20 1 9 REPORT - Institut Pasteur de Lille

 
20 1 9 REPORT - Institut Pasteur de Lille
20
                                                     REPORT

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P R I VAT E N O N - P R O F I T   F O U N D AT I O N S I N C E 1 8 9 8

                  www.pa steur-lille.fr
20 1 9 REPORT - Institut Pasteur de Lille
THE EDIT

    IN 2019, OUR FOUNDATION
    CELEBRATED THE 120TH
    ANNIVERSARY OF THE OPENING OF
    ITS HISTORIC BUILDING!

    120 years of innovation, research and fighting        and Higher Education (HCERES) highlighted
    disease. 120 years of commitment and joint            the excellence of the teams and the quality
    action. 120 years at the service of everyone's        of the research carried out on the campus.
    health. And, above all, 120 years of loyalty to the   In association with our partners – CNRS,
    ideas of Pasteur and the wishes of the pioneers       INSERM, Lille university hospital, University of
    of the institute: Pasteur, Calmette, Guérin.          Lille – the 8 mixed research units are therefore
                                                          developing their projects and organisation
2   It is this history, peppered with doubts,             around the longevity project, which is the
    efforts, major discoveries and successes              major objective of our foundation. Thanks to
    that provides the foundation on which the             the renewed support of the French Ministry
    future of Institut Pasteur de Lille is being built    of Research, we can continue our projects
    through its strategic project.                        on the issue of longevity and bear witness
                                                          to the scientific standards of our foundation,
    The evaluation of the research teams by the           confirmed by the 365 scientific publications
    High Council for the Evaluation of Research           of the research teams.

               ED ITO-
20 1 9 REPORT - Institut Pasteur de Lille
Convinced of the key importance of prevention     would not be possible without the strong
in improving health, the teams at the Centre      and ongoing support of the donors, patrons
for Health and Longevity has developed new        and companies that I would like to thank very
offers in 2019 for businesses and individuals.    warmly on behalf of all the researchers.
Through vaccination, the Longevity Course,
health coaching, clinical studies and training,   Together, let’s speed up research and take
the disease prevention efforts are tackled        action to promote tomorrow’s health.
on a cross-sector basis and must respond to                                                       3
the challenges of our society. As a result, the   Many thanks for your commitment alongside
collaboration with associations and healthcare    our teams.
agents promotes and enhances our actions in
the service of healthcare.
All these advances in healthcare, all these
innovations, all these fights against disease

                                                                        Prof. Xavier Nassif
                                                                             Managing director
20 1 9 REPORT - Institut Pasteur de Lille
CONTENTS

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    2019 ACTIVITY REPORT
    Design and production:
    Communications and sponsorship department - Institut Pasteur de Lille, Karbone14, Cam&Lou
    Photo credits:
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                                                                                                                    74
    ©Barbara Grossmann - ©Joaquim Dassonville Collectif DR - ©freepik.com - Adobe Stock: ©Marzanna Syncerz,
    ©rogerphoto, ©Darren Baker, ©agenturfotografin, ©WavebreakmediaMicro, ©science photo - Unsplash.com:
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20 1 9 REPORT - Institut Pasteur de Lille
HIGHLIGHTS

LO N G E V I T Y O B J E C T I V E
Speeding up research and acting for better health tomorrow
The strategic project of Institut Pasteur de Lille
 International relations
 Results from the 3rd CPER-CTRL call for projects
 Launch of the 4th CPER-CTRL call for projects (phase 4)

S P E E D I N G U P R E S E A R C H F O R B E T T E R H E A LT H TO M O R R OW
LONGEVITY: interdisciplinary teams for excellence in research
 The Campus Research Teams
 Technology platforms
 Biotechs

P R E V E N T TO DAY I N O R D E R TO AG E W E L L TO M O R R OW
Centre for Health and Longevity: Innovation for Ageing Well
 Health checks and educational activities                                        5
 Research within the Centre for Health and Longevity
 Nutrition and Physical Activity Department
 The International Vaccination centre
 Development unit
 Microbiological Safety Unit

S U P P O R T T H E F O U N DAT I O N , A DVA N C E TO G E T H E R !
Institut Pasteur members working together!
 Donations, legacies and solidarity events
 Business patronage
 The Institut Pasteur de Lille museum

B U I L D TO M O R R OW ’ S F O U N DAT I O N
A Foundation at the service of the population
 Institut Pasteur core values
 Our CSR Commitments
 The Executive Board
 Scientific and Administrative Organisational Chart
 Employment/Resources

S C I E N T I F I C PA P E R S

PA R T N E R S A N D S U P P O R T
20 1 9 REPORT - Institut Pasteur de Lille
KEY
    EVENTS
    2019
    2019: 120 YEARS OF RESEARCH AND INNOVATION

    1894        At the end of the 19th century, three      1898      The Foundation is a non-profit organisation,
    quarters of the planet were decimated by infectious    which is legally and financially independent of the
    diseases such as diphtheria, tuberculosis, cholera,    Institut Pasteur in Paris.
    smallpox and rabies. The Nord-Pas de Calais region
    was not spared and the city of Lille had to face a     9 APR 1899               Institut Pasteur de Lille
    major diphtheria epidemic. Doctor Emile Roux,          formally opened at its current premises on
    who studied the disease with Louis Pasteur in Paris,   Boulevard Louis XIV, on the same day as the
    discovered the toxin responsible for diphtheria.       statue of Louis Pasteur was unveiled on Place
    The decision to create the institute was approved      Philippe Lebon. This great day was conducted in
    by the municipal council of 9 November 1894.           the presence of ministers, official representatives
    Albert Calmette flew to Lille. An initial temporary    of the French Academy, the Academy of Sciences
    laboratory was created at the Halle aux Sucres in      and Medicine and Mrs Pasteur, without her
    the Vieux-Lille. The production of the diphtheria      husband, who had sadly died 4 years earlier.
    serum could begin.
                                                           This is how the history of Institut Pasteur de Lille began,
    20 NOV 1895                  The first stone of the    originating in discoveries that would be significant
    building is placed in the heart of the Saint-Sauveur   for Humanity, following in the footsteps of Louis
    district.                                              Pasteur and the example initiated by Albert Calmette.

6

                                       1899                       2019
20 1 9 REPORT - Institut Pasteur de Lille
INSTITUT PASTEUR DE LILLE, FROM ITS FOUNDATION TO TODAY

                                                                                                                       2000
                        1894                                                                                             evelopment of the activities of
                                                                                                                        D
                                                                                                                        the UMR1011 laboratory towards

                                                                                                    2005
Creation of Institut Pasteur de Lille                                                                                   metabolic diseases
 to r esolve a diphtheria epidemic      1898                                                                           New nuclear receptors such as
                                                                                                                         FXR and LXR at the heart of
                                         The Foundation was recognised as      Method for identifying a latent
                                                                                         tuberculosis infection          pathophysiological       processes
                                         a non-profit organisation of public
                                                                                                                         leading to cardio-metabolic

           9 APR 1899
                                         interest by presidential decree
                                                                                                                         diseases       such   as   obesity,
                                                                                                                         diabetes and its cardiovascular
Opening of Institut Pasteur de Lille
and unveiling of the statue of Louis
                                         1901                                                       2006                 complications
                                                                                                                         The beginnings of the study of
                                         Opening of the Émile Roux               evelopment
                                                                                D                of     a     nasal       chronobiology in Lille
Pasteur. In the presence of Albert
                                         dispensary, the first French           whooping cough vaccine, which             Identification of the nuclear re-
Calmette, his wife, Mrs Pasteur, his
                                         preventorium for the prevention        can be used for inoculation from           ceptor Rev-erbα as a target of
          children and grandchildren
                                         of tuberculosis                        birth                                      PPARα
                                                                                Discovery of the first genes
                                                                                 involved in severe infantile
                       1904
Opening of the first biological          1921                                                                          2007
water purification station in La
Madeleine, with a purification
                                         Discovery of the vaccine against
                                         tuberculosis:   BCG     (Bacillus
                                                                                                    2009               Identification of a new gene that
               process applied by                                                reation of EGID (European
                                                                                C                                      may cause type 2 diabetes
                                         Calmette and Guérin)
                  Albert Calmette                                               Genomic Institute for Diabetes),
                                                                                the first research institute in
                                                                                France dedicated specifically to

                        1945                                                    diabetes and its complications
                                                                                Identification of the genetic
Creation of the regional blood
              transfusion centre
                                         1948                                    determinants involved in 13%
                                                                                 of the forms of Alzheimer's di-
                                                                                                                       2010
                                         First international BCG congress        sease                                 Discovery of a biological marker
                                         at Institut Pasteur in Lille                                                  of heart failure, which can be
                                                                                                                       used to identify the risk by way of
                                                                                                                       a simple blood test
                          1951                                                                         2011
            Implementation of the        FROM   1966 TO 1970                    Identification of five new factors
 international vaccination centre
       intended for travellers, and
                                         Launch    of    a    tuberculosis
                                         prevention campaign in the
                                                                                 of genetic susceptibility to Al-
                                                                                 zheimer's disease                     2012
           approved by the WHO                                                   Sequencing in record time of          Involvement of rare mutations
                                         mining area where 200,000
                                                                                  the Escherichia coli bacteria          in common forms of type 2
                                         children and adolescents were

                         1975
                                                                                  responsible for food poisoning         diabetes and obesity
                                         screened and vaccinated with BCG
                                                                                                                         Certification of the programme
Installation of the Immunology and                                                                                        on tumour dormancy by the
         Parasitic Biology Department
                                         1979                                                                             National Cancer Institute
                                                                                                                          Equipex and Labex certification
                                         Identification and characterisation                                               of the work of researchers of Lille
                                                                                                                                                                 7
                                                                                                      2013
                                         of new oncogenes and their

                          1981           involvement in cancer
                                                                               Identification of genes involved
             Creation of the health                                             in the resistance of tuberculosis

                                         1984
               examination centre

                                         Installation of the Jean-Charles
                                                                                                                       2015
                                         Fruchart laboratory: First team                                                 reation of "Centre Transdis-
                                                                                                                        C
                                         from Institut Pasteur de Lille to
                                                                                                      2016              ciplinaire de Recherche sur la
                                                                                                                        Longévité"
                        1985
                                         take an interest in cardiovascular
                                         and metabolic diseases                   ignature of a framework
                                                                                 S                                      Creation of METIS: a website
                                                                                 agreement           for        an       with health recommendations for
  Creation of a nutrition department                                             interdisciplinary partnership on        international travellers
                                                                                 digital sciences and health with
                                         1986                                    the INRIA
                                                                                 A new biological stethoscope
                                         Launch of a new research                 for heart disease

                        1994             objective on infection by the AIDS
                                         virus (HIV) and on the immune
                                         response against the regulatory
                                                                                Creation of the first mathemati-
                                                                                 cal model to understand how the       2017
  Installation of a new team that                                               liver clock synchronises with the          Installation of Eurabio/Synlab,
   will work on the nuclear recep-       proteins of the virus in particular     rhythm of meals                             a medical biology laboratory, on
  tors as therapeutic targets                                                                                                the Pasteur Lille campus
   Creation of the high-field                                                                                             Tuberculosis and resistance to
    Nuclear Magnetic Resonance
                                         1996
                                                                                                                            antibiotics: discovery of a new
    (NMR) centre
     Elucidation of the action
                                                                                                      2018                  SMART-420
                                                                                                                        Heart surgery: Lille-based re-
      mechanisms        of     PPARα       reation of the Institute of
                                          C                                         he discovery of a new gene
                                                                                   T                                     searchers discovered the impact
      dependent       fibrates    on      Biology of Lille (IBL) on the            responsible       for childhood       of the time of day on the risk of
      lipoprotein metabolism              Pasteur Lille campus                     obesity                               heart complications
    Discovery of a genetic marker        Discovery of a biomarker for         Test-tubes containing the original      An edible mushroom that is pro-
    for diagnosing Alzheimer's di-         lung, stomach and liver tumours,      strains of the vaccine against           mising for the fight against hu-
    sease                                  and leukaemia                         tuberculosis (BCG) to be opened          man genetic diseases
                                           Discovery of two protective ge-      at Institut Pasteur de Lille             Creation of the Centre for Health
                                            nes againstatherosclerosis           Design of a new algorithm                and Longevity
                                                                                  for detecting the resistance of
                                                                                  tuberculosis strains which are not

                        1997             1998
                                                                                  detected by standard tests
                                                                                   The biological clock as an
Discovery of a new genetic element                                                  important ally in the fight
which has been used since 2007             ffects of nuclear receptors on
                                          E                                         against inflammatory diseases
for the molecular typing of               inflammation and atherosclerosis          Creation of the Longevity
                      tuberculosis        Discovery of the role of PPARs in         Course, an innovative course
                                           controlling inflammation during           in preventive medicine, in
                                           atherosclerosis. This discovery           partnership with the university
                                           led to the creation of Genfit, a
                                           start-up initially hosted by Ins-
                                                                                     hospital of Lille and the
                                                                                     University of Lille               2019
                                           titut Pasteur de Lille                 Cardiac and immune chronobio-        120 years since the opening of
                        1999                                                       logy: important role of Rev-erba
                                                                                   in cardiac chronobiology and
                                                                                                                         Institut Pasteur de Lille
                                                                                                                         Launch of the great creative
First trials of the bilharzia vaccine:                                             circadian immunity                     and collective challenge
                               Bilhvax                                                                                    #TousUnPeuChercheurs
20 1 9 REPORT - Institut Pasteur de Lille
OBJECTIVE
LONGEVITY
20 1 9 REPORT - Institut Pasteur de Lille
SPEEDING UP RESEARCH
AND ACTING FOR BETTER
HEALTH TOMORROW
Over the past 60 years, men and women have           But how are we ageing? And more specifically,
gained on average a 14-year increase in life         can we live better longer? At age 60 , on
expectancy. Life expectancy in a good state          average life expectancy is 20 years , ten of
of health is increasing at a slower rate than life   those in good health and the ten others with
expectancy. When one knows that by 2060,             a gradual loss of autonomy. So, extending the
France will count 250,000 100-year olds, the         period of life in good health is a challenge for
question of ageing well becomes essential.           research and public health.

                   CANCER                                     ALZHEIMER'S DISEASE
                 400,000                                              900,000
         new cases detected in 2017.                      people in France are not diagnosed
             1st cause of death

     CARDIOVASCULAR DISEASES                                          DIABETES
                 140,000                                            3.3 million                         9
                deaths per year,                            of people with diabetes in France.
               1,000,000                                              700,000
             cases of heart failure                      individuals unknowingly live with diabetes

          INFECTIOUS DISEASES                              ANTIBIOTIC RESISTANCE 2.0
                 4 million                                            700,000
               deaths worldwide                                 deaths worldwide in 2019
        (HIV, tuberculosis, malaria, viral
                 hepatitis, etc.)                                       12,500
                                                                         in France
                 480,000
          case of multidrug-resistant                                      1st
            tuberculosis every year                              cause of death by 2050

                          Having historically led the way in the fight
                          against infectious diseases, Institut Pasteur de
                          Lille now hosts some of the most well-known
                          international scientific experts in the field of
                          antibiotic resistance 2.0.
20 1 9 REPORT - Institut Pasteur de Lille
STRATEGIC PROJECT
     OF THE INSTITUTE
     The Institut Pasteur de Lille was created in 1894    and behavioural determinants or "stressors"
     to respond to public health concerns at the end      simultaneously affecting several organs, which
     of the 19th century, including the fight against     have a generalised impact on the state of health
     infectious diseases, through the research work       of the general public, the quality of life of our
     on pathogens, the development of vaccines            fellow citizens and require complex and costly
     and serum and the promotion of preventive and        treatments.
     hygienic measures. From the very beginning,
     Institut Pasteur de Lille has therefore organised    In the last two decades, the life sciences have
     its actions around the following three objectives:   also been deeply affected by the rapid growth
     high-level    fundamental     research,   disease    of the storage and computing capacities of
     prevention and the development of a healthcare       computers, at the same time as the sequencing
     offer aimed at the general public, that complies     capacities of the improvement of imaging
     with the core values of Institut Pasteur.            technologies (molecular, cellular, in vivo) and
                                                          the automation and miniaturisation of the
     The advances in research, vaccine development        many search operations were producing data
     and the discovery of antibiotics and, more           in exponentially growing volumes. As a result
     recently, antivirals, to which Institut Pasteur      of these parallel developments, if they are
     de Lille has contributed, have resulted in a         integrated within laboratories, our descriptions
     considerable reduction in the prevalence of          of living things can be refined and more complex
     certain infectious diseases.                         mechanisms can be understood.

     During the 20th century, new diseases linked
     to changing lifestyles and to the increase in life
     expectancy have developed with an epidemic
     progression, such as the cardiovascular diseases,
     diabetes      and    metabolic
     diseases, cancers and neuro-
     degenerative diseases. At
     the same time, economic
     and industrial changes in
     societies have also given rise
10   to the emergence of other
     diseases linked to several
     rapid changes in the environ-
     ment (long-distance travel,
     intensification of livestock
     farming, pollution, climate
     change) such as antibiotic
     resistant infections, emerging
     infectious     diseases     and
     respiratory ailments. Even
     more serious are the frequent
     combinations      of   genetic,
     environmental,       nutritional
Longevity objective

 POSITIONING AND STRUCTURING
 OF THE PROJECT
               To understand the significant changes in
               health needs, and fully exploit the rapid deve-
               lopment of scientific methods, Institut Pasteur
               de Lille has decided to organise its activities        WHAT'S MORE, INSTITUT PASTEUR DE
               within an interdisciplinary and multi-sector           LILLE HAS SET ITSELF TWO PRIORITIES:
               campus, whose central focus is to understand
                                                                          Degenerative diseases associated with
               the primary pathophysiological mechanisms of
                                                                      life styles, the extension of life time, and
               the most impactful diseases, in order to design
                                                                      changes in the environment:
               and develop diversified health products for
                                                                      - Diabetes and its complications
               sustainable healthcare: treatments, diagnostic
                                                                      - Cardiovascular and respiratory diseases
               assessments, vaccines and innovative disease
                                                                      - Neurodegenerative diseases
               prevention protocols.
                                                                      - Senescence, fibrosis and cancer

                                                                        Infectious diseases, in the context of
                                                                      antibiotic resistance

                                                                      These two objectives have strong scientific
                                                                      and     methodological      interconnections
                                                                      because both are linked to the functioning
                                                                      and ageing of innate and adaptive immunity,
                                                                      and of the microbiota. They can also be
                                                                      associated with effective disease prevention
                                                                      methods.

  THE STRATEGY OF INSTITUT PASTEUR DE LILLE
  CAN BE BROKEN DOWN INTO 4 INTERDEPENDENT
  OPERATIONAL OBJECTIVES

                            1
                                                                                                                     11
                                                  and industrial laboratories      population according to the
                                                  to facilitate the transfor-      mechanistic hypotheses on
                                                  mation of scientific results     the other hand. Regarding
                                                  into innovative healthcare       this third point, the expe-
                  Outlining an interdisci-        products (drugs, diagnostic      rience of Institut Pasteur
                  plinary research platform       assessments and vaccines,        de Lille is unique in France,
                  in pursuit of excellence        disease prevention proto-        and has no equivalent in
                  with a holistic approach        cols).                           the academic or hospital
                  to the organisation, by                                          infrastructures.

                                                            3
                  encouraging       collabora-
                  tions between academic

                                                                                             4
                  disciplines on the one
                  hand and research units
                  on the other, with the aim
                  of identifying the earliest
                                                  Conducting           assessed
                  stages of the pathophy-
                                                  healthcare measures, with
                  siological mechanisms of
                                                  a progressive deployment         Passing    on    "evidence-
                  diseases, on which cura-
                                                  from the Hauts-de-France to      based"     knowledge       by
                  tive or preventive action
                                                  all of France. These actions     participating in the "life-
                  will theoretically be more
                                                  will be implemented by buil-     long"     training      offer,
                  effective. Maintaining the
                                                  ding intensified exchanges       internally (career deve-
                  highest level of scientific
                                                  between research activities      lopment) as well as in
                  investigation thanks to
                                                  on the mechanisms of             partnership      with     the
                  the most recent means of
                                                  resilience and resistance to     University of Lille and the
                  observation and analysis
                                                  stressors on the one hand        I-site (ULNE) and the inter-
                  will be sought.
                                                  and     disease    prevention    national network of Institut
                                                  activities on the other. These   Pasteur, and by communi-

                            2
                                                  exchanges naturally go both      cating directly to the public
                                                  ways: from the fundamental       through conferences, and
                                                  research (including human        by exploiting all available
                                                  and social sciences) to the      channels and technologies,
                                                  disease prevention actions       to facilitate personalised
                  Developing            one's     evaluated on the population      communication for indivi-
                  inter-sector ecosystem by       on the one hand and from         dual coaching in particular.
                  bringing together academic      the observation of the
There are eight founding research units of Institut      implements a wide variety of complementary
                                       Pasteur de Lille. The 34 teams that make them            heuristic approaches, used to create numerous links
                                       up gather together the initial scientific capital        between epidemiological research (from the many
                                       (researchers, expertise, methods and results) in         cohorts of "control subjects" and patients which
                                       line with the two topical priorities of the institute.   they have formed), mechanistic and drug discovery
                                       These teams were highly rated during the 2019            (thanks to the many cell and animal models
                                       assessment wave of HCERES and the Specialised            of diseases they have developed) and disease
                                       Scientific Commissions of Inserm. Within Institut        prevention strategies (thanks to the unique disease
                                       Pasteur de Lille, they form the Interdisciplinary        prevention infrastructure that hosts 15,000 men and
                                       Research Centre for Longevity (CTRL).                    women each year).
                                       This Interdisciplinary Research Centre for Longevity
                                                                                                                    It works with the Centre for
                                                                                                                    Health and Longevity which
                                                                                                                    receives the public and designs,
       01 RISK FACTORS AND MOLECULAR DETERMINANTS OF DISEASES LINKED TO AGEING                                     implements and evaluates all the
       02 INTEGRATIVE GENOMICS AND MODELLING OF METABOLIC DISEASES                                                 disease prevention activities, in
                                                                                                                    collaboration with the hospitals
       03 NUCLEAR RECEPTORS, CARDIOVASCULAR DISEASES AND DIABETES                                                  of the Hauts-de-France region.
                                                                                                                    Diabetes-related      preventive
       04 TRANSLATIONAL RESEARCH ON DIABETES                                                                       measures are conducted within
                                                                                                                    the National Centre for Precision
       05 "CENTRE D'INFECTION ET D'IMMUNITÉ DE LILLE" (LILLE INFECTION AND IMMUNITY                                Medicine, called "Précidiab",
             CENTRE)                                                                                                in collaboration with several
                                                                                                                    hospitals in Hauts-de-France.
       06 HETEROGENEITY, PLASTICITY AND RESISTANCE TO CANCER THERAPIES
       07 IMPACT OF THE CHEMICAL ENVIRONMENT ON HUMAN HEALTH
       08 MEDICINES AND MOLECULES FOR ACTING ON LIVING SYSTEMS

     EXCELLENCE IN RESEARCH AT THE
     HEART OF THE PROJECT
12   In 2015, the Institut Pasteur de Lille created the        the most effective targets for therapeutic or
     Interdisciplinary Research Centre for Longevity           preventive intervention. It is these early alterations
     where scientists are engaged in basic and applied         (vulnerabilities which are not yet pathological)
     sciences to find the means to promote healthy             that the Centre for Health and Longevity detects
     ageing by understanding, preventing and treating          in "subjects" coming for consultation to offer
     the diseases linked to ageing. Because sustained          them personalised disease prevention protocols
     homeostasis at every level (e.g. genome,                  in several areas (sensory, cognitive, metabolic,
     endoplasmic reticulum (ER), mitochondria, cell,           skeletal, muscular).
     organ, organism) is the determining factor in             Together, the teams at Institut Pasteur de
     the internal stability of organisms over time,            Lille are studying the essential categories of
     our ability to cope with a variety of potential           genetic, infectious, nutritional, environmental
     endogenous or exogenous stressors is the key to           and behavioural stressors. They characterise
     the stability of our organism and to keeping it at        the structure, functions and their impact on
     its highest functional level.

     Healthy ageing is possible
     by     limiting     exposure     to
     preventable stressors and
     improving        resistance    and
     resilience     to      unavoidable
     stressors. One of the main
     objectives of our teams is
     therefore to identify the critical
     stress factors and their effects
     on the functions of cells,
     organs and organisms, as well
     as to understand the (patho)-
     physiological            processes
     (sensors       and       effectors)
     triggered in response to
     stressors, especially during
     the prodromal phase when
     functional losses are too low
     to have a detectable effect
     on       health.     Theoretically,
     these early mechanisms are
Longevity objective

                             the molecular and cellular biology of various           of disease and, ultimately, the human and social
                             target systems (neurological, immune, metabolic,        sciences. Indeed, they have radically different
                             neurological, respiratory, etc.) as well as the         "business models". For example, genomics research
                             integrated response of the organism as a whole          requires a substantial initial investment to create
                             through long-term in vivo studies. Regarding            and maintain cohorts, but then produces results on
                             the latter, we know that the role of hormonal,          an ongoing basis. As for the "hypothesis driven",
                             metabolomic,      immune     and     inflammatory       mechanistic and interventional studies needed
                             responses is crucial. The importance of research        to confirm the causal role of candidate genes or
                             in metabolism and immunology on the Campus              to further characterise biological or pathological
                             is an important advantage. Regarding the study          processes, they can be very slow and require a lot
                             of cancerisation mechanisms, the institute will         of work. The institute should increasingly turn to
                             prioritise research into the processes that link        strategies or technologies that are likely to bridge
                             primary stressors, senescence, fibrosis and cancer.     the "productivity" gap (such as high throughput
                                                                                     technologies,      non-mammalian       intermediate
                             The teams follow complementary heuristic                models, organoids, etc.) Further downstream, the
                             approaches, ranging from observational sciences         institute's project has already aroused the interest
                             (structural biology, Genome Wide Association            of several researchers in the field of human and
                             Study (GWAS), phenotyping, approaches asso-             social sciences (HSS) and their integration within
                             ciated with systems biology) to interventional life     the context of the project has begun. Visions on
                             sciences (such as in vitro and in vivo pharmacolo-      research objectives that are shared with disease
                             gy, microbiology, toxicology and chemical sciences      prevention and the biomedical sciences is necessary
                             (drug design, chemical biology, exploration of          to ensure effective collaboration.
                             chemical diversity, development of new chemical
                             syntheses, immunomodulation and vaccines). By
                             working on models of the disease, the latter esta-
                             blish the causal role of the determinants identified
                             by observational sciences.

                             The continued development of excellence for the
                             benefit of Institut Pasteur de Lille project depends
                             on the connection between the observational
                             sciences and interventional activities on models

                                                                                                                                            13

 In terms of academic disciplines, the strength        science activities. It should be noted that in several
 of the Institut Pasteur de Lille campus resides in    cases, translational projects on the discovery
 the close contacts that exist between biologists,     of vaccines and drugs have also facilitated
 chemists, physicists and specialists in scientific    new discoveries and the implementation of key
 data and public health. The creation and              fundamental programmes leading to articles in
 maintenance of productive interfaces between          the most highly reputed journals. The same type
 disciplines is essential to the creation of new       of links will be established between the disease
 concepts, research tools and, ultimately, having an   prevention research and HSS applications.
 impact in society. The main challenge is to define
 a scientific question that is common to scientists    It is worth bearing in mind that the
 from different disciplines and to avoid the usual     competitiveness of the researchers in the life
 customer/supplier       relationship.   Long-term     sciences and healthcare is increasingly dependent
 relationships between chemists and biologists         on cohorts and advanced observation tools such
 are particularly important in the field of drug       as genomics, transcriptomics, proteomics as
 discovery. All means of interpersonal, formal or      well as imaging, HCS/HTS, mass spectrometry,
 informal cultural exchanges must be practised on      immunophenotyping,        libraries   of    siRNA
 the campus.                                           compounds, etc. on the one hand, and the
                                                       processing of bio- and chemo-computer data on
 Translational research also feeds into basic          the other hand. The campus teams have access
 research. Downstream from the study of biological     to all of these tools, through several Equipex
 processes, the research includes translational        platforms in particular.
 activities in the discovery and prevention plans of
 drugs and vaccines directly related to our basic
KEY FACTORS
     OF SUCCESS OF THE PROJECT
     As with any organisation that bases its work on                 innovative health products and unite its ecosystem. It
     research, the 4 key factors of lasting success are the          is with the aim of enhancing these factors of success
     attractiveness (and influence), the creativity (risk            that the foundation's project is directing the actions
     taking) and the willingness to translate discoveries into       conducted on the existing capital.

                     0 1Attractiveness: increasing and renewing                    this presents an additional obstacle to the
                     human potential.                                               deepening of monodisciplinary research and a risk
                        cademic excellence (increasing the influence
                       A                                                            for careers and the team, which is often associated
                       of the 3 Labex and 2 Equipex of the campus);                 with a higher probability of breakthrough disco-
                                                                                    veries and is essential in translational research.
                       International influence and exposure;
                        ttractive (i.e. competitive) environment for
                       A
                       young researchers;
                                                                                    03      Willingness to translate discoveries into
                                                                                    innovative and useful health products: marketing
                        ttracting competitive funding (Horizon Europe,
                       A                                                            them will be a driver of economic growth for the
                       European Research Council (ERC), National                    institute, as has been the case twice in the past
                       Institute & Health (NIH), Bill & Melinda Gates               (CEREP, now Eurofins, and GENFIT).
                       Foundation, etc.)
                       Increasing scientific potential by adding to the            04 Uniting: In addition to these elements related
                        institute's resources in HSS, including in the              to the scientific integration of activities, Institut
                        behavioural sciences and in health economics.               Pasteur de Lille must also unite all the stakeholders
                                                                                    associated with its activities: healthcare players
                     02    Creativity: the institute must cover                     (CNAM, ARS, Ministry of Health, private social
                     the risk of the researcher, by promoting                       welfare players, hospitals, etc.), economic and
                     interdisciplinary research in particular. Indeed,              industrial players.

14
                                     Institut Pasteur de Lille supports its research               rent organs or diseases, which present identical,
                                     teams (management, help with the preparation of               comparable or interdependent pathophysiological
                                     files, accommodation, scientific staff, investment            mechanisms, e.g. fibrotic mechanisms. One of
                                     and maintenance in platforms) and stimulates                  the priority interdisciplinary bridges is research
                                     interdisciplinary research by funding cross-sec-              on disease prevention, with the participation of
                                     tor activities between the teams from various                 researchers in the human sciences, biologists,
                                     disciplines (chemistry, biology, physics, medicine,           doctors and paramedical staff.
                                     disease prevention) but also by studying diffe-

     KEY FIGURES

                                                                               34                                                     25,400
     50,000 m            2
                                           800                          research teams                        27                     vaccinations
          campus                         employees                                                      nationalities                  per year

                             365                                 3                             10                       15,080
                            scientific                   LabEx                          technological                  Preventive
                             papers                    (Excellence                        platforms                   Health Exami-
                                                       Laboratory)                    including 2 equipex                nations
Longevity objective

 THE DNA OF INSTITUT
 PASTEUR DE LILLE

                                                             RESEARCH

                         661                                 1 500                               8                     5,000
    researchers and technicians on campus             articles (over 5 years)           research units A/A+           citations/year
     epidemiology / genetics / pharmacology /                                         working towards a common
             biochemistry / chemistry                                                            goal

          TIES WITH THE ECONOMIC WORLD                                                PUBLIC HEALTH ACTIONS

          44                   6                  2                                              15,000
     active families       start ups         medicines                                        consultations/year
       of patents                        under development

                                                                                                                                       15

 INTERNATIONAL SCIENTIFIC
 COLLABORATIONS

                       Imperial College London             Ghent University                 Helmholtz Center Munich
                         University of London
                          Harvard University
                        Helmholtz association                                                         Italy
                         University of Oxford                   Spain
                       University of Cambridge
                             Univ Oxford
                                                                                                     Estonia
                      University College London

                                                      National institutes of health
                                                                NIH USA                       Karolinska Institutet
                                                        University of California
                        Erasmus University                       System
                            Rotterdam
                                                           Boston University
                                                                                                     Japan
                                                             Boston Univ
                                                        VA Boston healthcare
                                                                 system
                        University of Helsinki        Washington State University                 Switzerland
INTERNATIONAL
                                 RELATIONS
                                 Institut Pasteur de Lille is a leading research player   diseases. The mission of Institut Pasteur de Lille is
                                 and is developing relationships with organisations       to make progress with these two topics within the
                                 in different countries to share knowledge and            network at the level of the Europe region. During
                                 speed up research.                                       this meeting, Jérôme Weinbach, European adviser
                                                                                          to the health managing director at the Ministry of
                                 Since November 2018, Institut Pasteur de Lille has       Solidarity and Health, made a speech presenting
                                 been representing and coordinating the Europe            the health priorities of the European Commission
16                               region within the "Réseau International des              within the framework of the future Horizon Europe
                                 Instituts Pasteur" (international network of Pasteur     programme.
                                 institutes) under a 3-year mandate.
                                                                                          From 12 to 15 November 2019, the directors of the 32
                                 In 2019, in coordination with the "Institut Pasteur      RIIP institutes met at the Pasteur Centre in Yaoundé
                                 Hellenique", the institute organised a meeting of        in Cameroon to review the RIIP's activities and its
                                 the institutes of the RIIP Europe region in Athens       outlook for the future. This meeting also involved
                                 from 4 to 5 September 2019. The 7 European               discussions on the creation of new partnerships,
                                 institutes (Lille, Paris, Brussels, Saint Petersburg,    regulations around the sharing of samples, as
                                 Sofia, Rome and Athens), represented by their            well as several scientific priorities of the network
                                 directors, scientific directors and researchers,         including antimicrobial resistance. Each RIIP region
                                 presented the strategies, technological platforms        put forward a short and medium-term action
                                 and resources of each institute. Two major scientific    plan on the topics that are specific to each region
                                 topics were selected for the Europe region:              (antimicrobial resistance and neurodegenerative
                                 antimicrobial resistance and neurodegenerative           diseases for Europe).

                                         COLLABORATING AT THE INTERNATIONAL LEVEL TO
                                                     SPEED UP RESEARCH

     A bilateral meeting was organised on 28                resistance. Researchers from Institut Pasteur de
     November 2019 between 2 close neighbours of            Lille met their Belgian counterparts to initiate
     the RIIP: Institut Pasteur de Lille and Sciensano,     various scientific collaborations.
     its Belgian counterpart resulting from the merger
     of the ISP (Scientific Institute of Public Health)     A key formative event of the longevity project of
     and the CERVA (Centre for Veterinary and               Institut Pasteur de Lille was the 3rd International
     Agrochemical Study and Research). The objective        Symposium on Longevity, which was held in
     of the meeting was to gain a better understanding      December to address the subject of "Fundamental
     of the strengths of each institute, highlight the      science at the service of good health throughout
     complementary strengths and initiate interactions      life: disease prevention and treatment of age-
     between the researchers of both institutes in          related diseases". More than 130 international
     the field of infectious diseases and antimicrobial     scientists participated in this event.
Longevity objective

      Le Réseau International
      des Instituts Pasteur
      Une communauté humaine et scientifique mondiale unie par des valeurs
      et des missions communes au service de la santé.                                                                                           32
                                                                                                                                                 INSTITUTS MEMBRES
                                                                                                                                                                                        23 000                                                                         17
                                                                                                                                                                                        PERSONNES
                                                                                                                                                             25
                                                                                                                                                             PAYS

          Laval                                                                                     Saint-Pétersbourg
                                                                                 Lille                                                                                                                             Séoul
                                                                                       Bruxelles                Sofia
                                                                               Paris
                                                                                                                                                                                                                           Shanghai
                                                                                        Rome                                 Téhéran
                                                                      Alger                            Athènes                                                                                                      Hong-Kong
                      Pointe-à-Pitre                          Casablanca                    Tunis                                                                                                          Hanoï
                                                                                                                                                                                                    Vientiane       Nha Trang
                          Cayenne                                                                                                                                                                                  Hô-Chi-Minh-Ville
                                                                                                                                                                                                Phnom Penh
                                                                 Dakar
                                                                                             Niamey
                                                               Conakry
                                                                                                           Bangui
                                                                                                                                                                                                                                                      Nouméa
                                                                              Abidjan                  Yaoundé
                                 Rio de Janeiro

                             Montevideo                                                                                              Antananarivo

                                                  AMÉRIQUE                                                   Institut Pasteur de Lille                       AFRIQUE                                          ASIE – PACIFIQUE
                                                  Fiocruz (Rio de Janeiro)                                   Institut Pasteur (Paris)                        Centre Pasteur du Cameroun (Yaoundé)             Institut National d’Hygiène et d’Epidémiologie (Hanoï)
                                                  INRS-Institut Armand-Frappier (Laval)                      Institut Pasteur de Saint-Pétersbourg           Cermes Niger (Niamey)                            Institut Pasteur du Cambodge (Phnom Penh)
                                                  Institut Pasteur de la Guadeloupe (Pointe-à-Pitre)         Sciensano (Bruxelles)                           Institut Pasteur de Bangui                       Institut Pasteur de Corée (Séoul)
                                                  Institut Pasteur de la Guyane (Cayenne)                    Institut Stephan Angeloff (Sofia)               Institut Pasteur de Côte d’Ivoire (Abidjan)      Institut Pasteur d’Hô Chi Minh Ville
                                                  Institut Pasteur de Montevideo                                                                             Institut Pasteur de Dakar                        Institut Pasteur du Laos (Vientiane)
                                                                                                             MAGHREB-IRAN                                    Institut Pasteur de Guinée (Conakry)             Institut Pasteur de Nha Trang
                                                  EUROPE                                                     Institut Pasteur d’Algérie (Alger)              Institut Pasteur de Madagascar (Antananarivo)    Institut Pasteur de Nouvelle-Calédonie (Nouméa)
                                                  Institut Pasteur d’Italie – Fondation Cenci Bolognetti     Institut Pasteur d’Iran (Téhéran)                                                                Institut Pasteur de Shanghai, Académie chinoise des
                                                  (Rome)                                                     Institut Pasteur du Maroc (Casablanca)                                                           Sciences
                                                  Institut Pasteur hellénique (Athènes)                      Institut Pasteur de Tunis                                                                        Pôle de recherche Université de Hong Kong – Pasteur

 Present in 25 countries across all the continents,                                         numerous endemic disease zones, the RIIP has,
 the International Network of Instituts Pasteurs                                            on multiple occasions, demonstrated its major
 (RIIP) groups 32 institutions united by common                                             role as a sentry in the face
 missions and values for the benefit of the                                                 of infectious emergencies.      DRIVEN BY THE ETHICS AND RESPECT
 general public. Notably installed at the heart of                                                                          FOR INSTITUT PASTEUR'S CORE VALUES,
                                                                                                                            THE INTERNATIONAL NETWORK OF
                                                                                                                            INSTITUTS PASTEURS ENDEAVOURS TO
                                                                                                                            IMPROVE HUMAN HEALTH.
RESULTS OF THE 3RD COLLABORATIVE AND EXPLORATORY
     CPER-CTRL CALL FOR PROJECTS 2018
     In order to support interdisciplinary projects on          de Lille (MEL) and the ERDF fund. The CPER-CTRL
     longevity, Institut Pasteur de Lille is coordinating the   calls for projects aim to promote cooperation between
     CPER-CTRL programme for the 2016-2020 period               teams in the region on new
     (State-Region plan contract - Interdisciplinary Centre     issues related to longevity as         Following the 3rd CPER-CTRL call for
     for Research on Longevity) funded by the state, the        well as the emergence of new           projects launched in December 2018,
     Hauts-de-France Region, the Métropole Européenne           teams.                                 25 projects have been received and 11
                                                                                                       projects were selected for funding after
                                                                                                       evaluation by independent experts and by
                                                                                                       the International Scientific Council (CSI).

     EXPLORATION PROJECTS (€50K)
       PROJECT NAME                        APPLICANTS                                               PROJECT TITLE

                                   Anne TSICOPOULOS/CIIL                           Circadian clock of the lymphoid cells of the lungs
         CIRCASTHMA
                                    Hélène DUEZ/UMR1011                                         and severity of asthma

                                      Yves ROUILLE/CIIL                  Study of the interaction between peroxisomes and hepatitis C virus
           VIROPEX
                                    Yasmine SEBTI/UMR1011               replication complexes: impact on cell metabolism and oxidative stress

     COLLABORATIVE PROJECTS (€200K)
       PROJECT NAME                        APPLICANTS                                               PROJECT TITLE

                                Jérôme EECKHOUTE/UMR1011                 Transcriptional control of the hepatic stellate cell activation associated
             LivFib
                                 Laurent DUBUQUOY/U1286                                            with hepatic fibrosis

                                        Ruben Hartkoorn
18                                     Alain Baulard/CIIL
          ProActiv-2                                                                          Activation of Pro-Antibiotic-2
                                     Nicolas Willand/U1177
                                    Elisabeth Pradel/U1286

                                     Devrim KILINC/U1167                  Medium-throughput screening based on co-cultures of neurons in
        SynapseScreen
                                    Sophie HALLIEZ/U1172                  microfluidic chambers for physiologically relevant synaptic toxicity

                                 Jean-Sébastien ANNICOTTE/
                                                                        Role of E2F1 in the loss of β cell function linked to inflammation during
           MELODY                         UMR8199
                                                                                                           ageing
                                  Benoît POURCET/UMR1011

     COLLABORATIVE PROJECTS (€90K)
       PROJECT NAME                        APPLICANTS                                               PROJECT TITLE

                                     Muriel Pichavant/CIIL              Smoking and obesity: multi-organ impact of metabolic reprogramming
         COMMONLY
                                     Florence Pinet/U1167                                           in longevity

                                                                         Consequences of the induction of endoplasmic reticulum stress in
                                  Isabelle WOLOWCZUK/CIIL
        DESTRESS-Flu                                                     white adipose tissue during infection with the influenza virus on the
                                     Steve LANCEL/U1167
                                                                                          severity of infection in the elderly

                                 Alicia MAYEUF-LOUCHART/
                                                                             Circadian regulation of muscle regeneration during ageing: a
      ClockMuscleAging                      UMR1011
                                                                                  complementary approach in mice and drosophila
                                    Pierre DOURLEN/U1167

                                Rebecca DEPREZ-POULAIN/
                                                                              Modulation of the UPR response by IDE: consequences on
           IDE-NASH                        U1177
                                                                                    inflammation, steatosis and ageing in NASH
                                Nathalie HENNUYER/UMR1011

                                 Réjane PAUMELLE/UMR1011
                                                                         Role of FAT10 in hepatocyte senescence: impact in the development
           FATeNASH               Albin POURTIER/UMR8161
                                                                                                      of NASH
                                 Guillaume LASAILLY/U1286
Longevity objective

LAUNCH OF THE 4TH CPER-CTRL (PHASE 4)
CALL FOR PROJECTS
              In October 2019, Institut Pasteur de Lille launched   of the 2 objectives of the Longevity research
              the 4th CPER-CTRL call for research projects.         project. This call for projects is for the funding of
              Each project submitted must be presented by 2         collaborative projects and exploratory projects.
              teams from different units and be part of one

   25/10/2019                                10/12/2019                                                                Q3 2020
  Launch of the                          Hearing of projects                                                           Project
 call for projects                           by the CSI                                                                start-up

                         25/11/2019                                                        March 2020
                          Project                                                       Examination of the
                         reception                                                       funding request

 CPER-CTRL FINANCING

                                                                                                                                  19

 AN INTERNATIONAL
 SCIENTIFIC COUNCIL

                  Bernard                      Folkert                    Thomas                           Edward
                 THORENS,                     KUIPERS,                     THUM,                          PEARCE,
                Lausanne, CH               Groeningen, NL               Hannover, GE                    Freiburg, DE

                   Cristina                   Miroslav                    Peter                             Alain
              LEGIDO-QUIGLEY,                RADMAN,                  VANDENABEELE,                       FILLOUX,
                 London, UK                 Split, Croatia              Ghent, BE                        Londres, UK
SPEEDING UP
RESEARCH FOR
BETTER HEALTH
TOMORROW
LONGEVITY:
INTERDISCIPLINARY TEAMS
FOR EXCELLENCE IN
RESEARCH
Institut Pasteur de Lille hosts a centre for        Over the past ten years, these teams have
research on longevity divided into eight units 1,   endeavoured, together with their research
with multidisciplinary, cross-sector skills. This   partners, to get structured around excellence
inter-disciplinary research programme which         laboratories and facilities financed as part
mobilises all Institut Pasteur de Lille teams       of the "PIA" (investment programme for the
aims to identify and characterise the genetic,      future), including:
environmental, metabolic, and infectious factors
which contribute to lowering the functional                LabEx dedicated to Alzheimer's disease
                                                          a
performance of cells and the organism, which is           (DISTALZ)
what we call ageing. This then makes it possible
to prevent exposure to these factors, or to                LabEx dedicated to studying diabetes
                                                          a
reduce their impact by stimulating the resilience         (EGID)
of cells and the organism with the assistance of
innovative prevention strategies or treatment.             research centre on infection and immunity
                                                          a
                                                          (CIIL) involved in the ParaFrap LabEx
01 Risk factors and molecular deter-
     minants of diseases linked to ageing                  n EquipEx dedicated to cellular imaging
                                                          a
                                                                                                                    21
                                                          pharmacological screening (IMAGINEX
02 Integrative genomics and modelling of                 BIOMED)
     metabolic diseases
                                                           n EquipEx dedicated to genomics
                                                          a
03     uclear receptors, cardiovascular
      N                                                   (LIGAN‑PM)
      diseases and diabetes
                                                    Institut Pasteur de Lille's campus boasts
04 Translational research on diabetes               an exceptional concentration of high level
                                                    facilities and technology platforms to serve
05 Centre d'Infection et d'Immunité de Lille        all the researchers in the regional scientific
      (Lille infection and immunity centre)         community. It also has the largest molecule
                                                    library in Europe – the chemical library – where
06 H eterogeneity, Plasticity and Resistance       thousands of tests are conducted every year,
      to Cancer Therapies2                          helping in the discovery of new prescription
                                                    drugs.
07 Impact of the chemical environment on
     human health

08 M
    edicines and molecules for acting on               On 1 st January 2020
                                                    1

                                                    2
                                                        On 1 st January 2020, thereby replacing the Mechanisms of
      living systems                                    Tumorigenesis and Target Therapies (M3T) unit
RISK FACTORS
     AND MOLECULAR DETERMINANTS
     OF AGING-RELATED DISEASES
     This unit focuses on the fight against age-          determinants of Alzheimer's disease and cognitive
     related diseases, such as cardiovascular and         disorders". Each of these teams gained international
     neurodegenerative diseases. Prof Philippe Amouyel    recognition in the field of age-related diseases with
     coordinates the DISTALZ laboratory of excellence,    a great openness to the general public in terms of
     dedicated to Alzheimer's disease.                    disease prevention for successfully extending the
                                                          life expectancy of everyone in good health.
     Three teams interact on the "epidemiology
     and public health of age-related diseases", the                                            PROF PHILIPPE AMOUYEL
     "molecular determinants of heart failure and                                               MD PhD, University Hospital (CHU) of Lille
     ventricular remodelling", and on the "molecular                                            UMR1167 - Labex DISTALZ University of
                                                                                                Lille, Inserm, University Hospital of Lille,
                                                                                                Faculty of Medicine, Institut Pasteur de Lille.

                                   DISSECTING THE RISK FACTORS TO EXTEND                  ventricular remodelling associated with heart
                                   THE LIFE EXPECTANCY OF EVERYONE IN                     failure to ultimately prevent this accelerated
                                   GOOD HEALTH                                            ageing of the heart.
                                   This team, led by Dr Aline Meirhaeghe, analyses
22                                 the role of cardiovascular risk factors in the onset   DECIPHERING THE GENOME TO BETTER
                                   and progression of cardiac and cerebrovascular         UNDERSTAND ALZHEIMER'S DISEASE AND
                                   accidents and intellectual function disorders. Our     FIGHT IT MORE EFFECTIVELY
                                   work is based largely on recording all cases of        Alzheimer's disease is a disorder of the brain that
                                   cardiac and cerebrovascular accidents that occur       develops over several decades. The team led by Dr
                                   in the region of Lille and its surroundings.           Jean-Charles Lambert is interested in studying the
                                                                                          susceptibility we all have for Alzheimer's disease.
                                   DETECTION OF CARDIAC AGEING IN ORDER                   In this way, we have identified the majority of
                                   TO ANTICIPATE IT MORE EFFECTIVELY                      genes involved in the onset of this disease. Our
                                   After a heart attack, the heart is often no longer     research should result in the development of new
                                   able to eject enough blood to meet the body's          avenues of treatment and prevention.
                                   need for oxygen, which causes heart failure. Dr
                                   Florence Pinet, who leads this team, is looking for
                                   the early markers of heart failure. She developed
                                   bedside clinical research protocols that she
                                   used to discover early biological markers of left
Speeding up research for better health tomorrow

   KEY
   EVENTS

              1
                   Heart diseases and cerebrovascular diseases
                   are inextricably linked. Using data from the
                   Lille registers of ischemic heart diseases and
               strokes, we compared different indicators of these
               diseases in men and women aged from 35 to 74
               between 2008 and 2014. We found that the heart
               attack rates exceeded the stroke rates, especially
               in men. The death rate was 2.2 times higher for
               heart attacks than for strokes, regardless of the
               age and sex of the patients. The same was true

                                                                        3
               of the fatality rate (percentage of people who                 To characterise individual susceptibility to
               die after a heart attack or stroke) which was 1.5              Alzheimer's disease, we need to compare
               times higher for heart attacks than for strokes                the genomes of several thousand patients
               (Meirhaeghe et al Bull Epidemiol Hebd. 2019)             and controls. This is the thinking behind our
                                                                        decision to increase the size of our samples by
                                                                        25% (nearly 100,000 individuals in total) in 2019.
                                                                        This resulted in our discovery of five new genes
                                                                        supporting the involvement of APP metabolism
                                                                        and the Tau proteins that make up disease lesions
                                                                        in the brain (Kunkle et al, Nat Genet, 2019).
                                                                        We are also continuing to expand our working
                                                                        samples with the European project EADB

              2
                     Heart failure remains one of the leading           (European Alzheimer Disease Biobank), which
                     causes of death worldwide. We identified           we coordinate and which doubles the number
                     the proteins in our blood that could predict       of subjects studied and the ADES (Alzheimer
               premature death, within 3 years, among the               Disease Exome Sequencing) project on the
               patients with heart failure hospitalised at the          analysis of exomes of nearly 12,000 patients and
               Lille University Hospital. The patient's blood           10,000 controls. Thanks to this unique access to
               proteins were analysed using nanotechnologies            the largest genomic study in the world, we will be
               (SOMAscan Slow Off-rate Modified Aptamer                 able to identify new avenues in the fight against
               technique). This was used to identify 203 proteins       this disease more quickly.                           23
               that were modulated differently between the
               patients who died from cardiovascular death and
               those who were alive 3 years after the onset of
               their heart failure. We finally selected six proteins:
               C3 complement, cathepsin S, MAPK5, MMP1 and
               MMP7 to predict the risk of early death in these
               patients (Cuvelliez et al, 2019).
INTEGRATIVE (EPI)-GENOMICS
     AND MODELLING OF METABOLIC
     DISEASES
     UMR8199 included two teams:                            teachers,    docs/post-docs,        engineers,     and
     1 | "Genetic and Epigenetic of diabetes and obesity"   technicians. The unit is at the origin of LabEx-EGID
     co-directed by Philippe Froguel and Amélie             and of EquipEx-LIGAN-PM, the genomic platform
     Bonnefond, and 2 | "Molecular bases and modelling      for personalised medicine.
     of metabolic diseases" directed by Jean-Sébastien                                             PROF PHILIPPE FROGUEL
     Annicotte. It counts 63 individuals, researchers,                                             PU-PH - Lille University, Lille University
                                                                                                   Hospital, LabEx, UMR8199, EGID, CNRS,
                                                                                                   Institut Pasteur de Lille, Lille University

                                     UMR8199 aims to understand the genetic and            RHAPSODY (Risk assessment and progression
                                     pathophysiological mechanisms at the origin of        of diabetes); as well as at the Research
                                     diabetes and obesity in order to make progress        University Hospital (RHU). PreciNASH (PIA-
                                     towards personalised medicine for metabolic           ANR, coordinated by François Patou, UMR1190).
                                     diseases.                                             In these projects, our teams have a key role
                                                                                           in producing and analysing (epi)genomic,
                                     The unit’s research objectives are to identify        transcriptomic data, or derivative microbiomes,
                                     new genes implicated in diabetes and obesity,         starting with large European cohorts of
                                     and to better diagnose forms of diabetes and          diabetic and/or obese patients and control
                                     obesity of genetic origin which thus allows           populations (including human samples selected
                                     personalised medicine according to genetic            from pancreatic, hepatic, or muscular tissues).
                                     sub-type. All projects also have as an objective      The environment’s epigenetic effects (which
                                     to better stratify genetic and environmental          modify genetic activity) on the metabolism and
                                     risk factors, and the primary genetic causes,         hepatic and renal complications of diabetes are
                                     of metabolic diseases at different ages in life.      studied, consequently epigenetic variations in
                                     Different "multi-omic" approaches were taken          pre-diabetic conditions such as gestational or
                                     by means of our genomic platform which is             premature diabetes (EPx-GDM and EPIPRETERM
                                     unique in France (high-speed DNA and RNA              projects). Thanks to the UMR8199's organisation,
24
                                     sequencing, genotyping, and transcriptomic            which is divided up between two teams, new
                                     analysis by DNA chips, digital molecular              pathways can be identified leading to metabolic
                                     counting     using   NanoString     technology).      diseases, after which cellular or animal models
                                     Opening the LIGAN-PM platform to outside              can be established in order to conduct in-depth
                                     teams makes it possible to initiate collaborative     studies leading to the development of new
                                     research projects on other genetic diseases           diagnostic and therapeutic strategies. Beyond
                                     such as intellectual deficiencies associated, or      that, the goal of the European Genomic Institute
                                     not, with obesity, Crohn’s disease, breast and        for Diabetes (EGID) is to offer optimal conditions
                                     ovarian cancers (using exome sequencing).             for translational research on diabetes to truly
                                     The unit is a partner to several EU-H2020             ameliorate treatment of diabetics and their life.
                                     Innovative Medicines Initiative programmes :
                                     IMIDIA (Improving beta-cell function and
                                     identification of diagnostic biomarkers for
                                     treatment monitoring in Diabetes), DIRECT
                                     (Diabetes research on patient stratification) and
Speeding up research for better health tomorrow

   KEY
   EVENTS

              1
                   Genetic factors play an important role
                   in the development of obesity with a
                   heritability of about 70%. About 5% of
               obese patients in France have a "rare" form of
               obesity known as monogenic. We discovered a
               new form of monogenic obesity which has the
               unique characteristic of leading to diabetes and

                                                                      4
               early hypertension, opening up diagnostic and                  In   collaboration   with   AptamiR,    a
               therapeutic perspectives.                                      biotechnology      company       recently
               Loss-of-function mutations in MRAP2 are                        established in the Lille agglomeration in
               pathogenic      in   hyperphagic      obesity with     the Eurasanté incubator, the MetaboMIR industrial
               hyperglycaemia and hypertension. Nat Med. 2019         chair project entitled "Identification of new
               Nov; 25 (11): 1733-1738. Baron et al.                  therapeutic targets and their mode of action for
                                                                      the treatment of obesity, type 2 diabetes and
                                                                      non-alcoholic fatty liver disease", funded by the
                                                                      Métropole Européenne de Lille and I-SITE, aims

              2
                     Common obesity is very polygenic, a              to identify and validate new therapeutic targets
                     feature which was established in 2007 by         with good potential for technological transfer
                     the Lille team: currently nearly 400 genes       and their modes of action in order to ultimately
               contribute modestly to the risk of obesity.            generate new treatments against certain
               We show that the most common obesity genes are         metabolic diseases in humans, including diabetes,
               preferentially expressed in the brain. The surprise    obesity and "NFALD/NASH" non-alcoholic fatty
               of this study is the lack of preferential expression   liver disease.
               of common obesity genes in the part of the brain
               that controls hunger, i.e. the hypothalamus. On
               the other hand, we find an enrichment of these

                                                                      5
               genes in regions of the brain involved in the                Our goal was to identify genomic sites
               reward and addictions mechanisms.                            where the genotype significantly affects
               The expression of genes in top obesity-associated            the expression of genes located nearby
               loci is enriched in insula and substantia nigra        within the genome. Our study identified novel
               brain regions involved in addiction and reward.        genes for type 2 diabetes (T2DM) and eQTLs           25
               Ndiaye et al.                                          that have not yet been studied in the context
                                                                      of beta cell biology: their study will explain the
                                                                      pathophysiology of T2DM more effectively.
                                                                      Laser capture microdissection of human
                                                                      pancreatic islets reveals novel eQTLs associated

              3
                     Our UMR managed the Lille application that       with type 2 diabetes. Mol Metab. 2019 Jun; 24: 98-
                     brought together the University of Lille,        107 Khamis et al.
                     Institut Pasteur de Lille, Inserm and the
               CNRS for the contest of the Future Investment
               Programme of University Hospital Institutes
               2. An international panel of judges selected
               our PreciDIAB project which, thanks to funding
               from the state and local authorities (Métropole
               Européenne de Lille and Hauts-de-France
               region) obtained €23m for a period of 5 years
               with the objective of developing personalised
               medicine for diabetics within the framework of
               the new National Centre for Precision Medicine
               (PreciDIAB).
NUCLEAR RECEPTORS,
     METABOLIC AND
     CARDIOVASCULAR DISEASES
     UMR1011       studies   the      pathophysiological   and epigenetic alterations. Therapeutic approaches
     mechanisms at the molecular and cellular level,       centred on nuclear receptors are implemented.
     in preclinical models and in humans, at the origin
     of obesity, type-2 diabetes and its cardiovascular                                       PR BART STAELS
     (atherosclerosis, heart failure, valvular diseases)                                      PU-PH - Lille University, Lille University
     and hepatic complications (NASH).                                                        Hospital, U1011, Inserm, Lille University, Institut
     The impact on the immune system of circadian                                             Pasteur de Lille, Lille University Hospital

                                     Metabolic pathologies such as obesity and          complications further to myocardial surgery
                                     type-2 diabetes and their cardiovascular           in humans. The receptor’s molecular action
                                     complications are the primary cause of death       mechanism at the hepatic level was also
                                     not only in industrialised countries but also in   specified.
                                     developing countries. Using fundamental and        The contribution of other nuclear receptors and,
                                     translational approaches, UMR1011 studies the      more generally, transcription factors to hepatic
                                     physio-pathological processes at the origin of     functions was also highlighted (PPARα in septic
                                     these pathologies with a particular interest for   shock, FXR, bile acid receptor, in the control of
                                     the nuclear receptors which represent choice       neoglucogenesis and diabetes). Finally, we have
                                     therapeutic targets.                               interpreted a new cellular mechanism for the
                                     Over the course of 2019, major breakthroughs       formation of brown adipose tissue.
                                     touched on the role of the Rev-erbα nuclear        Unit 1011 published over the course of 2019.
                                     receptor, a major regulator of the circadian
                                     clock in controlling acute inflammatory
26                                   reactions in mice (hepatitis) and cardiovascular
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