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Pioneers in Dermatology and Venereology: an interview with Prof. Louis M.M. Dubertret

2020; Wiley; Volume: 34; Issue: 5 Linguagem: Inglês

10.1111/jdv.16413

1468-3083

Louis Dubertret,

Historical Medical Research and Treatments

Curriculum Vitae 1975: MD, Paris, France Since 1982: Professor of Dermatology 1979–1985: Coordinator of the French Psoralens Task Force (>150 international publications, 3 patents, Galien Award) 1987: Founder and Director of the ‘Laboratoire de Recherche Dermatologique’, Inserm U312, Paris 1989: Professor and Chairman, Department of Dermatology of Saint-Louis University Hospital, Paris 1990: EADV member 1991: President and Founder of the René Touraine Foundation for Dermatology, www.fondation-r-touraine.org 1987–2008: Responsible for four E.U. funded programs (1987, 1989, 1991, 2008) 1993: Founder and President of Centre Sabouraud for hairs and scalp diseases (>2000 outpatients/month) 1993–2012: Chair of the national DEA de Biologie et Pharmacologie Cutanée 1997: Founder and Director of Institute for Skin Research, Saint-Louis Hospital, Paris, France 1990–2000: Chairman of the board of directors, Institute Fournier for STD 2000: Founding member of the French Academy of Technologies, 2014 President of the ethical committee 2002: Vice President of the World Congress of Dermatology, Paris 2005: President of the French Psoriasis Task Force 2006: President of the board of European Dermatology Forum 2004–2007 & 2010–2013: President of the International Congresses on Psoriasis under the umbrella of the EADV Psoriasis Task Force 2007: President of Euroderm Excellence Publications -More than 450 international publications referenced in PubMed -H index 36. -More than 300 invitations to scientific meetings, abstracts, book chapters. -More than 200 interviews at the French national and international radios and televisions. 2019: Big Data: Questions éthiques; a multi expert opinion book 2006: Psoriasis: Consensus and Controversies, 2006; a multi expert opinion book 2004-2005-2008: Le Psoriasis: de la clinique au traitement, Med'Com, 2004, 159 p. (published in French, 2004; in English, 2005) 1995: Ozone, Sun, Cancer: molecular and cellular mechanisms, prevention, Inserm, 1995, 288 p. (Focus) 1993: Psoriasis, 1993 (published in French, English and Italian) 1993: La peau et le soleil, Hermann, 1993, 116 p. 1992: Cancers cutanés, Flammarion Médecine -Sciences, 1992, 583 p. (Encyclopédie des cancers) 1991: Thérapeutique Dermatologique, Flammarion Médecine - Sciences, 1991, 1288 p. (free online since 2001: www.therapeutique-dermatologique.org) 1975: L'homme et son Programme, Denoël, 1975 What brought you to Dermatology? My career was shaped by encounters with outstanding clinicians who trusted me. I started my career as an internist and I benefited from the advice and encouragement of the best French internist, Professor Fred Siguier. To become an internist, he advised me to do a 6-month dermatology residency with the best dermatology internist, Professor René Touraine. It was in his department that I saw the greatest number of systemic diseases and I became a dermatologist. Research developments The examination of the patients posed many questions and, although I did not have a PhD, Professor René Touraine trusted me when I suggested him, at the end of my residency, to create a research laboratory. I had to learn everything and it was the hematology laboratory directed by Professor Jean Rosa and Jeanine Breton-Gorius who welcomed and trusted me. What strategy to start? There were three choices; 1. It was important not to follow fashion but to develop new techniques which would allow us to see things that had not been seen until then. 2. It was better to avoid working on cell cultures in monolayers because it is a non-physiological situation leading therefore to non-predictive observations. 3. Neither would we work on animals if we were looking for results that can be transposed to humans. To better observe the skin On these bases, a very creative team was gradually formed and we developed methods of morphology allowing multiple observations on mini-biopsies of human skin. I had the pleasure of publishing the device making these techniques possible in the British Journal of Dermatology. It was, for example, possible to see in bullous pemphigoid, eosinophils spilling their lysosomal enzymes into the lamina lucida, to show that the desmosomes appeared and disappeared under the influence of a couple of proteases/antiproteases, to invent the technique of electronic immuno-microscopy used worldwide. The study of the Koebner phenomenon by successive biopsies allowed us to visualize an abnormal activation of proteases in the sub-corneal region long before the migration of neutrophils and lymphocytes. The living skin equivalent But we had to go further and, with the hope to obtain predictive results, reconstruct in the laboratory a living equivalent of human skin, dermis and epidermis, in order to work under physiological conditions. This was the occasion to work with Eugène Bell and the development of Organogenesis in Boston. All together we were able to observe the great difference between cell physiology in monolayer and in a matrix. We were the first to tan these skin equivalents. We have been able to show that psoriatic fibroblasts are capable of causing hyper-proliferation of normal keratinocytes and even a greater hyper-proliferation of psoriatic keratinocytes, all in the absence of inflammatory cells. We were the first to transplant in humans an organoid reconstructed in vitro: the skin, dermis and epidermis. These were on children with giant inoperable nevi. It took 100 days to build sheets of living skin equivalent from their own cells for each of them. The psoralen adventure Meetings have unpredictable results: As a young chief-resident, I was lucky enough to meet Raymond Latarjet, world-renowned photo-biologist. Here again, he trusted me and asked me to coordinate a transversal, multidisciplinary research of 8 laboratories, from synthetic chemistry, to photo-physical, photo-biology, photo-pharmacology and phototherapy around psoralens (150 international publications in 8 years). We synthesized a first molecule and then tested it in collaboration with Professor Mizuno's team in Japan. We identified its faults and were able to construct the theoretical identity card for the ideal molecule, which we were able to synthesize, study, test and patent. We earned, with the whole team, the Galien award given for the first time to a purely academic research team. In this line, we were the first to study the mutagenesis of a drug in human skin, the first to demonstrate the formation of singlet oxygen in the living human epidermis, the first to show that the infrared, every morning, induce in the living world a signal inducing a protection against the coming UV. It has been a very exciting teamwork. Teaching Throughout this work, I was struck by the lack of education/formations on normal skin physiology in the course of dermatology studies in France. To train myself I gave ten lessons during a year. Then, I had the chance to meet Professor Jacques Wepierre who had created the national diploma of skin pharmacology, the first step before PhD. I succeeded him and directed, for 19 years, the national course in skin biology and pharmacology where a whole team of teachers, academics and people from the cosmetic industry, collaborated to educate generations of researchers. Clinical developments During all these years of research and teaching, I have learned a lot from all my colleagues and collaborators. But the ones I learned the most from, were my patients. When you can cure, medical technology is enough. When you treat a chronic disease that can be alleviated but not cured, medical technology is not enough. I had invited patients to come to Saint-Louis Hospital to explain to young students the evolution of their relationship, throughout their lives, with their illness, with drugs and with doctors. The students discovered that not only did you have to learn to diagnose, to set up a treatment, but you also had to learn the patient. Since 2005 I had the chance to formalize and to teach through many conferences, including the Dohi Memorial Lecture on a care technique devoted for chronic diseases: the patient-based medicine. It is a four-stage technique: questioning, explanations, negotiation, shared choice. It was the source of my greatest joys and I continue to improve myself. This technique is necessary to properly treat a chronic illness. Everyone must learn it. Everyone practises it in their own way, through the doctor/patient dialogue: It is the art of treatment. Without it, medical science is a routine that will be quickly assumed by artificial intelligence. What was your greatest achievement in your professional life? I have had many happy events during my professional life and they were always granted through the friendship and trust: Succeeding in creating an INSERM research laboratory when I had no scientific training; transforming Saint-Louis Hospital, temple of dermatological botany, into a reference department for research and therapy in dermatology; edit, with the help of all my colleagues, the book Therapeutics in Dermatology and successfully put it on the web for free; create, with Pascal Reygagne, the Sabouraud Center for hair and scalp diseases (2000 consultants per month); build the Skin Research Institute at Saint-Louis Hospital (1200 square meters); being elected as a founding member of the French Academy of Technologies and lead its ethics committee. All of this was likely useful, but my greatest achievement, thanks to an international team of exceptional generosity, was the creation of the René Touraine Foundation: an international foundation for dermatology. It has reached adulthood and is now developing without me, thanks to the creativity and generosity of my successors. Its strategy: to develop dermatology care networks in order to improve patient care and develop clinical research, particularly in emerging countries. A major ethical concern: dealing with serious inequalities in access to care, inequalities which are further exacerbated by the development of very expensive medicines which are inaccessible to most of the patients who need them. (www.fondation-r-touraine.org) What was your greatest disappointment in your professional life? Disappointments are of course also frequent: failing to convince residents to ask questions during the visit! A young and brilliant associate professor telling me, after a discussion about the patient-based medicine: The only thing I ask my patients is to trust me! But, as always, the biggest disappointment comes from myself; when you go alone, you go faster, when you go as a team you go further and it is certain that I have often been too much in a hurry. Who would you list among the top ten dermatologists? Thanks to all my friends and to the development of the René Touraine Foundation, I have met many admirable dermatologists who put the quality of the cares they give long before the development of their own fortune. Throughout my scientific career, I have met many admirable dermatologists who have contributed, each in different fields, to decisive clinical and research developments in dermatology. I don't like scores: there is no substitute for dialogue to assess the severity of a disease or the quality of a dermatologist. I'm unable to name 10 of the best living or deceased dermatologists because that would exclude many others for no reason. What will be the greatest problem and breakthrough in Dermatology in the next ten years? The greatest progress and the greatest difficulties in dermatology in the next 10 years will be intimately linked. They will likely be the consequence of the very rapid advances in technology, in particular in the field of artificial intelligence. Dermatology is a botanical discipline, at clinical, histological, and molecular level. The images are particularly important for us, so it is a discipline particularly suited to the possibilities of diagnostic assistance offered by artificial intelligence. It is likely that the diagnostics business will be more and more performed by diagnostic algorithms. The danger lies in the fact that the results given by an algorithm must always be controlled by a human. This control requires a great deal of expertise. Expertise is something that is learned throughout life. We will therefore have on the one hand an artificial intelligence which will be able to almost completely relieve the doctor's memory and on the other hand the need for particularly experienced doctors. How will these doctors be trained? This illustrates the fact that, as soon as a technology helps man, man progressively loses the corresponding knowhow and risks finding himself in a position of being dependent on the tools he has built. On the therapeutic side, artificial intelligence will suggest therapeutic strategies based on published recommendations. The hierarchy of propositions will be based, and often already is, on levels of evidence. The hierarchy of levels of evidence does not consider the usefulness of a drug but only the quality of the methodology followed in clinical trials. This creates a hierarchy totally disconnected from the reality of the patient. On the other hand, the algorithms will easily consider the level of effectiveness of the drugs. The level of effectiveness is a statistical data and does not consider the essential element: the usefulness of a medicine. Usefulness is the ability to relieve a specific patient and, in particular, takes the price into consideration. For example, methotrexate is not the most effective drug for treating psoriasis but it is the most useful drug worldwide. Artificial intelligence will collect scientific data based on population analysis and the problem is to adapt data obtained from populations to a specific individual who is unique and different. It's the art of medicine that we've already talked about. We must therefore ensure that the use of artificial intelligence tools respects the art of treatment and the freedom to prescribe. This freedom is already endangered by the recommendations which, if not followed, can lead to heavy legal penalties. Many doctors no longer feel empowered to use their knowledge for practising a tailored medicine. The weight of insurance and legal risk greatly aggravates this phenomenon. We run the risk of developing therapeutic strategies which are secure from an administrative point of view but which are unsuitable for certain patients. I recently met a patient who had received as an answer to his questions: ‘This is the protocol’. Everything must be done so that medical progress does not lead to the disappearance of the patient as an individual. It would be very important for our dermatology societies to have an ethics committee. Note: The Pioneers in Dermatology and Venereology interview was conceived and conducted by Johannes Ring.