. .

IRCM Researchers

Creating new
knowledge

Exploring new avenues to develop tomorrow’s medical knowledge through an approach that integrates basic and clinical research

Our research units are led by principal investigators who collaborate in a spirit of collegiality and with the vision of bridging the gap between research and patients. They train the next generation of scientists and are independent and creative minds who work tirelessly to improve health.

 

Michel
Chrétien

Emeritus Research Professor, Functional Endoproteolysis Laboratory

Current research

"Since 1967, the guiding principle of our research has been the theory of prohormones. Nearly 60 years later, this revolutionary theory has led to exceptional medical breakthroughs in several fields of human biology, including obesity, diabetes, cholesterol, pain, sleep, addiction, cancer, virology, atherosclerosis, and more. It has become a rapidly expanding field, particularly in neuroendocrinology and metabolism."

Michel Chrétien, Emeritus Research Professor

Functional Endoproteolysis Laboratory

Since 1967, the guiding thread of our research has been the "Prohormone Theory." Nearly 60 years later, this theory has yielded remarkable medical applications, par-ticularly in the following areas: obesity, diabetes, cholesterol, pain, sleep, addiction, cancer, virology, atherosclerosis, etc. These applications constitute a rapidly expand-ing field, especially in neuroendocrinology and metabolism (Fig. 1).

 

CURRENT RESEARCH

  1. The role of the PCSK9/LDLR tandem in cancer;
  2. The activity and mechanism of action of a new generation of translational inhibitors of PCSK9 production suggested by AI;
  3. The therapeutic potential of new triterpene glycosides (dicitriosides) against Ebola virus and SARS-CoV-2 infections. 

Available positions Clinical studies

Team
  • Annie Roy Assistante de recherche Research Assistant Annie.Roy@ircm.qc.ca
  • Baptiste Coutaud Assistant de recherche Research Assistant Baptiste.Coutaud@ircm.qc.ca
  • Evelyne Joyal Adjointe administrative Administrative Assistant Evelyne.Joyal@ircm.qc.ca
  • Majambu Mbikay Chercheur associé Research Associate Majambu.Mbikay@ircm.qc.ca
  • Michel Chretien Directeur unité de recherche Director, Research Unit Michel.Chretien@ircm.qc.ca
  • Mieczyslaw Marcinkiewicz Chercheur invité Guest Researcher Mieczyslaw.Marcinkiewicz@ircm.qc.ca
Affiliations

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

  • 2015    Associate Researcher, Institut universitaire de gériatrie de Montréal (IUGM)
  • 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
Degrees and experience

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-LPH1-91), he discovered γ-LPH (β-LPH1-58), 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 CON-VERTASES 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 exponen-tially. Thus, the endoproteolytic cascade of prohormones by PCs became wide-spread and a fundamental cellular process that controls numerous biological func-tions (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 PCSK9Q152H MUTATION IN FRENCH CANADIANS

Due to its gain-of-function (GOF) mutations, PCSK9 is the third locus of familial hy-percholesterolemia (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 PCSK9Q152H (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, proPCSK9Q152H, 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 dicitri-osides (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 po-tential 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
Publications

Ongoing Projects

We are currently exploring three avenues:
1) Investigating the PCSK9/LDLR complex in cancer.
2) Developing a new generation of translational PCSK9 inhibitors.
3) Evaluating the antiviral activity of triterpenes.

Proposal for a clinical trial of isoquercetin as an antiviral agent against Ebola and COVID-19

PCSK9 released into the blood by the liver increases blood cholesterol levels. During our work on the regulation of this protein, we found that isoquercetin, a small molecule of plant origin known for its antioxidant and anti-inflammatory properties, could decrease the production of PCSK9 by the liver and its release into the blood. Based on the hypothesis that high blood cholesterol levels, caused by increased PCSK9 activity (among other things) could promote the proliferation of infectious agents, we set out to investigate the anti-infective effects of isoquercetin. In collaboration with the National Microbiology Laboratory (NML) in Winnipeg, we have demonstrated that this molecule can remarkably prevent and mitigate Ebola virus disease in mice. 

With the outbreak of the COVID-19 pandemic, our collaboration with NML quickly turned to this new disease caused by the SARS-CoV2 coronavirus. We showed that in vitro isoquercetin could stop the infection of cells by this virus. Trials on the efficacy of the molecule in mice susceptible to COVID-19 are underway. Furthermore, to explain this anti-SARS-CoV2 effect, we are investigating whether isoquercetin could disrupt certain facilitating links between the proteins of the virus and those of the human cell. 

In collaboration with J. Carver (ICAV: International Consortium of Anti-Virals), we propose to conduct a phase II clinical trial with the main objective of evaluating the effect of isoquercetin (IQC) on disease progression (length of hospital stay and mortality) and viral load reduction when administered orally. They hope that stopping the infection early will prevent the long COVID-19 syndrome that affects between 10-20% of patients.

PCSK9, isoquercetin, and liver cancer

PCSK9 is produced by the liver, but its overproduction seems to promote liver diseases, such as fatty liver, hepatitis, cirrhosis, and cancer. We have discovered in four French-Canadian families the Q152H variant of PCSK9, which prevents the cleavage required for the release of this protein into the blood. In addition to lowering blood cholesterol levels, this variant trapped in liver cells reduces stress in that organ, thus protecting carriers against both heart disease and liver disease. 

We also found that any uncleaved form of PCSK9, when released into the bloodstream as a result of any cellular abnormality, is recognized by the immune system, which produces antibodies against it. We are investigating whether these autoantibodies could serve as diagnostic and prognostic markers of liver pathologies, including cancer.

On the other hand, since isoquercetin, a phytocompound, in addition to being an antiviral agent, is also a potential anticancer agent, it is possible that this activity is mediated by its inhibitory effects on PCSK9. By studying its anticancer efficacy in PCSK9-producing and non-PCSK9-producing cells or mice, we will determine whether this molecule, alone or in combination with other agents (such as anti-PCSK9 monoclonal antibodies), could improve liver cancer therapy.

Important Discoveries

1967

Isolation, purification and characterization of g-lipotropic hormone from sheep pituitary glands

1976

Isolation of peptides with opiate activity from sheep and human pituitaries: relationship to b lipotropin

1977

In vitro biosynthesis of β-endorphin in pituitary glands

1980

A novel human pituitary peptide containing the g-MSH sequence

1982

Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide: homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60

1990

cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: Tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases

1995

Proprotein convertases and the pathophysiology of human diseases: prospective considerations. Proc. Assoc. Am. Physicians 107:47-66, 1995

2011

Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture

2021

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Tools

 
Press review
Press review
Grants
  • 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)
Recognitions and honors
  • 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.
 

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514 987-5664
michel.chretien@ircm.qc.ca

 

ACKNOWLEDGEMENTS

  1. Michel Chrétien pays tribute to his mentors: Jacques Genest, George Cahill, and Chao Hao Li.
  2. He expresses his gratitude to the many collaborators and colleagues who have supported him throughout his 65 years of scientific work*. He has supervised about a hundred students and interns who have made significant contributions. He is particularly grateful to Drs. Majambu Mbikay and Mieczyslaw Marcinkiewicz, both of whom are past the normal retirement age, for continuing their superb collaboration.
  3. He warmly thanks the IRCM, which enabled him to transform the THEORY OF PROHORMONES into a new chapter in biology and to bring about revolutionary breakthroughs in medicine.
  4. He thanks the funding agencies and foundations that have generously supported him since 1960, namely the CIHR, the CFI, the FRQS, the NIH (U.S.), as well as the following foundations: IRCM, J.A. DeSève, EJLB/Echo, Richard & Edit Strauss, Aclon (Geneva), J. Louis Lévesque, Jane Coffin (Yale), Macy (NY), Pizzagalli, Lazaridis Family (Waterloo), and Power Corporation of Canada.

* In particular, Susanne Benjannet, Nabil G. Seidah, Majambu Mbikay, Mieczyslaw Marcinkiewicz, Claude Lazure, Ajoy Basak, Janice Mayne, Francine Sirois, and Annie Roy.

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