Proceedings of the Sixtieth Annual Meeting ofthe American Society for Clinical Investigation, Inc.

Atlantic City, New Jersey, 1 May 1968

PRESIDENTIAL ADDRESS

KeystonesROBERTA. GOOD

The American Society for Clinical Investigationstands at the keystone of progress in American medi-cine. To be president of this distinguished body hasbeen a challenging educational experience.

As members of this society we do strange things.Analysis of our behavior in light of the new ethologyof Tinbergen (1) and Lorenz (2) and their inter-pretation by Ardrey (3) might help us understandour annual rites. Each spring on precisely a givenday members of the order gather from every cornerleaving, temporarily, families and activities vital toself and state and travel to familiar surroundingswhere a selected few display scientific accomplish-ments. Accepted behavior of the group demands thatachievements be challenged ruthlessly, destroyed ifpossible, and accepted only tentatively, with a "briefword of caution," if the ground is held. On an intel-lectual plane how comparable to activities of moreprimitive forms which migrate seasonally to a stamp-ing ground where a vital game is played (3, 4). Thestakes are different . . . in the case of the UgandoKob for example a succession of 'willing females seekout the proper addresses established by physical de-fense of a small artificial territory. Difference of re-ward may not be crucial. In addition to his magnifi-cent buttocks and chin (5), man must be distinguishedby complexity of his games and size and organizationof cerebrum. Exalted behavior is the aim. A leaderselected by previous vigor and successful defense ofintellectual territories is placed in central position,given an impossible task, and then dismissed from thegroup along with aged cohorts. The dismissed be-come useless and are granted permission to exerciseonly mild and inconsequential harassment of youngaspirants who year by year fight their way to thepositions of leadership. Sometimes these old fellowseven encourage the younger ones. Adapting to thisfutile role at first I struggled to the extent of thinkingI might fool everyone and instead of the expectedaddress gain 20 minutes for a paper on my latest

discoveries. In early days presidents tried this to noavail. It was not what was wanted and they were dis-missed anyway.

Recent history dictates a brief moment in anticipa-tion of oblivion which, as with certain adult insects,is used to display bold colors and form not seen dur-ing developmental stages. For the president this isthe time to express feelings previously unexpressed,to make exalted exhortations, or present an analy-sis of the relation of behavior in the learned societyto other human endeavor. Since I must play by therules my effort will be a mixture of all three adapta-tions.

Our society professes to stand for excellence. Tofoster excellence in clinical investigation we have,just as has occurred throughout nature, used selec-tion. Wehave selected for membership, for participa-tion in program, and for publication. Within theboundaries of human fallibility we have been fair andimpartial in our selections. Previous presidents haveargued this case and brought forth data to prove intheir swan song that in this the society has been suc-cessful. Surely we have drawn on the past and inlooking to successful cultures have used old methodsto achieve our goals. We have tried to create in-spirational leaders, heroes, even demigods through theyears.

When a distance or obstacle needs to be spannedor a firm support provided, cultures dating fromantiquity have employed the arch. Neolithic manleaned stones together in a triangular arch to bridgea gap. Curved profiles for spanning distances datefrom the cultures of the Tigris-Euphrates valley. Ina classic Roman arch there are various combinationsof wedge-shaped stones. Each of the stones strategi-cally placed is called a voussoir. At the apex of thearch sits the last stone to be placed; this is the key-stone, so called because of its critical position in thearch. This stone, although of no greater value to thespan than any other, has gained architectural sig-

1466 The Journal of Clinical Investigation Volume 47 1968

nificance from the prominence of its key position incompleting the span. Ben Johnson wrote ". . . tis thekeystone which makes the arch" (Fig. 1).

Throughout history societies and cultures haveused similar techniques to facilitate excellence of be-havior of man. Man can achieve exalted behaviorand seems to do best when he creates gods in hisimage and spans the gap from ordinary human be-havior to god-like behavior through a series ofvoussoirs of which his heroes stand at the keystone.He creates gods in his image, not impossibly remote,and encourages acceptance of leadership to approachthe keystone of heroic behavior through leadership.Could our selection of membership and developmentof leaders and heroes be an attempt at this traditionalmotivation? Another certain means to achieve excel-lence in culture is to assure that growth of knowledgeproceeds by geometric progression. Again a view ofthose cultures which many believe have achieved ex-cellence and which have made extraordinary contri-butions reveals the usefulness of a dialectic. At basethis, the most effective form, insists that every ques-tion be answered with a question, insuring maximalrate of growth. Knowledge, then, must be considereda succession of questions and not a succession ofanswers. Surely in our learned society we encouragethis view and worship the question in pursuit of sci-entific progress.

In the exalted Greek and Hebrew cultures forexample, magnificent heights have been reached.Participation of a high percentage of a small popu-

FIGURE 1

lation was certainly. not achieved by placing limita-tions on the participation of large numbers of a highpercentage of an aspiring population. It is on thispoint I often stumble as I consider our society. Iagree that we should set standards; I believe wveshould set them very high, but having done so wemust share membership, with all who attain thesestandards. We must, I believe, as soon as possible,find means to eliminate the hazard of either a stiflingor inflationary influence of an artificial number whichis used to determine the numbers of men admitted tomembership. Little basis, I feel, can be found to re-late progress or excellence to numbers of men, num-bers of their contributions, or numbers of anything.

Another question has been raised frequently inrecent years . . . are we accomplishing our goals?In his introduction of The Journal of Clinical Investi-gation in 1921, A. E. Cohn (6) admonished that theaim of medicine is to understand, treat, and cure dis-ease, and that the American Society for Clinical In-vestigation and its journal represent response to thecall of a new spirit to develop a true science of medi-cine which can facilitate achievement of this goal.Howwell have we fared?

In a recent article in the British Medical Journal,Lord Platt (7) maintains that clinical investigationhas failed. Particularly, he indicts the heavilyfinanced clinical investigation of America, and hestates that this discipline has contributed little to thegreat progress in treatment and cure of disease. In-stead he attributes all progress to either basic medi-cal sciences or pharmaceutical industry. In his au-dacious statement he cites numerous examples towhich he attributes no significant role to clinical in-vestigation. Time permitted meto research only a fewof his examples, and I am afraid my bias for clinicalinvestigation insists I express a divergent view. Iwill cite but a single example from Platt's own ma-terial and from that argue what I believe is the ridicu-lousness of his position. Platt contends that insulinwas discovered in a department of physiology and,thus, gives this discovery to the basic sciences. Whatwas the real story? It was known from the expatiativestudies of Van Merring and Minkowski (8) that re-moval of the pancreas produced an increase of bloodsugar. Excitement engendered by this discovery ledto numerous attempts to extract an active principle tono avail. In 1920, Banting, a young physician, re-cently returned from an army post after World WarI, and, apparently still having time to read, was per-using the clinical journal, Surgery, Gynecology andObstetrics. He happened upon a paper written byBaron of Minneapolis (9). The focal point of Baron'spaper was a single case which he as a young clinicalinvestigator had studied at autopsy. The patient hadhad an apparent congenital absence of Santorini'sduct and had developed a calculus in Wirsung's ductin the head of the pancreas. Behind the stone, presum-ably from secretory pressure, the acinar tissue hadbeen completely destroyed, but the islets remained

Presidential Address 1467

intact. The admonition from this experiment of na-ture was clear and the "eureka experience" of Bantingso compelling that he rushed to Macleod's departmentof physiology in Toronto and, with great enthusiasm,presented the experimental approach to Macleod.Only then, together with the medical student Best, didhe in a department of physiology proceed to executethe critical experiment. He tied off both pancreaticducts, destroyed selectively the acinar pancreas leav-ing islets intact, and extracted in simple aqueoussolution the internal secretion of the pancreas somuch sought in numerous basic science laboratoriesof the time. The control of pernicious anemia atabout the same time was also the triumph of clinicalinvestigation. These examples illustrate so clearlyto me the concept expressed in the following arch(Fig. 2). Clinical investigation, powerful as a sci-entific discipline in its own right, has its greatest in-fluence standing at the keystone of the arch to pro-gress in medical practice. This central position is de-rived from the frequency with which natural ex-periments are encountered that result, to borrowfrom Koestler, in fusion of matrices (10). Such fu-sion relieves the anguish of a blocked matrix oftenunresolved by efforts toward understanding that de-rive from inductive experiences of the sciences basicto medicine.

Another example of how little this role of clinicalinvestigation is understood in historical or contem-porary perspective is revealed by a recent indictmentof the transplantation surgeons. The indictment wasdirected toward the cardiovascular surgeons who elec-trified laity throughout the world with their hearttransplantation. This leading basic physiologist fo-cused on the failure of the cardiovascular surgeonsin national and international publicity deriving fromtheir adventure to recognize contributions from thebasic sciences which to that viewer had made pos-sible the technical contribution of heart transplanta-tion. A number of examples were cited in whichbasic contributions had paved the way for heartand organ transplantation. Included were such majoradvances as development of the science of circulatoryphysiology, control of infection, development of anes-thesiology, pharmacological support of cardiovascularfunction, technological progress permitting securediagnosis, control of the immune rejection, and others.From my somewhat prejudicial position, I seemed tohear a dramatic recitation of example after example inwhich investigation had led the way, asked the criti-cal questions, established the incisive view, or haddipped, even prematurely, into the methodology ofbasic and enabling sciences. Certainly the control ofinfection is in great measure attributable to leader-ship of clinical investigators. As examples one cancite Semmelweis and Holmes who independentlyinterpreted natural clinical experiments correctly;Lister, already a clinical investigator who was alertto the earliest unestablished reports from Pasteur, anda host of clinical investigators, some still in this room,

FIGURE 2

who established the safe and effective use of chemo-therapeutics and antibiotics in clinical medicine.

The discovery and application of anesthesiology, tome, also derives from interpretation of several naturalexperiments and conduct of critical clinical investi-gations. The professional physiologists have contrib-uted much to the understanding and control of thecirculation, but was not the discovery of the circu-lation of the blood primarily an interpretation of aclinical experiment of nature? I think so. The dis-covery of the foxglove, the first of the cardioactivepharmacalogicals, was made as a consequence of anatural clinical experiment. Establishment of thecredibility of this insight, too, was the function of amost precise clinical investigation. Finally, to me itseemed that the application of certain poorly under-stood antimetabolites or cancer chemotherapeuticagents for immunosuppression has launched the trans-plantation era. Was this not the audacious manipula-tion by a young clinical hematologist now a memberof our society who had achieved a vector from clini-cal and experimental forces? Wemust not only un-derstand and insist on proper support of the basic andenabling sciences, but we must insist that the fruitsof clinical investigation are real. Over the past sev-eral years I have collected more than 100 strikingexamples from medical history and contemporarymedicine in which natural experiments have contrib-uted uniquely and in a major way to the solution ofan important medical or biological problem. The ma-

1468 Robert A. Good

jority of these examples come from clinical medicineand clinical investigation. Soon I hope to compilethese into a new look at medical history.

To me the power of the clinic and clinical investi-gators is not only to contribute to the solution of animmediate problem, but also to provide unique ques-tions, bases for hypotheses, and direction and pur-pose for investigations in the so-called basic sciences.In spite of the criticisms that have been leveled, Imust keep clinical investigation at the keystone of myarch to progress in both basic science and medicalpractice. Fig. 3 reflects what I consider to be theessence of the power of the clinic in spanning the gapbetween the basic and enabling sciences and medicalpractice. Certainly in establishing fact it is rare ifever that scientists use a purely inductive process(10-13); although from the time of Bacon they havedeluded themselves into thinking that this is theirway (12). Chance and intuition often derived fromdistraction, unconscious mulling, or interposing ex-periences most frequently play a critical role. Thecreative experience in the science of medicine as inall other science can often be attributed to enchant-ment by these maidens . . . chance and intuition(11). The stories we tell and the excitement of ouradventure are in large part a function of surprises.The clinic and clinical investigations have so oftenprovided the opportunity for the chance conjunctionof a natural event and the uniquely prepared mindthat they represent a veritable methodology for achiev-ing Koestler's "fusion of matrices" (Fig. 4). Intui-tion and chance of course are not enough, and reason

FIGURE 3

FIGURE 4

must be brought to bear to lead to construction oftestable hypothesis which is followed in turn by rigid.and critical experimental efforts to refute the hy-pothesis and thus bridge the gap from creative im-pulse to the establishment of useful fact. Hypothesesare not right or wrong; like classifications, they areuseful or not useful.

In a most brilliant analysis, Popper (13) long agopointed out that postulates have scientific value notas a consequence of their explanatory power but byvirtue of their refutability. This characteristic is theessence of testability. Satisfactory fittings or obser-vations which agree with an hypothesis do not in anyway establish its worth or even strengthen it as ascientific instrument. It is only the hazard of refuta-tion, the susceptibility to disproof which distinguishesa scientifically powerful and useful hypothesis from ascientifically useless one. Popper cites as examples ofexplanatory hypotheses which do not have scientificvalue the hypotheses of Marx and Freud and Adler(13). Establishing credibility of a postulate whichhas been derived from the creative experience is themajor function of scientific analysis. The processesof creativity and establishment of credibility are, in-deed, completely separate processes; they are separatetypes of functions (11). Both are essential to scientificprogress, each is important in its own right, and eachmust be properly and efficiently used. Clinical investi-gation offers a rich complement of stimulation tocreative experience. But credibility must be derivedby analysis at the bench or in carefully controlledclinical experimentation. The rules of this operationin the clinical arena can be no different from thosedemanded in the basic biological, physiological, orbiochemical laboratory. The analyses must demon-

Presidential Address 1469

strate reproducibility, reveal statistical force, andlead to predictability. To meet these demands of rigor-ous scientific demonstration is not always easy in theclinical arena. The demands, however, cannot andmust not be compromised. In these spheres our so-ciety and journal stand impeccable.

The intensely emotional nature of the creative ex-perience, I believe, accounts to some extent for whathas always seemed to me a set of extraordinary in-congruities in the behavior of scientists when dealingwith their own brain children. From the earliest daysof our introduction to science we are taught to singpopular songs about science. Science is objective;science is unemotional; science is altruistic; progressis facilitated by unreserved sharing and by freedomof communication. Nothing can give a scientistgreater pleasure than to see his work as a steppingstone to progress. A scientist cannot be distressedby refutation of his hypothesis since this is the fateof all hypotheses as a consequence of progress, andprogress is the goal. Even in our own group one seesover and over again, and from the most effectivescientists, evidence of all human frailities . . . jeal-ousy, hostility, selfishness, secretiveness, even sur-reptitiousness, and predjudice . . . these traits aremost likely to leap to the fore when the intellectualterritory staked out in relation to a creative experi-ence, an original insight, a chance association isthreatened by another scientist. Very few of us, nonewith whom I am acquainted, have entirely escapedfrom this hazard. Perhaps this emotional territorialityhas value understandable in ethological relations to thephysical territoriality of our species (3). Much studywould be required to establish such a relationship, butit is an interesting thought which might be foundtestable.

It is, however, saddening to realize that clinicalinvestigators and all scientists for that matter regard-less of their early indoctrination remain people withall of man's difficulties. Perhaps this apparently un-fortunate behavior has advantage for the species.Whatever that might be, the behavior seems fromscientific perspectives destructive and useless. If sci-entists cannot be persuaded to exhibit behavior whichtranscends their animal instincts, what is to be ex-pected of less-well educated or less thoroughly indoc-trinated peoples? Perhaps like the dinosaurs we willhave had it by virtue of our superspecialization asfighting beasts.

But science goes on, and biology and clinical medi-cine have made such great strides that as enterprisesthey threaten the very ecological niche which manmust habitate. I relish the opportunity to talk withstudents of all ages. Recently I spoke to a group of250 of the brightest high school seniors in our five-state area trying to picture for them our glimpse intothe transplantation era. I had finished talking oflogarithmic growth of scientific and medical knowl-edge. I had stressed the impact of our growing un-derstanding with ultimate control of certain forms of

aging, prevention and treatment of cancer, treatmentof kidney disease, heart disease, chronic and recurrentinfection, to say nothing of license for allogeneic andxenogeneic transplantation which might derive frommanipulatable understanding of the lymphoid systemand immunological capacity. One of the youngstersasked: "Dr. Good, doesn't your logarithmic curveextrapolate into an impossible world?" . . . Ladiesand gentlemen, it does. So does our understanding ofdeclining energy resources of our solar system, in-creasing knowledge of physics, chemistry, or gene-tics. This question brings me to my final keystonewhich I have derived from reflections on Rene Dubos'recent look into the incredible future.' Fig. 5 indi-cates the polarity of technocracy and humanity andrepresents my effort to span this gap with a finalarch. As scientists we must be the servants of ourculture, the very slaves of our artists, our poets, andour philosophers. Our science must be hard-nosedand critical unto itself, but it must be at the same timesensitive to needs of our cultures and peoples. No-where in science is it so natural to develop and ex-press this sensitivity as in clinical investigation.As the diseases and distresses of people change, somust, of necessity, a change occur in our science.Clinical investigation must continuously take on newchallenges and provide new solutions and new under-standing for new kinds of problems.

1 Dubos, R. New York Academy of Science Sesquicen-tennial Celebration. December 1967.

1470 Robert A. Good

As a society and as individuals we must be sensi-tive to the needs not only of our science but also ofclangiing needs and changing diseases of man. Wecan begin by standing ready to admit to program,publication, and membership scientists who are ap-proaching behavioral problems with refutable hy-potheses; we must include those scientists workingin new or less well-developed facets of clinical in-vestigation who are enjoying and critically inter-preting questions derived from natural experiments.Wemust not let our learned society become simplya society for selection of professors of academic in-ternal medicine but should insist on the vigor thatwill continue to derive from welcoming the clinicaldevelopmental biologists and those obstetricians andsurgeons who worship clinical investigation as aprimary function. We must listen to those of ourgroup who, like Rutstein (14), become concernedwith the delivery of the fruits of our sciences withmaximal efficiency. Personally, I would like to seea scientific explanation of the challenging clinicalobservation that infant mortality is higher in someAmerican ghettos than it is in Peru. Why?

I think in some respects our society and our jour-nal have developed a threatening conservatism. If weare to survive and thrive as a learned society, wemust make an increasing effort to develop the re-sources of youth. More and more exciting youngpeople are available, and the best should be recruitedto clinical investigation. Wemust listen with greatersensitivity than we have to the creative impulse andprovide for its expression, we must be more preparedto set aside our cherished views and to change theobjects of our analyses, and we must develop deeperawareness to the cries of our fellows who demandhumanization of scientific progress. Wemust not re-ject mission-oriented research in which the missiondemands we face new problems and new questionswith proved strength. Wemust respond to the chang-

ing medical problems of our people with a sensitivescience of clinical investigation at the keystone.

ACKNOWLEDGMENTS

I would like to express appreciation to Joanne Finstad-Good for help in formulating preparation of this address,and to Louis Tobian and all my students, past and pres-ent, for provocative discussions.

REFERENCES

1. Tinbergen, N. 1951. The Study of Instinct. Claren-don Press, Oxford.

2. Lorenz, K. D. 1952. King Solomon's Ring. ThomasY. Crowell Company, New York.

3. Ardrey, R. 1966. The Territorial Imperative. DellPublishing Co., Inc., New York.

4. Carrighar, S. 1965. Wild Heritage. Houghton MifflinCompany, Boston.

5. Ardrey, R. 1961. African Genesis. Dell PublishingCo., Inc., New York.

6. Cohn, A. E. 1921. An introduction to clinical investi-gation. J. Clin. Invest. 1: 1.

7. Platt, L. 1967. Science: master or servant? Brit. Med.J. 4: 439.

8. Van Merring, and Minkowski. 1889. Diabetesnach pankreasextirpation. Arch. Exptl. Pathol. Phar-makol. 26: 371.

9. Baron, M. 1920. Relation of islets of langerhans todiabetes. Surg. Gynecol. Obstet. 31: 437.

10. Koestler, A. 1964. The Art of Creation. Dell Pub-lishing Co., Inc., New York.

11. Beveridge, W. I. C. 1950. The Art of Scientific In-vestigation. Vintage Books, New York.

12. Medawar, P. B. 1967. The Art of the Soluble.Methuen & Co., Ltd., London.

13. Popper, K. R. 1963. Conjectures and Refutations.Routledge & Kegan Paul Ltd., London.

14. Rutstein, D. D. 1967. The Coming Revolution inMedicine. The M.I.T. Press, Cambridge.

Presidential Address 1471