SPECIAL ARTICLE * ARTICLE SPECIAL
Clinical research Jacques Genest, CC, MD, MACP, FRCP, DSc (Hon) C linical research is a variant of the pursuit of truth, of the desire of man to explore the unknown and to uncover the laws that control life, nature and the universe. It is restricted to the study of human health and the mechanisms, cure and prevention of disease. Its basis is essentially the scientific method of weighing the evidence provided by physical or chemical investigations and by accurate instrumentation to measure what is observed, to hypothesize and to experiment. Clinical research is a part of the continuum of biomedical research (Fig. 1). In most cases the study of biologic functions and disease must be carried out in a university hospital, which provides the optimal conditions (e.g., in terms of dietary controls, research assistant nurses, laboratories, ease of consultation with other experts). Clinical research may involve metabolic studies, studies of the clinical effects of drugs and behavioural research and may be fundamental at the molecular and cellular levels, provided the questions are directly related to hu-
mans, healthy or not. In addition, it requires close, repeated observation and, most important, original thinking and imagination. As with fundamental research clinical research demands the intellectual disciplines of objective observation, clear thinking, precise expression, intellectual integrity and critical sense. To a great extent clinical research depends on advances made in fundamental research for new basic methods and instrumentation. The same physical and chemical investigations are used to measure observed phenomena in the two types of research. Both types of research can involve animal experimentation if necessary. The questions asked in clinical research can be at three levels: (a) molecular and cellular, (b) tissues, organs and systems and (c) the whole person. For the latter the research may be epidemiologic, evaluative and operational (Fig. 1), but the means of investigation must consist mostly of social, economic and statistical measurements. A "research" qualification has a certain aura of prestige for the media and the public; Biomedical research
Objective
Instrumentation
Fundamental
Clinical
Epidemiologic
Operational
Evaluative
To understand isolated basic phenomena at the molecular and cellular levels
To understand function and disease in humans
To understand factors involved in diseases in populations
To determine better use and distribution of health care
To compare efficacy of various diagnostic and therapeutic procedures
resources
Detection of phenomena
Social, economic and
and measurement by physical or chemical means
statistical observations and measurements
Fig. 1: Objectives and instrumentation of biomedical research - a continuum. Dr. Genest is professor of medicine at the University ofMontreal, consultant to the Clinical Research Institute of Montreal and professor of Dr. Genest is professor of medicine at the University of Montreal, consultant to the Clinical Research Institute of Montreal and professor of experimental medicine at McGill University.
Reprint requests to: Dr. Jacques Genest, Clinical Research Institute of Montreal, 110 Pine Ave. W, Montreal, PQ H2W JR 7 CAN MED ASSOC J 1990; 143 (5)
383
antigtaImle
serhn"esl
eoe
anything that implies "searching" easily becomes created in Britain, mainly under the influence of Sir research.
History Before 1920 government and private agencies did not organize or support clinical research. It was strictly the fruit of individual efforts of such famous men as Bernard, Laennec, Louis and Pasteur in France, Addison, Bright, Hodgkin, Parkinson and Sydenham in Britain, and Ehrlich, Koch, Muller, Virchow and Volhard in Germany. Until the middle of the 19th century medical research was descriptive and correlative - the clinicopathologic method. It became experimental with the use of animals, mostly by Claude Bernard in the latter part of the 19th century. Clinical research as we know it today is one of the outstanding US contributions to the world and to the understanding of the mechanisms and prevention of disease. In the last 50 years clinical research has expanded phenomenally and in many directions: hormones, electrolytes, metabolic and physiologic studies, clinical pharmacology of new drugs, molecular biology, recombinant DNA and genetic engineering. Early in the 20th century eminent US physicians, including Cole, Flexner, Osler and Welch, introduced the concept of full-time chiefs of clinical departments and clinical investigators. Clinical research laboratories were established in the clinical departments of teaching hospitals so that the basic disciplines could be integrated with clinical teaching and the care of patients. At this time the great philanthropic foundations, such as the Rockefeller Foundation, and later the expanded National Institutes of Health (NIH) played a major role in the extraordinarily rapid growth of clinical research in the United States. Another major contribution was the creation of several medical associations, which provided a forum for the exchange of ideas and research contributions and for active discussion and collaboration. These included the American Clinical and Climatological Association, founded in 1884, the Association of American Physicians, in 1885, the Interurban Clinical Club, in 1905, the American Society for Clinical Investigation, in 1909, the Peripatetic Club, in 1933, and the American Federation for Clinical Research, in 1940. The creation of research laboratories in the clinical departments of university hospitals permitted a close link between the care of patients and biomedical research and the rapid communication of research results to those in charge of patient care. In addition, the laboratories provided a scientific environment in which to study the whys and hows of disease. This system was greatly superior to the one 384
CAN MED ASSOC J 1990; 143 (5)
Thomas Lewis, in which clinical research units with 6 to 10 beds in university hospitals had no direct contact with the clinician-practitioners, the students or the registrar staff. Those units were headed by one investigator, whose interests determined the research. The successive leaders of the Royal Postgraduate Medical School (Sir Francis Fraser, Sir John McMichael and Sir Christopher Booth) noticed the weaknesses of the British system and provided an organization at Hammersmith Hospital very similar to that at university hospitals in the United States. ' The growth and importance of clinical research in the United States can be measured by the spectacular increases in the budget of the NIH ($7.2 billion in 1988). Also spectacular is the $8.2 billion allocated in 1990 for research and development by the main US pharmaceutical corporations, several of which spend 8% to 15% of their sales revenue ($300 to $850 million per year) on research into new and more effective drugs (unpublished data). During my 1937 and 1938 sojourns at Harvard University and my postgraduate studies from 1945 to 1951 at Johns Hopkins University and the Rockefeller Institute one theme was recurrent in the high circles of medical education and research in the great US institutions. It reflected the advice given by Anton Dohrn, of the Naples Zoological Society, to Simon Flexner, who was visiting research institutes before becoming the first director of the Rockefeller Institute, in 1902: "Give them [the research workers] perfect freedom, let them search where and how they will, help in every way you can, but do not pretend to be the master of them."2 Detlev Bronk simplified it when he was president of the Rockefeller Institute: "Find the right man, back him up, stay out of the way!"3 Alfred Newton Richards, one of the leaders in US medicine, said it similarly: "The unit of scientific advance - in medicine as well as in the natural sciences - is a human individual endowed with curiosity and eagerness to satisfy it, who can identify unanswered questions, and imagine ways of answering them. It is the prime business of such an institution as ours [University of Pennsylvania Medical School] to select such individuals."4 Medical research in the United States attracted many such men; all had a true dedication to research and the motivation to serve the common good. Upon receiving the Kober Medal in 1927 Welch repeated the advice he had given to young research fellows throughout his career. Allow nothing to divert you from your professional and scientific work. While maintaining a spirit of cooperation, resist the call to give general addresses, especially at a distance from home, to serve on committees, to assume time-consuming administrative duties, and to show visi-
tors around laboratories, clinics and buildings.... If you have found your problem, it should absorb you and its successful pursuit should make you the happiest of mortals in the consciousness of adding something to the body of ordered knowledge.... Strive for and be content with a scientific reputation based on the judgment of the best workers in your field.... Such reputations are enduring.5
There were difficulties and many confrontation-s between clinical scientists and their colleagues in the basic sciences who were trained between 1880 and 1910 in European laboratories, mainly in Germany. Clinician-scientists were restricted at the bedside to observe patients and follow up the natural history of the disease; they did not have access to laboratories and animal experimentation. Such a confrontation occurred in the early years of the Rockefeller Institute; Flexner supported research but only as long as the physicians practised at the bedside and not in the experimental laboratories. In 1911 Cole, as director of the Rockefeller Institute Hospital, reacted in a letter to the trustees: "Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in Rockefeller Institute Hospital, every man who was caring for patients should also be engaged in more fundamental studies."6 Upon his retirement, in 1938, Cole said: "No restriction has ever been placed on the nature of the investigations or methods to be employed: they could be as fundamental as the training of the man permitted, but it has always been felt that workers in hospitals should have in the backs of their minds the relief of suffering and the cure of disease."7 The factors responsible for the remarkable progress of clinical research in the last 30 years were (a) the availability of micromethods of measuring biologic components, (b) the rapid progress in electronics, microprocessors, computers and noninvasive techniques, (c) the availability of radioactive and stable isotopes and (d) the advent of vascular catheterization and tissue biopsy. Discoveries are most often the result of wellplanned experiments and critical observations. But they can also come from intuition or by chance; Kempner's rice diet is one such example. In 1942, a farmer's widow with chronic glomerulonephritis and papilledema, patient of Dr. Kempner, was confused by Kempner's German accent. On discharge from the hospital, she understood that she was to eat rice and to return in two months. After that period, she returned with dramatic reduction of her blood pressure and disappearance of retinal hemorrhages and papilledema and a significant decrease in heart size. This was the beginning of the rice diet.8
Another example is the discovery of penicillin.
Fleming had shown in ;1929 that cultures of staphylococci were dissolved when they grew near the fungus Penicillium notatum. He [Fleming] had no conception of the magnitude of his discovery.... He wrote in 1940 that it did not seem worth the trouble of making it. His main interest in the penicillin appeared to be in its selective antibacterial action which facilitated the isolation of certain organisms from mixed cultures. It clearly never occurred to him that penicillin might be introduced in the blood stream to cure infections; hence, for more than 10 years after his initial observation, penicillin remained little more than a curiosity.9
Modern organization of clinical research In the summer of 1948 and during 1951-52 I had the unique opportunity, on behalf of the Quebec government and with the help of Dr. Rolf Struthers, of the Rockefeller Foundation, and Mr. L. FarrerBrown, secretary of the Nuffield Foundation in Britain, to visit most of the leading clinical and medical research centres in the United States, Britain, France, Germany, Switzerland, Holland, Denmark and Sweden. From these visits it was clear that clinical research laboratories were scattered, depending on the local needs and possibilities, on the various floors and wings of the university hospitals. This resulted in poor communication and coordination between the clinical researchers and needless duplication of expensive instrumentation. Progressively from these visits and the many discussions I had with leaders in medicine and biomedical research the concept of concentrating clinical research in one geographic area with well-defined characteristics began to form as an answer to the somewhat chaotic, although phenomenal, growth of clinical research in teaching hospitals.'0 The thoughts that led us in the early 1960s to the creation of the Clinical Research Institute of Montreal were that (a) such institutes could be integrated either as a separate building or wing attached to a university hospital or as an autonomous organization affiliated with such a hospital or a university, depending on local factors, (b) the basic and full-time clinical scientists should be concentrated in one geographic area, (c) the administration should be separate from that of the university or the teaching hospital and be under the authority of a scientific director, as found at the Rockefeller Institute (now Rockefeller University), (d) extensive auxiliary facilities should be available (e.g., shared high-cost equipment, audiovisual department, specialized library, and common animal and meeting rooms), (e) each researcher should be obliged to obtain grants for projects from public or private agencies that have referees and a peer review system, CAN MED ASSOC J 1990; 143 (5)
385
(f) there should be access to patients in the clinical services or outpatient departments by joint hospital appointments and (g) researchers should supervise graduate students for MSc and PhD degrees and research fellows and participate in teaching medical students, interns and residents. Such a concept of a clinical research institute was supported by Hollenberg and Siminovitch," who wrote in 1986 that it was generally realized that our medical schools and most of our teaching hospitals are "no longer adequate to meet all of the technologic and interdisciplinary demands of contemporary medical research" and that "many of the important medical research problems of our time, including most of those bearing directly on human disease, can only be approached . . . by mobilizing the efforts of relatively large groups of scientists with differing scientific backgrounds and by providing these groups with necessary and often high-cost technology. Such concentrations of talent and equipment are beyond the present capacities of Canadian universities." In 1988 Friesen,'2 one of the most able biomedical researchers in Canada, wrote: "Advances in understanding human biology and its derangements by disease depend on the exercise of the talents of individuals trained in a wide variety of disciplines. Their work must span the spectrum from the basic research on the molecular mechanisms of life to epidemiological research involving populations, from research on fundamental phenomena to study of specific applications." This concept of the organization of modem clinical research is now accepted in many parts of the world. The success of the Clinical Research Institute of Montreal, which was founded on the basis of this concept, is also due to an effective three-tier evaluation system. First, the head of each laboratory must finance research projects by grants obtained from peer-reviewed private or public agencies. Second, the institute holds an annual 2-day "retreat" in a country hotel to allow the researchers to discuss current projects and future plans. Two external referees from Europe, Canada or the United States participate at the retreats, and each presents a general evaluation directly to the Board of Trustees. Third, every 5 years international experts are invited to spend 4 days at the institute to evaluate thoroughly the scientific productivity of the researchers and the policies and administrative organization of the institute. Visitors have included top scientists such as J. Edward Rall, Albert Renold, Louis Siminovitch, Sir Christopher Booth, Henry Friesen and Gordon Dixon. One of the best examples of the success of the concept of multidisciplinary and pluridisciplinary research concentrated in one geographic area has been the work done at the Montreal institute on 386
CAN MED ASSOC J 1990; 143 (5)
atrial natriuretic factor (ANF). The research covered almost all aspects: the isolation and the elucidation of the amino acid sequence of ANF, the cloning of its gene and its chromosomal localization, the biosynthesis of analogues, the distribution of ANF in extra-atrial tissue, the isolation and characterization of ANF receptors, the mode of action of ANF, mediated through cyclic guanosine monophosphate, the physiologic effects of ANF on aldosterone and vasopressin and the physiopathologic features of ANF in human hypertension and congestive heart failure."3 This work covered the spectrum from molecular biology to patients, and all contributions by the various collaborating laboratories were accomplished in house because of the concept of research organization at the institute. This work was recognized by the American Heart Association, which gave its 1988 Distinguished Research Award concurrently to the institute's Hypertension Research Group and to Needleman's group in St. Louis. The importance of good research administrators cannot be stressed enough: "Progress in medicine has always depended not only on medical scientists but also on those who create the conditions under which their creativity and originality can flourish."12
The clinical scientist I am among those convinced that clinical scientists are and will still be the leaders of tomorrow's medicine; therefore, their preparation and training is of utmost importance. It is essential that clinical scientists spend 4 to 6 years in specialized biomedical research training in first-rate laboratories. I believe that they should acquire a PhD degree and receive training in the clinical specialty of their research field; this should enable them to obtain either a certification of clinical competence or a fellowship in the appropriate college. In a presidential address to the members of the Association of American Physicians in 1982 John Oates showed that "not more than 12% of the clinical investigators with less than 2 years' training were successful in obtaining research grants from the NIH."'4 During and after training it is relatively important for clinical scientists to spend from 5% to a maximum of 20% of their time on clinical work in their specialty. One cannot but have the greatest admiration for the Howard Hughes Foundation Program, directed by George Cahill, which encourages the training of selected second-year medical students in NIH research laboratories for 1 year. The aim is to acquaint medical students with modern research and to prepare more young physicians for such a career. In its first year of operation in 1964 the Medical Research Council (MRC) of Quebec had proposed a similar
program for undergraduate students in medicine, dentistry and pharmacy, so great was the need to train clinical scientists. Such a program was an important recommendation of the Vannevar Bush 1945 report to the president of the United States on postwar scientific research."5 The Quebec MRC met with failure, probably because of the lack of "environmental" stimuli in the appropriate milieu. Medicine has become "disconnected" as a result of the deep dissociation between the clinical care of the patient and the importance of molecular biology and genetics in clinical research. Unfortunately, this derives from (a) the lack of elementary knowledge of molecular biology by medical practitioners and even academic clinicians, (b) the esoteric language used by molecular biologists, who have so many subdialects and acronyms that it makes communication difficult with those who take care of patients, and (c) the deficient training or lack of interest of molecular biologists in human biology. This is currently a major problem confronting medicine. At the Montreal institute one solution was the proposal made by Dr. Michel Chretien to establish a weekly 2-hour course in molecular biology; this has been ongoing successfully since 1970. Physiopathology, which should be the bridge between the "molecular" bench and the clinical bed, has almost become extinct. Therefore, it is not surprising that practitioners and academic physicians over 45 years of age have difficulty in following presentations by molecular biologists. Unless clinical investigators continue to ask the basic questions about the pathophysiology of diseased organs and systems, molecular biologists will eventually have little idea of what to study and what to do with their findings. Without solid training in molecular biology modern clinical scientists cannot achieve progress, especially in relation to recombinant DNA, sequencing of nucleotides and proteins, gene cloning and monoclonal antibodies. As exemplified by its success at my institute, the laboratory teamwork of a basic scientist (PhD) and a clinical scientist (MD) can be extremely productive, provided that there is a high degree of compatibility in the "chemistry" between them. Such an association gives broader views and a closer integration with the patients' problems. Clinical scientists help to contribute to the clinical environment and to the teaching of research and provide a critical sense in the assessment of phenomena and findings. Such scientists should not succumb to short-sighted pressures from politicians, bureaucrats and social scientists to conduct research "for immediate social relevance". In addition, they should resist orienting research projects toward the priorities of groups or councils, which has led to the strong and widely held viewpoint that they "were
doomed to produce a mediocre work compared with the spontaneous and motivated work of individuals". I
The difficulties in establishing priorities are due mainly to the scarcity of scientists who have a broad view of the aspects of biologic research, including molecular biology, biochemistry, physical chemistry, sociology and psychology. Too many set priorities according to their own immediate interests. In conclusion, clinical research, as conceived in the last half century, is at a crossroads because of the phenomenal growth of molecular biology. Clinical research must be redefined in relation to molecular biology, genetic engineering and the care of patients and to prevent the gap in understanding and exchange between molecular biologists and clinicians. A more efficient organization of clinical research is necessary. I thank Drs. Alvan Feinstein and Peter Woodford for their valuable comments and criticisms.
References 1. Booth CC: Medical science and technology at the Royal Postgraduate Medical School: the first 50 years. Br Med J 1985; 291: 1771-1779 2. Research Profiles, Rockefeller, New York, 1987 3. Walsh J: The Rockefeller University: 2. Designs on behavioral biology. Science 1965; 150.: 1794 4. Richards AN: Scientist and man. Ann Intern Med 1969; 8 (suppl): 1-89 5. Welch WH: On receiving the Kober Medal, 1927. In McGehee Harvey A: The Association of American Physicians, 1886-1986 - a Century of Progress in Medical Science, Waverly Pr, Baltimore, Md, 1986: 245 6. McGehee Harvey A: Science at the Bedside, Johns Hopkinsg, Baltimore, Md, 1981: 94-95 7. Cole R: Retirement address, 1938. In McCarty M: The University Clinical Research Center. Rockefeller Univ Rev 1968; Mar-Apr: 14-15 8. Skyler JS: Walter Kempner. A biographical note. Arch Intern Med 1974; 133: 752-755 9. Abraham EP: The beta-lactam antibiotics. Sci Am 1981; 244: 76-86 10. Genest J: Modern concept of the organization of clinical research. Clin Invest Med 1986; 9: 256-260 11. Hollenberg CH, Siminovitch L: Importance of national centres of research to Canadian health care and medical science. Can MedAssoc J 1986; 135: 195-196 12. Friesen HG: The impact of the National Institutes of Health on the development of Canadian biomedical research. Clin Invest Med 1988; 11: 310-314 13. Genest J, Cantin M: The atrial natriuretic factor: its physiology and biochemistry. Rev Physiol Biochem Pharmacol 1988; 110:1-145 14. Oates J: Clinical investigation: a pathway to discovery [presidential address]. In Proceedings of the 85th Meeting of the Association ofAmerican Physicians, vol 95, 1982: 78-90 15. Bush V: Science, the Endless Frontier: a Report to the President on a Program for Postwar Scientific Research, US Govt Printing Office, Washington, 1945: 53 16. Illsley R: Priorities, social constraints and conflicting direction in research. In Kendrew J, Shelley JH (eds): Priorities in Research, Excerpta Medica, Amsterdam, 1983: 71 CAN MED ASSOC J 1990; 143 (5)
387
Clinical research Jacques Genest, CC, MD, MACP, FRCP, DSc (Hon) C linical research is a variant of the pursuit of truth, of the desire of man to explore the unknown and to uncover the laws that control life, nature and the universe. It is restricted to the study of human health and the mechanisms, cure and prevention of disease. Its basis is essentially the scientific method of weighing the evidence provided by physical or chemical investigations and by accurate instrumentation to measure what is observed, to hypothesize and to experiment. Clinical research is a part of the continuum of biomedical research (Fig. 1). In most cases the study of biologic functions and disease must be carried out in a university hospital, which provides the optimal conditions (e.g., in terms of dietary controls, research assistant nurses, laboratories, ease of consultation with other experts). Clinical research may involve metabolic studies, studies of the clinical effects of drugs and behavioural research and may be fundamental at the molecular and cellular levels, provided the questions are directly related to hu-
mans, healthy or not. In addition, it requires close, repeated observation and, most important, original thinking and imagination. As with fundamental research clinical research demands the intellectual disciplines of objective observation, clear thinking, precise expression, intellectual integrity and critical sense. To a great extent clinical research depends on advances made in fundamental research for new basic methods and instrumentation. The same physical and chemical investigations are used to measure observed phenomena in the two types of research. Both types of research can involve animal experimentation if necessary. The questions asked in clinical research can be at three levels: (a) molecular and cellular, (b) tissues, organs and systems and (c) the whole person. For the latter the research may be epidemiologic, evaluative and operational (Fig. 1), but the means of investigation must consist mostly of social, economic and statistical measurements. A "research" qualification has a certain aura of prestige for the media and the public; Biomedical research
Objective
Instrumentation
Fundamental
Clinical
Epidemiologic
Operational
Evaluative
To understand isolated basic phenomena at the molecular and cellular levels
To understand function and disease in humans
To understand factors involved in diseases in populations
To determine better use and distribution of health care
To compare efficacy of various diagnostic and therapeutic procedures
resources
Detection of phenomena
Social, economic and
and measurement by physical or chemical means
statistical observations and measurements
Fig. 1: Objectives and instrumentation of biomedical research - a continuum. Dr. Genest is professor of medicine at the University ofMontreal, consultant to the Clinical Research Institute of Montreal and professor of Dr. Genest is professor of medicine at the University of Montreal, consultant to the Clinical Research Institute of Montreal and professor of experimental medicine at McGill University.
Reprint requests to: Dr. Jacques Genest, Clinical Research Institute of Montreal, 110 Pine Ave. W, Montreal, PQ H2W JR 7 CAN MED ASSOC J 1990; 143 (5)
383
antigtaImle
serhn"esl
eoe
anything that implies "searching" easily becomes created in Britain, mainly under the influence of Sir research.
History Before 1920 government and private agencies did not organize or support clinical research. It was strictly the fruit of individual efforts of such famous men as Bernard, Laennec, Louis and Pasteur in France, Addison, Bright, Hodgkin, Parkinson and Sydenham in Britain, and Ehrlich, Koch, Muller, Virchow and Volhard in Germany. Until the middle of the 19th century medical research was descriptive and correlative - the clinicopathologic method. It became experimental with the use of animals, mostly by Claude Bernard in the latter part of the 19th century. Clinical research as we know it today is one of the outstanding US contributions to the world and to the understanding of the mechanisms and prevention of disease. In the last 50 years clinical research has expanded phenomenally and in many directions: hormones, electrolytes, metabolic and physiologic studies, clinical pharmacology of new drugs, molecular biology, recombinant DNA and genetic engineering. Early in the 20th century eminent US physicians, including Cole, Flexner, Osler and Welch, introduced the concept of full-time chiefs of clinical departments and clinical investigators. Clinical research laboratories were established in the clinical departments of teaching hospitals so that the basic disciplines could be integrated with clinical teaching and the care of patients. At this time the great philanthropic foundations, such as the Rockefeller Foundation, and later the expanded National Institutes of Health (NIH) played a major role in the extraordinarily rapid growth of clinical research in the United States. Another major contribution was the creation of several medical associations, which provided a forum for the exchange of ideas and research contributions and for active discussion and collaboration. These included the American Clinical and Climatological Association, founded in 1884, the Association of American Physicians, in 1885, the Interurban Clinical Club, in 1905, the American Society for Clinical Investigation, in 1909, the Peripatetic Club, in 1933, and the American Federation for Clinical Research, in 1940. The creation of research laboratories in the clinical departments of university hospitals permitted a close link between the care of patients and biomedical research and the rapid communication of research results to those in charge of patient care. In addition, the laboratories provided a scientific environment in which to study the whys and hows of disease. This system was greatly superior to the one 384
CAN MED ASSOC J 1990; 143 (5)
Thomas Lewis, in which clinical research units with 6 to 10 beds in university hospitals had no direct contact with the clinician-practitioners, the students or the registrar staff. Those units were headed by one investigator, whose interests determined the research. The successive leaders of the Royal Postgraduate Medical School (Sir Francis Fraser, Sir John McMichael and Sir Christopher Booth) noticed the weaknesses of the British system and provided an organization at Hammersmith Hospital very similar to that at university hospitals in the United States. ' The growth and importance of clinical research in the United States can be measured by the spectacular increases in the budget of the NIH ($7.2 billion in 1988). Also spectacular is the $8.2 billion allocated in 1990 for research and development by the main US pharmaceutical corporations, several of which spend 8% to 15% of their sales revenue ($300 to $850 million per year) on research into new and more effective drugs (unpublished data). During my 1937 and 1938 sojourns at Harvard University and my postgraduate studies from 1945 to 1951 at Johns Hopkins University and the Rockefeller Institute one theme was recurrent in the high circles of medical education and research in the great US institutions. It reflected the advice given by Anton Dohrn, of the Naples Zoological Society, to Simon Flexner, who was visiting research institutes before becoming the first director of the Rockefeller Institute, in 1902: "Give them [the research workers] perfect freedom, let them search where and how they will, help in every way you can, but do not pretend to be the master of them."2 Detlev Bronk simplified it when he was president of the Rockefeller Institute: "Find the right man, back him up, stay out of the way!"3 Alfred Newton Richards, one of the leaders in US medicine, said it similarly: "The unit of scientific advance - in medicine as well as in the natural sciences - is a human individual endowed with curiosity and eagerness to satisfy it, who can identify unanswered questions, and imagine ways of answering them. It is the prime business of such an institution as ours [University of Pennsylvania Medical School] to select such individuals."4 Medical research in the United States attracted many such men; all had a true dedication to research and the motivation to serve the common good. Upon receiving the Kober Medal in 1927 Welch repeated the advice he had given to young research fellows throughout his career. Allow nothing to divert you from your professional and scientific work. While maintaining a spirit of cooperation, resist the call to give general addresses, especially at a distance from home, to serve on committees, to assume time-consuming administrative duties, and to show visi-
tors around laboratories, clinics and buildings.... If you have found your problem, it should absorb you and its successful pursuit should make you the happiest of mortals in the consciousness of adding something to the body of ordered knowledge.... Strive for and be content with a scientific reputation based on the judgment of the best workers in your field.... Such reputations are enduring.5
There were difficulties and many confrontation-s between clinical scientists and their colleagues in the basic sciences who were trained between 1880 and 1910 in European laboratories, mainly in Germany. Clinician-scientists were restricted at the bedside to observe patients and follow up the natural history of the disease; they did not have access to laboratories and animal experimentation. Such a confrontation occurred in the early years of the Rockefeller Institute; Flexner supported research but only as long as the physicians practised at the bedside and not in the experimental laboratories. In 1911 Cole, as director of the Rockefeller Institute Hospital, reacted in a letter to the trustees: "Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in Rockefeller Institute Hospital, every man who was caring for patients should also be engaged in more fundamental studies."6 Upon his retirement, in 1938, Cole said: "No restriction has ever been placed on the nature of the investigations or methods to be employed: they could be as fundamental as the training of the man permitted, but it has always been felt that workers in hospitals should have in the backs of their minds the relief of suffering and the cure of disease."7 The factors responsible for the remarkable progress of clinical research in the last 30 years were (a) the availability of micromethods of measuring biologic components, (b) the rapid progress in electronics, microprocessors, computers and noninvasive techniques, (c) the availability of radioactive and stable isotopes and (d) the advent of vascular catheterization and tissue biopsy. Discoveries are most often the result of wellplanned experiments and critical observations. But they can also come from intuition or by chance; Kempner's rice diet is one such example. In 1942, a farmer's widow with chronic glomerulonephritis and papilledema, patient of Dr. Kempner, was confused by Kempner's German accent. On discharge from the hospital, she understood that she was to eat rice and to return in two months. After that period, she returned with dramatic reduction of her blood pressure and disappearance of retinal hemorrhages and papilledema and a significant decrease in heart size. This was the beginning of the rice diet.8
Another example is the discovery of penicillin.
Fleming had shown in ;1929 that cultures of staphylococci were dissolved when they grew near the fungus Penicillium notatum. He [Fleming] had no conception of the magnitude of his discovery.... He wrote in 1940 that it did not seem worth the trouble of making it. His main interest in the penicillin appeared to be in its selective antibacterial action which facilitated the isolation of certain organisms from mixed cultures. It clearly never occurred to him that penicillin might be introduced in the blood stream to cure infections; hence, for more than 10 years after his initial observation, penicillin remained little more than a curiosity.9
Modern organization of clinical research In the summer of 1948 and during 1951-52 I had the unique opportunity, on behalf of the Quebec government and with the help of Dr. Rolf Struthers, of the Rockefeller Foundation, and Mr. L. FarrerBrown, secretary of the Nuffield Foundation in Britain, to visit most of the leading clinical and medical research centres in the United States, Britain, France, Germany, Switzerland, Holland, Denmark and Sweden. From these visits it was clear that clinical research laboratories were scattered, depending on the local needs and possibilities, on the various floors and wings of the university hospitals. This resulted in poor communication and coordination between the clinical researchers and needless duplication of expensive instrumentation. Progressively from these visits and the many discussions I had with leaders in medicine and biomedical research the concept of concentrating clinical research in one geographic area with well-defined characteristics began to form as an answer to the somewhat chaotic, although phenomenal, growth of clinical research in teaching hospitals.'0 The thoughts that led us in the early 1960s to the creation of the Clinical Research Institute of Montreal were that (a) such institutes could be integrated either as a separate building or wing attached to a university hospital or as an autonomous organization affiliated with such a hospital or a university, depending on local factors, (b) the basic and full-time clinical scientists should be concentrated in one geographic area, (c) the administration should be separate from that of the university or the teaching hospital and be under the authority of a scientific director, as found at the Rockefeller Institute (now Rockefeller University), (d) extensive auxiliary facilities should be available (e.g., shared high-cost equipment, audiovisual department, specialized library, and common animal and meeting rooms), (e) each researcher should be obliged to obtain grants for projects from public or private agencies that have referees and a peer review system, CAN MED ASSOC J 1990; 143 (5)
385
(f) there should be access to patients in the clinical services or outpatient departments by joint hospital appointments and (g) researchers should supervise graduate students for MSc and PhD degrees and research fellows and participate in teaching medical students, interns and residents. Such a concept of a clinical research institute was supported by Hollenberg and Siminovitch," who wrote in 1986 that it was generally realized that our medical schools and most of our teaching hospitals are "no longer adequate to meet all of the technologic and interdisciplinary demands of contemporary medical research" and that "many of the important medical research problems of our time, including most of those bearing directly on human disease, can only be approached . . . by mobilizing the efforts of relatively large groups of scientists with differing scientific backgrounds and by providing these groups with necessary and often high-cost technology. Such concentrations of talent and equipment are beyond the present capacities of Canadian universities." In 1988 Friesen,'2 one of the most able biomedical researchers in Canada, wrote: "Advances in understanding human biology and its derangements by disease depend on the exercise of the talents of individuals trained in a wide variety of disciplines. Their work must span the spectrum from the basic research on the molecular mechanisms of life to epidemiological research involving populations, from research on fundamental phenomena to study of specific applications." This concept of the organization of modem clinical research is now accepted in many parts of the world. The success of the Clinical Research Institute of Montreal, which was founded on the basis of this concept, is also due to an effective three-tier evaluation system. First, the head of each laboratory must finance research projects by grants obtained from peer-reviewed private or public agencies. Second, the institute holds an annual 2-day "retreat" in a country hotel to allow the researchers to discuss current projects and future plans. Two external referees from Europe, Canada or the United States participate at the retreats, and each presents a general evaluation directly to the Board of Trustees. Third, every 5 years international experts are invited to spend 4 days at the institute to evaluate thoroughly the scientific productivity of the researchers and the policies and administrative organization of the institute. Visitors have included top scientists such as J. Edward Rall, Albert Renold, Louis Siminovitch, Sir Christopher Booth, Henry Friesen and Gordon Dixon. One of the best examples of the success of the concept of multidisciplinary and pluridisciplinary research concentrated in one geographic area has been the work done at the Montreal institute on 386
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atrial natriuretic factor (ANF). The research covered almost all aspects: the isolation and the elucidation of the amino acid sequence of ANF, the cloning of its gene and its chromosomal localization, the biosynthesis of analogues, the distribution of ANF in extra-atrial tissue, the isolation and characterization of ANF receptors, the mode of action of ANF, mediated through cyclic guanosine monophosphate, the physiologic effects of ANF on aldosterone and vasopressin and the physiopathologic features of ANF in human hypertension and congestive heart failure."3 This work covered the spectrum from molecular biology to patients, and all contributions by the various collaborating laboratories were accomplished in house because of the concept of research organization at the institute. This work was recognized by the American Heart Association, which gave its 1988 Distinguished Research Award concurrently to the institute's Hypertension Research Group and to Needleman's group in St. Louis. The importance of good research administrators cannot be stressed enough: "Progress in medicine has always depended not only on medical scientists but also on those who create the conditions under which their creativity and originality can flourish."12
The clinical scientist I am among those convinced that clinical scientists are and will still be the leaders of tomorrow's medicine; therefore, their preparation and training is of utmost importance. It is essential that clinical scientists spend 4 to 6 years in specialized biomedical research training in first-rate laboratories. I believe that they should acquire a PhD degree and receive training in the clinical specialty of their research field; this should enable them to obtain either a certification of clinical competence or a fellowship in the appropriate college. In a presidential address to the members of the Association of American Physicians in 1982 John Oates showed that "not more than 12% of the clinical investigators with less than 2 years' training were successful in obtaining research grants from the NIH."'4 During and after training it is relatively important for clinical scientists to spend from 5% to a maximum of 20% of their time on clinical work in their specialty. One cannot but have the greatest admiration for the Howard Hughes Foundation Program, directed by George Cahill, which encourages the training of selected second-year medical students in NIH research laboratories for 1 year. The aim is to acquaint medical students with modern research and to prepare more young physicians for such a career. In its first year of operation in 1964 the Medical Research Council (MRC) of Quebec had proposed a similar
program for undergraduate students in medicine, dentistry and pharmacy, so great was the need to train clinical scientists. Such a program was an important recommendation of the Vannevar Bush 1945 report to the president of the United States on postwar scientific research."5 The Quebec MRC met with failure, probably because of the lack of "environmental" stimuli in the appropriate milieu. Medicine has become "disconnected" as a result of the deep dissociation between the clinical care of the patient and the importance of molecular biology and genetics in clinical research. Unfortunately, this derives from (a) the lack of elementary knowledge of molecular biology by medical practitioners and even academic clinicians, (b) the esoteric language used by molecular biologists, who have so many subdialects and acronyms that it makes communication difficult with those who take care of patients, and (c) the deficient training or lack of interest of molecular biologists in human biology. This is currently a major problem confronting medicine. At the Montreal institute one solution was the proposal made by Dr. Michel Chretien to establish a weekly 2-hour course in molecular biology; this has been ongoing successfully since 1970. Physiopathology, which should be the bridge between the "molecular" bench and the clinical bed, has almost become extinct. Therefore, it is not surprising that practitioners and academic physicians over 45 years of age have difficulty in following presentations by molecular biologists. Unless clinical investigators continue to ask the basic questions about the pathophysiology of diseased organs and systems, molecular biologists will eventually have little idea of what to study and what to do with their findings. Without solid training in molecular biology modern clinical scientists cannot achieve progress, especially in relation to recombinant DNA, sequencing of nucleotides and proteins, gene cloning and monoclonal antibodies. As exemplified by its success at my institute, the laboratory teamwork of a basic scientist (PhD) and a clinical scientist (MD) can be extremely productive, provided that there is a high degree of compatibility in the "chemistry" between them. Such an association gives broader views and a closer integration with the patients' problems. Clinical scientists help to contribute to the clinical environment and to the teaching of research and provide a critical sense in the assessment of phenomena and findings. Such scientists should not succumb to short-sighted pressures from politicians, bureaucrats and social scientists to conduct research "for immediate social relevance". In addition, they should resist orienting research projects toward the priorities of groups or councils, which has led to the strong and widely held viewpoint that they "were
doomed to produce a mediocre work compared with the spontaneous and motivated work of individuals". I
The difficulties in establishing priorities are due mainly to the scarcity of scientists who have a broad view of the aspects of biologic research, including molecular biology, biochemistry, physical chemistry, sociology and psychology. Too many set priorities according to their own immediate interests. In conclusion, clinical research, as conceived in the last half century, is at a crossroads because of the phenomenal growth of molecular biology. Clinical research must be redefined in relation to molecular biology, genetic engineering and the care of patients and to prevent the gap in understanding and exchange between molecular biologists and clinicians. A more efficient organization of clinical research is necessary. I thank Drs. Alvan Feinstein and Peter Woodford for their valuable comments and criticisms.
References 1. Booth CC: Medical science and technology at the Royal Postgraduate Medical School: the first 50 years. Br Med J 1985; 291: 1771-1779 2. Research Profiles, Rockefeller, New York, 1987 3. Walsh J: The Rockefeller University: 2. Designs on behavioral biology. Science 1965; 150.: 1794 4. Richards AN: Scientist and man. Ann Intern Med 1969; 8 (suppl): 1-89 5. Welch WH: On receiving the Kober Medal, 1927. In McGehee Harvey A: The Association of American Physicians, 1886-1986 - a Century of Progress in Medical Science, Waverly Pr, Baltimore, Md, 1986: 245 6. McGehee Harvey A: Science at the Bedside, Johns Hopkinsg, Baltimore, Md, 1981: 94-95 7. Cole R: Retirement address, 1938. In McCarty M: The University Clinical Research Center. Rockefeller Univ Rev 1968; Mar-Apr: 14-15 8. Skyler JS: Walter Kempner. A biographical note. Arch Intern Med 1974; 133: 752-755 9. Abraham EP: The beta-lactam antibiotics. Sci Am 1981; 244: 76-86 10. Genest J: Modern concept of the organization of clinical research. Clin Invest Med 1986; 9: 256-260 11. Hollenberg CH, Siminovitch L: Importance of national centres of research to Canadian health care and medical science. Can MedAssoc J 1986; 135: 195-196 12. Friesen HG: The impact of the National Institutes of Health on the development of Canadian biomedical research. Clin Invest Med 1988; 11: 310-314 13. Genest J, Cantin M: The atrial natriuretic factor: its physiology and biochemistry. Rev Physiol Biochem Pharmacol 1988; 110:1-145 14. Oates J: Clinical investigation: a pathway to discovery [presidential address]. In Proceedings of the 85th Meeting of the Association ofAmerican Physicians, vol 95, 1982: 78-90 15. Bush V: Science, the Endless Frontier: a Report to the President on a Program for Postwar Scientific Research, US Govt Printing Office, Washington, 1945: 53 16. Illsley R: Priorities, social constraints and conflicting direction in research. In Kendrew J, Shelley JH (eds): Priorities in Research, Excerpta Medica, Amsterdam, 1983: 71 CAN MED ASSOC J 1990; 143 (5)
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