milwaukee. I told the Chairman of Internal Medicine, who had made the offer, that I would give him my answer at the meeting in Atlantic City. We met for breakfast and I told him I had decided not to accept the offer. Unfortunately I told him this before we had settled the bill. He made me pay for own breakfast, teaching me the important lesson that if you are going to give a negative response at the meal, wait until after the bill has been paid.

Working in the laboratory of Curt Richter on homeostatic processes had shown me the excitement of doing research. The three clinical research projects during my 3 years on the Osler housestaff at Hopkins provided further experience in carrying out research that involved patients, even those seriously ill. The two years at the NIH provided me with a virtual PhD, improving my ability to carry out research. I came in close contact with many of the giants of biomedical research, such as Julius Axelrod, who were to win the Nobel prize. Beyond any doubt what I wanted was a career in academic medicine.

At the end of those happy days in Bethesda, I was not allowed to leave the NIH without taking the orientation course. So, every morning of my last week, I went down to the auditorium of the Clinical Center at NIH and signed in even though I never went to any of the sessions. We then headed off to England.

After two years at the NIH, Anne, then pregnant with our fourth child, and I, with our three children, left New York City on the Cunard Line ship, Scythia. It was the last voyage of the ship, so that first class tickets cost less than tourist on other ships. We took salt water baths, and the stewardess would bring a basin of fresh water to wash off the salt. Anne and I got little sleep during the 10 day crossing of the Atlantic, because we spent evenings with the older passengers and entertained our children during the day. One evening during dinner, a mental patient eluded his attendant and jumped overboard. A sailor threw him a ring life preserver, that fortunately the patient grabbed. A lifeboat was lowered, he was picked up, and we were underway after 20 minutes.

Our three children ate during the childrens' meal hours, with a steward or stewardess cutting their meat and otherwise taking care of them. Since Anne and I were 28 and 30 years old, we were part of the family crowd on the ship during the day and part of the young adult group in the evening. We would carry messages from one group to the other, informing people of their assigned playing times in the table tennis competition.

One evening, at a dance, everyone was to come dressed as the title of a song. I wore a dress with a pillow simulating pregnancy. Anne was obviously pregnant with our fourth child. The song I depicted was: "Anything you can do, I can do better." We won first prize, a bottle of champagne.

After a brief stop in Cork, Ireland, to let off a group of priests and nuns, we sailed on to Liverpool, where I suddenly found myself on the dock, with a wife and 31/2 children, our first time out of the United States, not counting the days when the U.S. Coast Guard had taken me and fellow cadets to several Caribbean islands. Traveling by train to London, row after row of chimney pots left no doubt that we were beginning a new adventure. When we arrived in London, we stayed for a few days at the Queen's Court Hotel but checked out when an elderly guest, waiting with us for an elevator (lift), growled: "Children: Bah!"

We moved to a single room in a boarding house, called J.D. Residential, in Earl's Court. Mr. John Derrick, the owner, suffered from bronchitis. His periodic clearing of this throat brought to our minds a typical Englishman. The cost for room and board for the five of us was $33.00 per week. I wanted to stay there for the rest of the year, an idea vetoed immediately by Anne. We went to a real estate agent in London. A week after I started to work at Hammersmith Hospital, we moved to a wonderful, old fashioned three-story house, called Broomfield, with a lovely garden in Woking, Surrey, a quaint town on the last stop on the train from London and an hour and 15 minute drive from Hammersmith Hospital. We inherited a maid, Mrs. Blondell, who came with the house. The owners of

Broomfield were the Berry's, who lived next door. Mr. Berry had been knighted for his service in India before his retirement. The previous tenants at Broomfield were five young fliers from the U.S. Navy. Mrs. Blondell told us of some of their great parties. She was great with our children, making it possible for Anne and me to take several trips to the continent. We had purchased a Borgward station wagon, which was two weeks late in arriving from Germany because of a slip-up in our ordering it in Bethesda before we left.

Our oldest child enrolled in a small private school in Woking, and in the first grade learned "reading and sums" as we were told he would when we registered him. One Saturday, I attended a parents meeting at the school, where every mother spoke eloquently on the topic: "Should games be compulsory on Saturday?" Our daughter attended kindergarten at a private school, called Halstead. Both schools were within walking distance of our house. When winter came, we wondered why people complained about their houses being cold. We told them we had no problems because we had electric room heaters. After six months, we got our electric bill, and it was so high, the electric company gave us industrial rates. Needless to say, we turned to covering our shoulders with a blanket when we went to the toilet, and put glass-topped beer bottles full of hot water under the covers before we got in bed. Once I got the flu and Anne wanted me to stay home. I told her that I was too sick to stay home, and left for the warmth of Hammersmith Hospital.

Dr. Roland Morgan, Chief Registrar in Radiation Therapy at Hammersmith Hospital, was a proper Englishman, who lived up the street from us. We alternated days driving to the hospital. One hot day, nine months after we had been enjoying these daily trips, Roland surprised me by asking: "Do you mind if I loosen my tie?" I replied: "Roland, I don't care if you take your shirt off."

In those days before the passage of controlling legislation, the fog and smog were at times so thick that one could drive only by following the red tail lights of the car in front. Occasionally, a driver would find a whole string of cars lined up behind him as he drove into his driveway. When we would drive by a field, we would hear disoriented motorists crying: "Anyone on the road, please call out." Having a left hand drive in our Borgward was a huge advantage because you could look out of the window for the next curb, as you crossed the intersection to the next block.

Anne had the interesting experience of having our fourth child in England at the Woking Maternity Hospital. We thought that Guy's Hospital in London was too far away. The Woking maternity hospital had been founded by Dr. Grantley Dick Reed, famous in those days because of his invention of "natural childbirth." The only medication was minimal use of the anesthetic, nitrous oxide. Anne and our new daughter, Anne Elizabeth, were kept in the hospital for a week, which was routine in those days. The total hospital bill for the week's stay was $18.00. After leaving the hospital, milk and fruit juice were delivered daily to our house, courtesy of the National Health Service.

On October 4, 1957, a 184-pound satellite, called Sputnik, was launched into orbit by the Soviet Union. My British colleagues could not resist the temptation to gloat over the triumph of Soviet science and technology over American. They also took the occasion to tell me that they weren't happy over our purchase of a German automobile. They thought the American invention of beer in cans instead of bottles was a step backward.

Physicist Edward Teller called Sputnik a "technological Pearl Harbor." Americans were undergoing a national crisis of confidence, made even worse one month later, when a second satellite, Sputnik II, six times larger than Sputnik I, carrying a small dog, Laika, had been launched into orbit. The Russians also announced that they would soon put a man into space. The failure of the U.S. Navy to successfully launch a 4-pound satellite, called Vanguard, shortly thereafter was mocked in British newspapers as "Kaputnik," "Flopnik," and "Stayputnik."

Although my work under the direction of Professor Russell Fraser concerned thyroid disease, I was fascinated by the work going on in the Medical Research Council facility at Hammersmith, using tracers made by a cyclotron built two years before I arrived.

One of my responsibilities at Hammersmith was to distill iodine-132 from its parent radionuclide, tellurium-132, which produced iodine-132 in the process of radioactive decay. One of my mentors, physicist John Mallard, told me that, when I returned to the United States, I should look into a new method of obtaining iodine-132. Stang and Richards at Brookhaven National Laboratory had used resin columns to separate "daughter" radionuclides from their "parents". In addition to the tellurium-132/iodine-132 system, they had also developed a "radionuclide generator," also called a "radioisotope cow," that made possible separation of technetium-99 m from its parent radionuclide, molybdenum-99. The radionuclide technetium-99 was to become the foundation of nuclear medicine for decades beginning in the 1960s.

Technetium does not occur in nature. Both of its isotopes are radioactive and have therefore decayed since the formation of the earth. The element was discovered in 1937 by Segre and Seaborg in Berkeley, California. The technetium-99 m generator was developed by Stang and Richards in 1960. In the case of technetium-99 m with a six-hour half-life, the parent radionuclide has a half-life of 67 hours, long enough for a hospital to obtain a shipment of the generator once a week. The six-hour half life of the techne-tium-99 m and its decay by the process of isomeric transition without emitting a beta particle made it ideal for nuclear medicine.

In 1961, the catalogue of commercially available radionuclides included technetium-99 m and iodine-132 on its cover in letters 2 inches high. No one recognized the important characteristics of technetium-99 m for radioisotope scanning until 1963, when Paul Harper, Catherine Lathrup, and Alex Gottshalk administered technetium-99 m pertech-netate for scanning of the thyroid; technetium-99 m sulfur colloid for the study of the reticulendothelial system in the liver, spleen, and bone marrow; and later pertechnetate for detection of brain tumors. Paul Harper also worked with indium-113 m, and had a poster in his lab describing it as the "Isotope of the Week." Paul has written: "Henry Wagner's chemist came by for a visit (Manny Subramanian) and saw this poster on the wall, but he didn't say much about it. But it wasn't too long until Henry Wagner was working with indium-111 and it became his favorite isotope."

We began using technetium-99 m pertechnetate for brain scanning at Hopkins in January 1964. Its attractive physical characteristics included the short physical half-life of 6 hours, the absence of beta emission, which greatly reduced the radiation dose to the patient, and the energy of the emitted photons was 140 Kev, ideal for their being detected and imaged with external scanners. By June 1964, we had scanned 137 patients for suspected brain tumors. The results with technetium-99 m were far better than with the previous agents, iodine-131 albumin or Hg-203 chlormerodrin. The doses could be given either intravenously or by mouth, although the former was preferred.

Figure 23 Technetium-99m pertechnetate gamma camera image.

By 1983 these were some of the questions being asked routinely at Hopkins with technetium-99 m radiopharmaceuticals:

  1. Is a thyroid nodule functioning?
  2. Is the thyroid overactive?
  3. Does the patient have a brain tumor?
  4. Does he or she have a cerebral infarction or subdural hematoma?
  5. Has the patient had a pulomonary embolus?
Figure 24 Cover of the Brookhaven National Laboratory catalogue, advertising technetium-99m generator three years before it was recognized as being ideal for nuclear medicine.

Figure 25 First PET scanner designed by Dr. Yamamoto of the Brookhaven National Laboratory in the 1970s.

  1. What is the blood flow distribution between the lungs or in different lung regions?
  2. Is the patient able to withstand lung surgery?
  3. What is the cause of the patient's chest pain?
  4. How severe is the patient's heart disease?
  5. Is the patient responding to treatment of heart failure?
  6. Is the right ventricle failing from lung disease?
  7. In a patient with shortness of breath, is the problem the right or left ventricle or the lungs or both?
  8. Does the patient have acute cholecystitis?

Figure 27 Dr. Benedict Cassen, inventor of the first rectilinear scanner.

Figure 29 Imaging of the normal spleen superimposed on an abdominal radiograph, an early "fused" image of structure and function.
  1. Does the patient have skeletal lesions?
  2. Is there osteomyelitis?
  3. Is a renal transplant working well?

By 1983, we had carried out and followed for one year 243 consecutive patients in whom technetium-99 m pertechnetate was used in the diagnosis of hyperthyroidism.

During my year at Hammersmith in 1957, I had read the classic book on nuclear medicine written by Norman Veall of Guy's Hospital and another by William Beierwaltes at the University of Michigan. These, plus the work with cyclotron-produced radionu-clides, were an eye-opener. I concluded that the use of radioactive tracers could help solve the medical problems that I had been learning about since I started medical school.

Figure 31 Image of radioiodine accumulation in thyroidal tissue at the base of the tongue. Its location was established by superimposition of the rectilinear scan on to a radiograph of the neck. This was routine from the beginning in nuclear medicine at Johns Hopkins and represents an early version of "fused" images. The identification of the nature of the lesion prevented surgical removal.

Figure 31 Image of radioiodine accumulation in thyroidal tissue at the base of the tongue. Its location was established by superimposition of the rectilinear scan on to a radiograph of the neck. This was routine from the beginning in nuclear medicine at Johns Hopkins and represents an early version of "fused" images. The identification of the nature of the lesion prevented surgical removal.

I tried to imagine what Claude Bernard could have done if he had had radioactive tracers and the means to detect and quantify their distribution within the body. Here were tools to directly measure the "dynamic state of body constituents" within the bodies of the living animals.

Bernard wanted very much to relate chemical processes in the laboratory to those occurring within the complexity of the living body. In this famous book Principles of Experimental Medicine, he wrote of the "great error" being made by those who thought that the physicochemical phenomena within organisms were identical to those which took place outside of them. "It is that error into which certain chemists have fallen, who reason from the laboratory to the organism, whereas it is necessary to reason from the organism to the laboratory." This same error is often occurring in genetic medicine today.

Advances in science often occur when experimental techniques developed for one purpose are brought in close and effective relationship with different and independent scientific disciplines. A classical example is when Einstein related energy and matter. A whole new science was created. The sciences of chemistry and physiology were brought together in 1843, when Carl Lehmann became Professor of physiological chemistry at Leipzig. His Lehrbuch der physiologischen Chemie in 1842 provided an organized view of this new science. Its goal was "to discover precisely and in their causal connections the course of the chemical phenomena that accompany vital processes," and to "derive them from known physical and chemical laws." What remained was to determine the "topography" of these processes within the fluids, tissues, and organs of the body. A hundred years later, we are witnessing the evolution of "molecular imaging"! We must remind ourselves always what Bernard often stated: "the physiological point of view must dominate the chemical point of view."

After a year at Hammersmith, I returned to Hopkins as Chief Resident in Internal Medicine on July 1, 1957.

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