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The Americansociety for Clinical Investigation PROCEEDINGS OF THE FORTY-EIGHTH ANNUAL MEETING OF THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION HELD IN ATLANTIC CITY, N. J., APRIL 30, 1956 PRESIDENTIAL ADDRESS THE INDIVIDUAL IN MEDICAL RESEARCH AND THE ROLE OF THE UNIVERSITY CENTER IN HIS TRAINING By A. MCGEHEE HARVEY It is the custom that there be a Presidential address. versity Center is the medical storage battery for the My thesis is not new. It concerns the importance of the training of investigators. individual in research and of the University Medical The University is represented by a single active cell. Center in his training. Within the University are schools indicated by mito- This Society was established as a meeting ground for chondria, one of which is the University Medical Center. those interested in clinical investigation in its broad- (Fig. 1, A and B.) When the intact mitochondrium is est aspects. If it has a fundamental objective, it is the working in the presence of molecular oxygen, oxidation creation and preservation of a "Heritage of Excellence" of food stuffs is completed, phosphorylation occurs, and in research. The term "heritage of excellence" was ATP is formed. To carry out its objectives completely, coined by Alan Gregg as a penetrating expression of the the Medical Center must have molecular oxygen in the abiding influence of Dr. Welch and his associates on the form of strong academic and financial support. The spirit of creative scholarship at the Johns Hopkins Medi- mitachondrial membrane is selectively permeable; only cal Institutions. those factors essential to operation of the cycle gain en- It is important for University clinics to provide and to trance. In the Medical Center it is important to select preserve opportunity for the training of the individual good candidates for a career in medicine and to select a in clinical research, to promote creative scholarship. faculty that will foster in the student a keenness for self What does this entail? As Dr. Gregg has expressed it: education and a desire to contribute to the search for new "Men of superior character and capacity should have knowledge. freedom, responsibility and expectation." Let us look upon the cycle itself as the complex format There are many men on the threshold in medicine to- for training students and investigative recruits fed into day who have the right qualities of character and ability the University Medical Center. The cycle is self-per- in abundance. It is the responsibility of University petuating, constantly replenishing itself and constantly Centers to maintain in full measure the opportunity for furnishing energy. Just as the cycle supplies 95% of their development as investigators and teachers. Arnott the body's energy, the University Center is the major has said: "It should be a basic article of faith that criti- source of trained investigators for the total realm of cal scholarship and search for new knowledge is the medicine. The fat, protein and sugar feeding the cycle primary aim of the University. Not merely actual dis- represent those qualities that determine selection of the covery, not merely even the attempt to discover, but the prospective candidates represented by Acetyl-CoA. creation and cultivation of the spirit of discovery." This The candidate investigators must have intelligence, in- spirit should permeate the Medical Center. Granted that tegrity, a suitable personality, and ability to communi- the combination of circumstances is such that only a few will achieve outstanding discoveries, everyone of us can promote such discoveries by facilitating fruitful associ- w ations with the so-called "pure scientist" and by criticism and discussion foster the spirit of inquiry. As was pointed out from this rostrum not long ago, medical progress is in the logarithmic phase of growth. What has been the effect of this upon the ability of Uni- versity Medical Centers to provide freedom, responsi- bility and expectation and to maintain an environment really conducive to creative scholarship on the part of ATP young physicians? I shall draw upon a crude analogy to present the situ- ation as I see it and take as the model of a University Medical Center the Citric Acid cycle, the final common pathway for the oxidation of all three major food stuffs. It is the major source of body energy just as the Uni- FIG. IA 683 684 PROCEEDINGS OF THE FORTY-EIGHTH ANNUAL MEETING . POTENTIAL RESEARCH WORKER tUNVERSITY POTENTIAL RESEARCH IN1SON THE MEDICAL CENTER WORKER UNIVERSITY MEDICAL CENTER FACULTY MEMBER OTHER *- FACULTY MEMBER EARLY DEVELOPMENT DEMANDS EARLY DEVELOPMENT LETHAL SYNTHESIS TECHNIQUES ITECHNIQUES PRODUCTIVE TRAINING PROGRESSES N HA TRAINING PROGRESSES RESEARCH | \-- ~~~~~~IDAUNCOUJPLING HEAT SYNTHESIS OF IDEAS INDEPENDENT IDEAS INVESTIGATOR FIG. lB FIG. 2B cate. Curiosity, initiative, and constructive imagination optimal the conditions, the higher the PtO ratio in the are essential. They should be resourceful and capable cycle-the greater the amount of worthwhile research of self discipline. A questioning attitude to balance im- for the input of funds and facilities. aginative enthusiasm and a real measure of critical judge- It is to be emphasized that mitochondria are the only ment complete the picture. The student or young investi- elements of the cell that carry out the complete oxidation gator joins with the teacher (oxalacetate) and proceeds of carbohydrate, fat and protein just as the University through the training cycle. Medical Center is the only medical environment which There are specific conditions which must be maintained exists for the complete training of young investigators. if these integrated enzymatic reactions in the cycle are to The ways in which the effective activity of the cycle progress optimally. Productivity requires time and free- can be blocked are many. (Fig. 2, A and B.) dom to express admixed with responsibility-freedom The reaction rate is slowed by the removal of exala- one's ideas, freedom to choose one's own research prob- cetic acid (the teacher). The contributions of a senior lems, and to teach and take opportunity responsibility staff are reduced proportionately by time spent in ad- for the care of patients without compulsion to do so at ministration, so-called postgraduate training, society too great expense of time for research. Freedom, re- sponsibility and finally expectation; the expectation of meetings, and, of course, committees. inhibition of succinate malonate is ex- backing without strings, and contact with stimulating Competitive by colleagues. emplified by the curtailment of research activities of the too or At several in the electron transport to young investigator imposed by many teaching points cycle, routine responsibilities necessary to supplement his re- the cytochrome system occurs with oxidation and the of bonds. muneration. After our candidate has almost completed creation high energy phosphate The progress the cycle, the final step into a productive research career of a young investigator in developing new ideas and fostering them well planned experiments is can be blocked by financial pressures to enter practice by similarly as surely and completely as cyanide can paralyze cyto- of his studies at as punctuated by reports meetings such chrome oxidase. Furthermore, oxidation can occur with- this one and finally culminates in a well written paper. out phosphorylation. Uncoupling of oxidative phos- Proper coupling is necessary for oxidative phosphoryla- phorylation results from certain drugs such as dinitro- tion to occur with the greatest efficiency. The closer to phenol. In this circumstance there is generated unusable energy in the form of heat. Flitting from one problem to another, or taking on too many diverting functions like ACETYL-CoA \ ~~~~DAblAGEDDAMAGE dinitrophenol, may produce enough heat to result in pot- boilers, but real research accomplishment suffers. The recognition of these metabolic antagonists to cre- .-OXALACETATE ative scholarship is an easy matter in the gross, but CITRATE there are subtle and insidious forms of inhibition that I-LETHALFLUOROACETATE are not so obvious. Fluoroacetate is unusual. Its action SYNTHESI is not that of 'EKTIT1r 4 like iodoacetate, which combines with SH IN OIBION HCYTOCHRO&IESH groups, and no enzyme is known to be poisoned by it. SUCCINATE Its action is one that Peters has termed "lethal synthe- ATP sis." The non-toxic fluoroacetate is converted to fluoro- OXIDATIVE citrate which blocks aconitate and the result is "jam- PHOSPHIORYLATION ming" of the cycle at the level of citric acid which then accumulates in the tissues. The cell fails to recognize H~~~~~~EATFIG. 2A that it is poisoning itself-too much of a good thing. AMERICAN SOCIETY FOR CLINICAL INVESTIGATION 685 Even with good departnents and a fine professional staff Some no longer want to bother with the tribulations of in a school, the production of well trained investigators personally conducted experimental studies. Administra- can still be blocked. What are the sources of "lethal tive duties, membership on local and national committees, synthesis" in the Medical Center? The answers go right and the ever increasing demand to take part in additional to the root of our research structure and affect the young educational exercises before local, state and national investigator from his earliest medical experiences. medical groups are obviously important but can also be- Common interest in the study of a given problem, with come socially acceptable excuses. A great scientific po- different
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