IRCM Researchers

LEADERSHIP POSITIONS

• 1998–2001    Scientific Director and CEO, Loeb Health Research Institute, Ottawa
• 1984–1994    Scientific Director and CEO, Montreal Clinical Research Institute 
• 1978–1984    Head of Endocrinology, Hôtel-Dieu de Montréal, Montreal

RESEARCH POSITIONS

• 2012    Director, Functional Endoproteolysis Laboratory, Montreal Clinical Research Institute
• 1998–2012    Director, Diseases of Aging Unit, Ottawa Hospital Research Institute (OHRI), Ottawa
• 1967–1999    Director, Molecular Neuroendocrinology Laboratory, Montreal Clinical Research Institute

ACADEMIC POSITIONS

• 2014    Physician, Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM)
• 2012    Emeritus Research Professor, Montreal Clinical Research Institute (IRCM)
• 2008    Emeritus Researcher, Ottawa Hospital Research Institute (OHRI)
• 2008–2012    Founder and Scientific Director, Foundation on Antivirals (FAV)
• 2006–2008    Senior Researcher, Hormone, Growth & Development, Ottawa Hospital Research Institute (OHRI)
• 2005    Senior Member and Co-Founder, Ottawa Institute of Systems Biology (OISB)
• 2004    Co-Founder and Board Member, International Consortium on Anti-Virals (ICAV)
• 2002    Emeritus Professor, Université de Montréal
• 2002–2017    Full Professor, Department of Biochemistry, Microbiology and Immunology, University of Ottawa
• 2002–2012    Member of the Faculty of Graduate and Postdoctoral Studies, University of Ottawa
• 1998–2017    Full Professor, Department of Medicine, Faculty of Medicine, University of Ottawa
• 1998–2012    Member, Department of Endocrinology, The Ottawa Hospital
• 1996–1999    Associate Member, Department of Medicine, Montreal Heart Institute (MHI)
• 1994–1998    EJLB Chair, Montreal Clinical Research Institute (IRCM)
• 1975–1999    Full Professor of Medicine, Faculty of Medicine, Université de Montréal
• 1970–1999    Assistant Professor, Faculty of Medicine, McGill University, Montreal
• 1969–1999    Associate Member, “Experimental Medicine,” Faculty of Medicine, McGill University
• 1967–1999    Physician, Department of Endocrinology, Hôtel-Dieu de Montréal

Graduated in medicine (U. Montreal, 1960) and in experimental medicine (MSc, U. McGill, 1962), Michel Chrétien specialized in clinical research with J. Genest (U. Montreal, 1960-62), in endocrinology with G. Cahill & G. Thorn (U. Harvard, 1962-64); in protein chemistry with C.H. Li (UC. Berkeley, 1964-67), and in neuroendocri-nology with R. Guillemin & L. Iversen (Salk Institute/U. Cambridge, 1979-80) (1).

I. THE PROHORMONE THEORY AND THE DISCOVERY OF β-ENDORPHIN.

Endocrinologist Michel Chrétien chose to study the chemistry of pituitary hormones by joining Dr. CH. Li at Berkeley (1964-67). While sequencing β-lipotropin (β-LPH_1-91), he discovered γ-LPH (β-LPH_1-58), the two-giving rise to β-MSH (β-LPH_-41-58) following an enzymatic cleavage located at pairs basic amino acids (Fig. 2) (2).

This is how, simultaneously with D.F. Steiner's discovery of proinsulin, a) the Pro-hormone Theory and b) the concept of "proprotein convertases" (PCs) were born, both of which would have revolutionary repercussions in biology and medicine (2-5).

Upon his return to the IRCM in 1967, he confirmed the validity of his theory (Fig. 3) (6-10), which led him to discover β-endorphin in 1976, which is the β-LPH_-61-91 fragment (Fig. 4) (11).

In 1977, he chemically demonstrated that β-endorphin does indeed originate from the enzymatic cleavage of β-LPH at basic sites (12).

Simultaneously, multiple observations, including his own, confirmed the existence of a long precursor containing both β-LPH and ACTH (AdrenoCorticoTropic Hormone), which was named pro-opiomelanocortin (POMC) (13).

Between 1976 and 1979, Michel Chrétien and his group (Crine, Benjannet, Seidah, Gianoulakis, and Boileau) described, with definitive chemical evidence, the endopro-teolytic cascade of POMC into β-endorphin, MSHs (melanocyte-stimulating hormones), and ACTH (Fig. 5) (13). POMC became the quintessential model for multi-hormonal precursors (4, 14).

II. PROPROTEIN CONVERTASES (PCs), also known as PROPROTEIN CONVERTASES SUBTILISIN/KEXIN-LIKE (PCSKs).

The race for PCs became frenzied among several laboratories (15). The IRCM team, comprising Chrétien, Seidah, Mbikay, Benjannet, Lazure, and Marcinkiewicz, was among them. In 1990, they and Steiner simultaneously discovered PC1 and PC2 (16-18).

This breakthrough attracted the attention of the journal Science, which wrote: “Their (PCs) discovery by Steiner and Chrétien groups is extremely fitting. Biologists will be greatly aided in their quest to understand brain function and the developmental pathway the embryo follows, two of the most fundamental mysteries,” Jean Marx, 1991 (19).
Shortly thereafter, Benjannet et al. (20) observed that PCI and PC2 act in tandem to mature POMC into its active fragments. Marcinkiewicz et al. definitively proved that PC1 and PC2 are linked to POMC by demonstrating the pituitary colocalization of POMC and its fragments with PC1 and PC2 (Fig. 6) (21, 22).

The period from 1990 to 2003 was very fruitful. Not only were nine PCs discovered, seven of them at the IRCM (23), but the number of precursors increased exponentially. Thus, the endoproteolytic cascade of prohormones by PCs became widespread and a fundamental cellular process that controls numerous biological functions (4, 24, 25).

Dr. Gary Thomas summarizes this breakthrough as follows: “Concurrent studies by Michel Chrétien and Choh Hao Li on the structural relationships between β-MSH, γ-LPH, and β-LPH, a subset of peptides derived from a complex pituitary prohormone, pro-opiomelanocortin (POMC), provided the first clues to the greater generality of proprotein processing (25).

The Prohormone Theory opens a new chapter in human biology and applies to several diseases (4). It revolutionizes neuroendocrinology and homeostases (Fig. 1).

III. THE PCSK9^Q152H MUTATION IN FRENCH CANADIANS

Due to its gain-of-function (GOF) mutations, PCSK9 is the third locus of familial hypercholesterolemia (FH) (26, 27). Even more impressive are the loss-of-function (LOF) mutations which lower plasma LDL-C. Thus, PCSK9 has led to revolutionary therapies for treating hypercholesterolemia (27).

Michel Chrétien discovered the hypocholesterolemic mutation PCSK9^Q152H (28) in a French-Canadian family (Fig. 7). Its main characteristics are:
- It is present in only two other families in Quebec (29) and nowhere else in the world.
- It is one of the most hypocholesterolemic mutations in Caucasians (4,29) (Fig. 8).
- Among the thirty-three carriers of the mutation, three are homozygous (Fig. 8) (4) and three of the heterozygotes are centenarians.
- Located at the Pro-PCSK9 cleavage site, it results in a new protein, proPCSK9^Q152H, which protects against heart disease and liver dysfunction (Fig. 9) (29).
- Finally, it is a prime target for gene therapy (30).

IV. DICITRISOIDES: TRITERPENE GLYCOSIDES AGAINST SARS-CoV-2 AND THE EBOLA VIRUS. (A DETOUR INTO VIROLOGY).

Based on the premise that cholesterol affects infectious diseases (31), including ma-laria, M. Mbikay demonstrates that LOF mutations of PCSK9 decrease infant mor-bidity and mortality caused by malaria (32,33). Simultaneously, he observes that isoquercetin (IQC) extracts decrease cholesterol and PCSK9.

Based on these two findings, the Chrétien/Mbikay duo, in collaboration with the Na-tional Microbiology Laboratory in Winnipeg, demonstrate that IQC is a potent antivi-ral against the Ebola virus (EB0V) and Zika virus (34,35). In 2020, they observed the same phenomenon against SARS-CoV-2, but this time with quercetin, the bioactive derivative of IQC (36).

Suspecting that the antiviral activity of IQC originated from contaminants rather than IQC itself, they discovered, in collaboration with Dr. Guido Pauli's group in Chicago, that the activity actually stemmed from two novel triterpene glycosides called dicitriosides (nDCTs) (Fig. 10)(37). These inhibit syncytia formation in specialized human HEK293 cells and prevent EBOV infection of Vero E6 monkey cells. Thus, these nDCTs are broad-spectrum antivirals with expanded therapeutic potential.

CONCLUSION

More than 50 years after its promulgation, the Prohormone Theory has become a major game changer in biology and medicine. Its importance is amplified by the potential existence of thousands of active substances derived from hundreds of pro-proteins cleaved by PCs (38). It is revolutionizing neuroendocrinology and leading to major clinical breakthroughs in diabetes, obesity, appetite-satiety, sleep, cholesterol, pain, and addiction (Fig. 1). The discovery of dicitriosides as a new antiviral is an important addition to the laboratory's portfolio.

DEGREES AND CERTIFICATIONS

• 1973    FRPC(C) Fellow of the Royal College of Physicians of Canada
• 1969    CSPQ (Endocrinology) Collège des médecins du Québec
• 1962    M.Sc. (Experimental Medicine) Faculty of Graduate Studies, McGill University, Montreal, Quebec
• 1960    M.D. (Cum Laude)    Faculty of Medicine, Université de Montréal
• 1955    B.A. (Cum Laude)    Séminaire de Joliette

POSTDOCTORAL TRAINING

• 1979–1980    Sabbatical year, Professor Les Iversen    Cambridge University (Molecular Pharmacology), Professor Roger Guillemin    Salk Institute (La Jolla, CA) (Neuroendocrinology)
• 1964–1967 Assistant Biochemist    Hormone Research Laboratory (Protein Chemistry), Dr. C. H. Li    UC Berkeley (USA), UCSF (USA)
• 1962–1964 Resident    Peter Bent Brigham Hospital, Boston, USA, Dr. George W. Thorn    Harvard Medical School, Boston (USA), Dr. George Cahill
• 1960–1962 Resident    Internal Medicine and Clinical Research, Hôtel-Dieu de Montréal, Dr. Jacques Genest, Dr. J. S. L. Browne    Experimental Medicine, McGill University, Montreal
• 1959–1960 Internship    Université de Montréal,  Affiliated university hospitals

• Fondation J-Louis Lévesque : Proprotein convertases in Health and diseases (1/1/2019 - 31/12/21)
• Aclon Foundation, Geneva : Role PCSK9 in human liver cancer (1/1/2019 - 31/12/21)
• Fondation Mérieux : Quercetin-3-Glucoside: Mechanism of action and proof of concept on malaria and Ebola (1/7/2016 - 30/6/2019)    
• Strauss Canada Foundation : Ongoing projects on proprotein convertases in health and diseases (11/1/2008 - 10/31/2021)
• Fondation Pizzagalli/Notre-Dame de Zeitoun : Studies on functional endoproteolysis in Health and Diseases (1/1/2010 - 1/1/2021)
• Lazaridis Family Foundation : Clinical Pharmacology Platform for the IRCM Functional Endoproteolysis Laboratory (2020-2021)
• Power Corporation : Clinical Pharmacology Platform for the IRCM Functional Endoproteolysis Laboratory (2020-2021)

• Fellow, Royal Society (London) (FRS)
• Fellow, Royal Society of Canada (FRSC)
• Fellow, American Association for the Advancement of Science (FAAAS)
• Fellow, Royal College of Physicians and Surgeons of Canada (FRCPC)
• Fellow, American College of Physicians (FACP)
• Honorary Professor, Chinese Academy of Medical Sciences and Peking Union Medical College (PUMC)
• Officer, Order of Canada (OC)
• Officer, Ordre National du Québec (OQ)
• Officer, National Order of the Legion of Honour, France (OLH)
• Killam Prize, Art Council of Canada
• Prix Wilder-Penfield, Government of Quebec
• McLaughlin Medal, Royal Society of Canada
• Arthur Wynne Award, Canadian Society for Biomolecular Sciences
• Boehringer-Mannheim Award, Canadian Society for Biomolecular Sciences
• Henry Friesen Award, Royal College of Physicians and Surgeons of Canada
• Clarke Institute of Psychiatry Prize, Toronto
• Prix Archambault, ACFAS, Canada
• Fuller Albright Medal, Peripatetic Club, USA
• PMAC Health Research Foundation Medal of Honour, Canada
• Award of Distinction, Manning Foundation, Canada
• Jeremiah Metzger Lecturer, Am. Clin. Climatological Association (USA)
• Scholar, Josiah Macy Jr. Foundation (USA)
• Scholar, Jane Coffin Childs Memorial Fund for Medical Research (USA)
• Entry in the Dictionnaire Larousse.

Cellular model of POMC, the precursor of beta-endorphin, ACTH and MSHs. Sculpture designed by Mrs. Suzanne Benjannet and realized by Mrs. Diane Mineau.