From public health to medical research, from INH to Inserm, 1941-2001
(M. Adamson, J.-F. Picard, 2003)
The origins of scientific medicine
At the beginning of the nineteenth century in France, the rise of the descriptive sciences, nosology and anatomical pathology gave birth, in the hospital, to scientific medicine. But if these disciplines lifted the clinical art to its greatest height, they included hardly any therapeutic applications. A few decades later, Claude Bernard with physiology and Louis Pasteur with microbiology brought medicine into the field of experimental science. The development of vaccines against rabies, diphtheria, and tetanus, of BCG, opened the way to preventive medicine. Thus the first labs dedicated to medical research arose more out of public health than out of the clinic. The turn of the twentieth century witnessed the creation of the Instituts Pasteur in Paris, Lille and overseas, or even the Office national d'hygiène sociale that was created in 1924 to direct the fight against tuberculosis. Louis Bugnard, director of the INH, later recalled, "Since for several centuries one had been concerned to improve the human condition, the discovery of germ theory, and the notion of contagion which resulted and which made immunization possible imposed on governments an increased responsibility in the field of health care. Therefore, national health services were created and developed in each country around the globe".
1941 - The birth of the Institut national d'hygiène (INH)
The great conflicts of the twentieth century proved propitious as far as concerns the development of medical research in public health. In occupied France, André Chevallier, a professor on the faculty of Marseilles, sent a note to his friend, Dr. Serge Huard, State Secretary for Health in the Vichy government. In his letter Chevallier explained: "The State Secretary for Family and Health will not be able to accomplish the technical task incumbent on him and thus assume the place deserving of a great technical minister having at his side an organization presenting all scientific certitude". Thus, thanks to the strong support of the Rockefeller Foundation, a law passed 30 November 1941 by Marshall Pétain created the INH, a public establishment. Put under the direction of Pr. André Chevallier, it was endowed with a dual mission : to carry out laboratory work related to public health, and to coordinate public health studies to be directed in a country conquered and occupied by the Germans.
The four divisions of the INH
* The 'Section des Maladies Sociales' was devoted to the study of tuberculosis, alcoholism and syphilis, as well as cancer. In 1942, Dr. Pierre Denoix assembled, from 35,000 case files provided in part by the Parisian welfare service, the first French survey of cancerous maladies.
* The 'Section de la Nutrition' dealt with child nutrition. Professor Chevallier, author of noted works concerning the amount of vitamins in the human diet, was reminded that here lies a crucial problem in a country subject to rationing, in addition to being one with the greatest observed demographic shortfall in the world
* The 'Section d'Hygiène' was charged principally with the problem of water supply and workplace health care.
* The 'Section d'Epidémiologie,' directed by a woman, Dr. Alice Lotte, published mortality statistics in the Recueil des Travaux de l'Institut National d'Hygiène.
1945 - modernizing medicine
As a leader of the Conseil médical de la Résistance, Pr. Robert Debré, an important clinician who directed the pediatrics service at the Hôspital des Enfants Malades of Paris, elaborated a plan - a plan destined to modernize French medicine - in which he expressed a two-fold concern : to carry out this indispensable effort in such a way as not to leave behind the clinic, while avoiding with the latter a socialization that might presage the creation of the French social security health service (October 1945). While he outfitted research laboratories in his 'Service des Enfants Malades' (directed by Georges Schapira), Professor Debré was named President of the INH in 1946, where he could supervise the launching of a Committe for Social Security Health Studies, an organ intended to fund public health research. Debré's other preoccupation was to find André Chevallier's successor at the head of the INH. His choice was Louis Bugnard, a doctor, polytechnicien, and professor of biophysics in Toulouse where ha had been a resistant during the war.
Training medical scientists
Louis Bugnard's first task was to assemble a body of medical researchers. While the INH was endowed with a Scientific Council, a new decree fixed the legal status of its researchers with that of their colleagues in the Centre National de la Recherche Scientifique (CNRS). A close formed between the two organizations. It was strengthened in 1950 when Bugnard was named president of the CNRS 'commission of experimental medicine'. The INH thus paid for a hundred personnel, including doctors who would leave a historical legacy : obstetrician Alexandre Minkowski, cancerologist Maurice Tubiana, Constant Burg or Philippe Laudat, these two to become later Inserm CEOs. Thanks to contacts with Anglo-Saxon research - notably through the Rockefeller and Ciba foundations - Bugnard established a system of grants that allowed him to send several young interns to the United States to complete their training, as well as enabling him to collect the precious technical means needed to modernize French medical research.
The first budgets ot the INH, a modest draw on the public coffers
In 1942, the initial budget of the INH was 15 million Francs. This annuity was raised to 21 MF in 1944 and 50 MF in 1947. At the time, this represented only a miniscule part of the overall budget for public research (13 billion F in 1948) compared to the one billion allocated to institutions like the CNRS, CEA or Institut Pasteur. In 1964, the INH budget reached 54 million new francs (one new franc = 100 old francs), following a spectacular augmentation in 1958. As far as concerns the number of personnel supported by the INH, from 100 agents in 1944, numbers rose to 200 by 1958 and in 1963, on the eve of the creation of Inserm, 700.
In the matter of research, Louis Bugnard vectored the INH towards medical physics. In close cooperation with the French Atomic Energy Commission (CEA), the INH developed and expanded the use of radioelements, the isotopic markers indispensable to cellular biology. On the therapeutic front, the INH participated in the installation of the first large-scale instruments for cancer treatment. One, a betatron, was installed in 1948 at Villejuif, while at the same time Bugnard organized training for those doctors using radioactive isotopes. The INH contributed as well to the development of a dosage system intended for workers in the nuclear industry and it took part in a study of atmospheric fall-out from American and Russian atomic explosions. The Institute became one of France's principal national correspondents with the World Health Organization (OMS), while it also encouraged the creation in 1956 of the SCPRI (Service for the Testing of Ionizing Radiation).
The meeting of medicine and biology
Restricted by its modest budget and also by the priority given to problems in medical physics, the INH found no way to respond to the new expectations of the clinic. At the conclusion of the war, a new generation of clinicians were concerned that medical research be included in the veritable revolution sweeping the life sciences. If until then issues of public health had acted as engines of medical progress, cellular physiology and then molecular biology, biochemistry, and indeed genetics seemed to open new, extraordinary perspectives in pathology and therapy. Thus, the neo-clinicians were more interested in cancer, nephritis, cardiovascular disease - then in infectious maladies which seemed close to being eradicated by the new antibiotics (sulfamides, penicillin, etc). In 1952, at the instigation of the neo-clinicians, the Parisian hospital admininistration (Assistance publique de Paris) created the 'Association Claude Bernard', an organization that would install their laboratories in hospitals - an enterprise soon taken over by the INH, then by Inserm.
Research Centers established by the Association Claude Bernard, the INH (to become Inserm units in 1964)
1950, by INH
CR on nutrition, Trémolières, the first research unit of Inserm (UR1)
1956-1959, by Association Claude Bernard and INH
CR for Nephrology, UR25, J. Hamburger at Necker
CR for Immunology. Dir: B. Halpern at hôp. Broussais hosp., UR20 (allergies and immunology)
CR for Leukemia and blood disorders at J. Bernard at Saint-Louis hosp.
CR for immuno-pathology and respiratory pathology at R. Kourilsky at Saint-Antoine hosp, UR23
CR for applied neuro-physiological medicine, J. Scherrer at Salpetrière hosp., UR3
CR for neo-natal biology, A. Minkowski at Cochin Port-Royal hosp., UR29
CR for biology (radioisotope research), R. Fauvert at Baujon hosp., UR24
CR for gerontology, Bourlière at Sainte Perrine hosp.
CR for experimental pharmaceutical research, Lechat at Les Cordeliers
CR for experimental surgery, Vaysse & Dubost at Broussais hosp.
CR for cardiology, Lenègre & Scébat at Boucicat hosp.
CR for cellular physiology as applied to radiology and cancer studies, Latarjet at Fondation Curie, U22
CR for pathological surgery, Mallet-Guy at Edouard Herriot hosp. (Lyon)
CR for tuberculosis, R. Debré at Limeil-Brévanne hosp.
Research unit for medical genetics, M. Lamy, Necker hosp., U12
1958 - a period of reform
With the return to power of General de Gaulle in 1958, the Fifth Republic gave new impulse to the modernization of the country.Initiated by Robert Debré and Jean Dausset, the ordinance of 30 December 1958 called for the fusion of clinical and medical faculties into Centre Hôspitalo-Universitaires (CHU).
Greatly increased (in 1959 to 400 MF, almost 170% greater than the year before) this research budget permitted the launching of plans of action (Actions concertées) that would boost new scientific fields. Among the first twelve 'Actions concertées', five dealt with medicine and biology: 'Neurophysiology and psycho-drug dynamics,' 'Nutrition', 'Applications of genetics,' 'Cancers and leukemias,' and 'Molecular biology.' This last was conferred to Jacques Monod, who would receive the 1965 Nobel prize along with his Institut Pasteur colleagues André Lwoff and François Jacob for their work on genetic regulation. Inspired by the American medical reformer Abraham Flexner, the `Debré reform' established a body of full-time hospital university professors (designated PU-PH) whose task, in theory, would be to ensure the triple function of care, instruction, and medical research. Between 1964 and 1967 the ordinance was finalized by a series of implementing decrees, one obliging each CHU to set aside square meters for research labs, another giving intern examinations the status of post-graduate study. Simultaneously, the Fifth Republic created the Délégation Générale à la Recherche Scientifique et Technique (DGRST), in practice if not in name a veritable ministry of research. This institution managed a budget equivalent to all other public research combined (enveloppe recherche).
1964 - the metamorphosis of the INH into Inserm
The transformation of the INH into the Institut National de la Santé et de la Recherche Médicale issued from these new policies. They were a product of the will of the Minister of Health to keep control of the organization charged with medical research, as well as the need to harmonize public health initiatives of the INH with those of the clinicians of the Association Claude Bernard. At the initiative of the Minister of Health, Raymond Marcellin, a 18 July 1964 decree created Inserm. Direction of the new organization was conferred to the former Director-General for Health in Ministère de la Santé, Dr. Eugène Aujaleu. Georges Mathé, councilor to the Minister of Health, played an essential role in this metamorphosis. Mathé, the founder of the Institute of Oncology and Immunology, symbolized the irresistible rise of the fundamental sciences within medical research. From this trend he came to conceive of the scientific organization of the new institute. Inserm was invited to reinsert in its scientific programs certain DGRST plans of action (100 million Francs were budget for this purpose under the auspices of the Fifth Plan, 1965-1970), while its new director launched a laboratory construction program (of which half were located in the provinces) thanks to a new system of registration with the Health Ministry that involved both university and regional hospital centers. At the same time, Inserm's Scientific Council created thirteen scientific departments, the arrangement of which demonstrated that, from then on, priority would go to biological research.
Inserm's scientific divisions (commissions scientifiques spécialisées) in 1964
CSS 1 Cellular and tissue pathology, cancer research, radio-pathology
CSS 2 Genetics, immunology, and molecular pathology
CSS 3 Microbiology, and infectious and parasitic pathology
CSS 4 Organic metabolism and hepatic and digestive pathology
CSS 5 Inorganic metabolism, physiology, and renal pathology
CSS 6 Physiology and cardio-vascular and respiratory pathology
CSS 7 Endocrinal physiology and pathology
CSS 8 Neurology, neuro-physiology, psychology and psychiatry
CSS 9 Pharmacology and therapy
CSS 10 Experimental surgery
CSS 11 Environmental hygene
CSS 12 Diet and nutrition, laboratory project for food additives, at Vésinet
CSS 13 Epidemiology and preventive medicine
The 70s - Pushed by the molecular biology wave, the immunology takes off
During the 1970s, under the auspices of its new directors, Prs. Constant Burg and Philippe Laudat as well as its president, Pr. Jean Bernard Inserm became a central actor in French medical research. Stemming from developments in molecular biology, the work of Pr. Etienne-Emile Baulieu on the chemistry of steroids led to the invention of the anti-progesterone RU-486 (the morning-after pill). Immunology also witnessed remarkable developments. The term `immune system' entered the Institute's scientific nomenclature (CSS 3), while new teams entered the field. At the Hôspital Necker, Jean-François Bach succeeded Jean Hamburger as director of U 25 (Auto-immune diseases, genetics, mechanisms, and treatments). The Hayem Center at the Hôpital Saint-Louis expanded in order to create within it the laboratories of Maxime Seligman (U 108, Immuno-chemistry and immuno-pathology) and of Jean Dausset (U 93, Transplant immuno-genetics) where work that led to the development of the Human Antigene was undertaken (the discovery of the HLA system merited the 1980 Nobel Prize for Medicine). Work in this latter lab also included applied research on organ transplant (France transplant). In addition, Pr. Jean-Paul Lévy created U 152 (Immunology and oncology for retroviral diseases) which became the nucleus of the future Institut Cochin for Molecular Genetics (ICGM), Axel Kahn. There remained the question of developing centers of excellence in the provinces. In Strasbourg, Inserm helped the Research Center for the Biochemistry of cancerous Cells become the Institute for Cellular and Molecular Biology and Genetics (IBGCM). Finally, following a move symbolic of the politics of decentralization extoled by the powers-that-be, Inserm conferred to François Kourilsky the task of setting up the Insitute of Marseille-Luminy, a scientific campus created in cooperation with CNRS as a center for 'Integrated immunology.' That is to say, it was intended as much for the study of immune system response as for developing genetic markers. Opening the door to the era of biotechnology, the discovery of the first monoclonal antibodies encouraged the teams in Marseilles to develop Inserm's first industrial subsidiary, Immunotech.
today directed by Pr.
At the beginning of the 1970s, Inserm, inspired by the CNRS, adopted new measures of scientific planning: `Thematic Plans of Action' (ATP) later re-baptized `Coordinated Research Programs (PRC). Inserm's first 'thematic plans of action' concerned not only advanced areas like immunology, but other domains where french medical research suffered some backwardness, such as in drug dynamics. Following an agreement reached in 1974 between the French and American governments and according to the same logic of scientific planning, Inserm became a French partner of the US National Cancer Program launched by pdt. Nixon a few years earlier.
Inserm's first Thematic Plans of Action
- Clinical pharmacology
- Cellular interactions
- Behavioral biology
- Immunopathology of the nervous system
- Epidemiology and mechanisms of premature birth, of fetal suffrance and malformities
- Physio-pathological action of long-chain fatty acids on the myocardium (particularly the human myocardium)
- Aging mechanisms
- Bronchial-pulmonary pathology and pollution (excluding tobacco and silicosis); Effects of hormones on the digestive tract
- Immuno-pathology of glomerulonephritis
- Circulatory physio-pathology
- Neo-antigens of experimental and human cancers
- Alcohol: pharmacological aspects and psycho-sociological impact
- Direct and indirect impact of water, considered as a biological factor, on human life
1984 - Inserm becomes a Public scientific and technological establishment (EPST)
Philippe Lazar, named Inserm's director in 1982, organized the 'Assises de la recherche', a general meeting of French scientists intended for a collective reflection initiated by the new Minister of Research, Jean-Pierre Chevènement. Here one contemplated the means to insure the freedom of fundamental research in the spirit of rendering significant public service. Leaving the supervision of the Ministry of Health for that of Research, Inserm became a Public Scientific and Technological Establishment (EPST) as other French public agencies (CNRS, INRA, IRD, etc.) . Philippe Lazar, a polytechnicien trained by Daniel Schwartz in the school of statistical epidemiology, re-organized the Institute and created for it a Council for Scientific Direction (CODIS). Researchers were now included in the statute serving fonctionnaires (by the decree of 28 December 1984), thus leading to a significant recruitment of non-medical researchers - in fact, three-fourths of recruits during this period. Finally, Inserm's administration was decentralized by a 1983 decree that instituted Regional Delegating Administrations.
|Inserm in the 1980s, a spectacular expansion
When it commemorated its first twenty years of activity, the Inserm could boast its spectacular expansion : by 1984, its workforce, like the number of research units, had multiplied four-fold (1000 employees and 50 units in 1964, 4000 employees and more than 200 URs in 1984), while its budget tripled, increasing from approximately 50 MF to nearly a billion and a half Francs. In 1994, ten years later, Inserm's workforce had again grown by another thousand employees and its budget had topped 2.5 billion Francs.
Enlarging the scope of human sciences
Opening Inserm to fundamental research permitted it to tackle all of the human sciences considered in their widest sense, from the most reductionist of approaches (man as an ensemble of nerves) to the most holistic (man as a social being). The pasteurien Jean-Pierre Changeux, named president of the scientific council in 1983, supported the development of the neurosciences whereas Philippe Lazar, anxious to enlarge epidemiological pursuits to the level of dilemmas involving broader society, decided to introduce to Inserm the human and social sciences. Nevertheless, the choice to privilege research freedom over planning drove Inserm to envision cooperation with other organizations created to deal with the evolving scientific circumstances. Thus, in 1987, the resurgence of infectious diseases pushed the French administration to create the National Agency for AIDS Research (ANRS) with pr. J P Levy at the head and the 'Institut national de veille sanitaire' under the supervision of the Ministry of Health, while medical genome studies evolved first into the Center for the Study of Human Polymorphism (CEPH), a private foundation settled by Professor Jean Dausset, and then 'Généthon' a network of laboratories settled in 1991 by the French Association against Myopathy (AFM).
The 90s - Return to the 'Clinic'
The 1990s marked a return to the clinic, as Inserm addressed the latest clinical concerns. Predictive medicine produced advances in fundamental research that might involve questions of public health as well as medical practice. This movement gained its impulse from the Ministry of Health, which launched a 'Hospital Program for Clinical Research (PHRC). Simultaneously, Inserm elaborated a plan for 'federated research institutes' (IFR) destined to re-organize the laboratories installed in the CHU and the CHR around a new joint scientific strategy at a new unceasingly more complex technical level. This return of the clinicians was embodied by the nomination of two professors from the Hôpital Necker to direct Inserm - Claude Griscelli in 1996 and Christian Bréchot in 2001. In fact, the nature of medical research had profoundly changed since the beginning of the Institute in the 1960s. Henceforth, it covered therapeutic trials as well as investigation genetic therapies. Thus, Inserm generalized the mechanism of 'Center for clinical investigations' (CIC) envisaged by Professor Pierre Corvol, in the same time the Institute supported research on gene therapy, such of U 429, the `Normal and pathological development of the immune system' of Pr. Alain Fischer. In truth, this research, sometimes qualified as `clinical,' often no longer differed from high-level fundamental research - if such a fact only further confirmed its effectiveness. In regard to problems of public health, from then on identified with the smooth functioning of developed societies, they saw the social sciences put to the difficult task of optimizing medical practice in order to render the most effective service at the least cost.