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\DOI{10.5802/crbiol.140}
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\dateposted{2023-12-19}
\datepublished{2024-03-29}
\begin{document}

\begin{noXML}

\makeatletter
\def\TITREspecial{\relax}
\def\cdr@specialtitle@english{A tribute to Fran\c{c}ois Gros, a founding father of molecular biology}
%\def\cdr@specialtitle@french{Un hommage \`a Fran\c{c}ois Gros, un des p\`eres de la biologie mol\'eculaire}
\makeatother

\title{Our journey with Fran\c{c}ois Gros}

\alttitle{Notre voyage avec Fran\c{c}ois gros}

\author{\firstname{Gillian} \lastname{Butler-Browne}\CDRorcid{0000-0002-3431-242X}}
\address{Sorbonne Universit\'{e}, Inserm, Institut de Myologie, Centre
de Recherche en Myologie, F-75013 Paris, France}

\author{\firstname{Vincent} \lastname{Mouly}\CDRorcid{0000-0003-3809-4033}\IsCorresp}
\addressSameAs{1}{Sorbonne Universit\'{e}, Inserm, Institut de
Myologie, Centre de Recherche en Myologie, F-75013 Paris, France}
\email[V. Mouly]{vincent.mouly@upmc.fr}

\begin{abstract}
Gillian Butler-Browne began working on muscle at the Institut Pasteur
in the laboratory of Fran\c{c}ois Gros in 1978. She characterized the
expression profile of different myosin isoforms during both human and
rodent development. Vincent Mouly joined this laboratory for his PhD in
1982, and defined the different populations of myoblasts appearing
during development in birds and then in humans. Together, they
demonstrated the impact of the limit in proliferation of the precursor
cells on the regenerative capacity of human skeletal muscle, and their
group developed models to evaluate the regenerative potential of
skeletal muscle {in vitro}, measuring the telomeric erosion, and
identified the involvement of a stress pathway in the proliferative
arrest of muscle progenitors. A platform to produce human immortalized
muscle cell lines was the successful result of this research, initiated
with Fran\c{c}ois Gros and W. E. Wright. The {in vivo} regenerative
potential of human muscle cells was evaluated by injection into muscles
of immunodeficient mice. Their group in collaboration with the clinical
team of Professor Jean Lacau St-Guily and Professor Sophie Peri\'{e}
completed a successful autologous myoblast transplantation clinical
trial for Oculo-pharyngeal muscular dystrophy. This common scientific
career was made possible thanks to the precious and always benevolent
support of Fran\c{c}ois Gros.
\end{abstract}

\begin{altabstract}
Gillian Butler-Browne a commenc\'{e} \`{a} travailler sur le muscle
\`{a} l'Institut Pasteur dans le laboratoire de Fran\c{c}ois Gros en
1978. Elle a caract\'{e}ris\'{e} le profil d'expression des
diff\'{e}rentes isoformes de myosine au cours du d\'{e}veloppement de
l'homme et du rongeur. Vincent Mouly a rejoint ce laboratoire pour son
doctorat en 1982, et a d\'{e}fini les diff\'{e}rentes populations de
myoblastes apparaissant au cours du d\'{e}veloppement chez les oiseaux
puis chez l'homme. Ensemble, ils ont d\'{e}montr\'{e} l'impact de la
limite de prolif\'{e}ration des cellules pr\'{e}curseurs sur la
capacit\'{e} de r\'{e}g\'{e}n\'{e}ration du muscle squelettique humain,
et leur groupe a d\'{e}velopp\'{e} des mod\`{e}les pour \'{e}valuer le
potentiel de r\'{e}g\'{e}n\'{e}ration du muscle squelettique \textit{in
vitro}, en mesurant l'\'{e}rosion t\'{e}lom\'{e}rique, et a
identifi\'{e} l'implication d'une voie de stress dans l'arr\^{e}t de la
prolif\'{e}ration des prog\'{e}niteurs musculaires. Une plateforme de
production de lign\'{e}es de cellules musculaires humaines
immortalis\'{e}es a \'{e}t\'{e} le r\'{e}sultat fructueux de cette
recherche, initi\'{e}e avec Fran\c{c}ois Gros et W. E. Wright. Le
potentiel de r\'{e}g\'{e}n\'{e}ration \textit{in vivo} des cellules
musculaires humaines a \'{e}t\'{e} \'{e}valu\'{e} par injection dans
des muscles de souris immunod\'{e}ficientes. Leur groupe, en
collaboration avec l'\'{e}quipe clinique des professeurs Jean-Lacau-St
Guily et Sophie Peri\'{e}, a r\'{e}alis\'{e} avec succ\`{e}s un essai
clinique de transplantation autologue de myoblastes visant \`{a}
traiter la dystrophie musculaire oculo-pharyng\'{e}e. Cette
carri\`{e}re scientifique commune a \'{e}t\'{e} rendue possible par le
soutien pr\'{e}cieux et toujours bienveillant de Fran\c{c}ois Gros.
\end{altabstract}

\keywords{\kwd{Actin and myosin isoforms}
\kwd{Classes of myoblasts}
\kwd{Immortalization}
\kwd{Muscular dystrophies}}

\altkeywords{\kwd{Isoforms d'actine et de myosine}
\kwd{Classes de myoblasts}
\kwd{Immortalization}
\kwd{Dystrophies musculaires}}

\maketitle

\twocolumngrid

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\xsection{}

\section*{Gillian Butler-Browne}

I carried out my PhD as a travelling SRC/UK scholar studying the
reconstitution of chromatin using various biophysical techniques. I was
working with Dr.~Stanley Bram at the Institut Pasteur to carry out
\mbox{X-ray}
diffraction on chromatin extracted from calf thymus. This entailed
weekly visits to the local ``abattoir'' (slaughterhouse). At the same
time Fran\c{c}ois Gros lab had chosen to isolate myoblasts from calf
fetuses in order to make large-scale cultures to isolate RNA, and this
is how I met the people from Fran\c{c}ois Gros' laboratory at the
Institut Pasteur who instilled in me my interest for muscle biology.

Fran\c{c}ois Gros then allowed me to learn the technique of culturing
muscle cells while I was still finishing my PhD, and to join into the
lab reunions in his office. In 1977, I was awarded a fellowship from
the Royal Society in London to undertake a postdoctoral fellowship in
Fran\c{c}ois' laboratory with the aim of studying with Bob Whalen the
expression of isoforms of contractile proteins specific to the
differentiated state. We used, or developed, several biochemical
techniques to characterize the contractile proteins expressed during
myogenic differentiation in primary rat and calf cultures, as well as
in cell lines such as L6~\cite{1}. The Institut Pasteur was a very nice
place to work, bubbling with activity, great seminars and good
discussions, Fran\c{c}ois' door was always open to discuss experiments,
and he even came and pipetted sometimes next to us in the lab while we
showed him our latest techniques and results.\linebreak Using the
2D-electrophoresis we had developed in the lab, we identified three
different isoforms of actin, two present in myoblasts and one specific
for the differentiated myotubes. We also identified a new myosin light
chain (MLC1emb) characteristic of embryonic muscles and cultured
cells~\cite{2}. At this time, I also had my first child who spent many
evenings sleeping in Fran\c{c}ois' office while I set up my
experiments. By using a combination of novel techniques developed in
the laboratory, including peptide mapping and native gel
electrophoresis, we also identified two new myosin heavy chains
isoforms, embryonic and fetal/neonatal that were specific to early
stages of muscle development and differentiated myotubes in
culture~\cite{3}. The work I carried out in Fran\c{c}ois' laboratory at
the Institut Pasteur led me to define certain stages of embryonic
skeletal muscle development in molecular terms, using rodents as a
working model and myosin heavy chain as the main marker. I was thus
able to define the order of expression of the different myosin heavy
chain isoforms during development and their regulation by the nerve and
by hormones~\cite{4}. Fran\c{c}ois always gave us the freedom to follow
our scientific projects as we felt best, the money always seemed to be
available to carry out our projects, if not he pushed us in the right
direction to look for financial support. We were also encouraged to
present our data at international meetings, which was quite hard when
you were presenting data which went against the dogma in the field.
Fran\c{c}ois had asked me to present my data at a Gordon conference and
at a FASEB meeting, a great start to a career. The notion of
developmental isoforms was not easy to get accepted, especially when
you present this as a young postdoc at this sort of international
meetings. It was during my postdoc that I also met some of the people
that were to become very important to me. Ketty Schwartz, director of
an INSERM Unit\'{e} working on the heart, who will later become head of
the research unit of the Myology Institute, came to work with us in the
lab to learn the different techniques we had developed and apply it to
the heart. She was a great scientist and friend and helped me many
times during my career. Fran\c{c}ois also introduced me to Michel
Fardeau, a clinician internationally renowned in the field of
neuromuscular disorders and future head of the Myology Institute in
Paris, AFM (French association against myopathies) and particularly
Bernard Barateau, who was then president of AFM. The discussions
between us directed the rest of my scientific career. It was thanks to
these discussions with Fran\c{c}ois, Michel and Bernard that I applied
all the knowledge and technology I had developed to study human muscle
development and disease. It was also thanks to a lunch with Professor Mongi
Ben Hamida, a distinguished clinician then Minister of Health of
Tunisia, that I discovered Tunisia and the Neurology Institute where I
made many trips, setting up the novel techniques of
immunohistochemistry in his service. Some of the best muscle biologists
seemed to have passed through Fran\c{c}ois' lab and this gave us an
amazing place to work. 

\section*{Vincent Mouly}

I joined the laboratory of Fran\c{c}ois Gros, the famous 6th floor of
the Monod Building in Pasteur, in 1982. My past education was not
particularly brilliant: after failing medicine (I made substantial
progress on saxophone at that time), I had enrolled in biology in
Jussieu. I had spent 18 months in Pasteur Dakar in Senegal (as a
surrogate to military services) and was looking for a lab to host me
for my DEA (which was the equivalent of master 2 at that time). I
visited several labs in virology (my field at that time) in Pasteur,
including that of Marc Girard, and added at the last minute the 6{th}
floor advised by Denise Paulin, who headed the DEA of microbiology. I
first met Marc Fiszman, who was heading a team in Fran\c{c}ois'
laboratory, and still keep a vivid memory of my first steps on the
6{th} floor. Marc had a tiny office open on a tiny lab of two small
rooms, packed with people. Marc was extremely nice, smoking his pipe
and listening to FIP (the French jazz radio station), and my decision
was immediately taken. There was still a pending problem: Marc was
working on muscle cells in birds, with very little connection to
virology! This was the time of the boost of oncogenes, and Marc had
shown in a \textit{Nature} paper in 1975 that temperature-sensitive
expression of sarc, the oncogene of the RSV, could allow manipulation
of muscle cell differentiation. There was the link! I joined the 6{th}
floor to work with Marc and Didier Montarras, who was finishing his
these d'\'{E}tat (much longer than the PhD) with Marc and taught me
everything about oncogenes. I met soon after Fran\c{c}ois, whose office
was at the other end of the corridor, guarded by Genevi\`{e}ve Antolini
and Annie Lassudrie-Duch\^{e}ne. Fran\c{c}ois had just resigned from
the direction of the Institut Pasteur to work as a scientific adviser
to the prime minister. Needless to say, exchanges with him were as
precious as sparse, and usually late in the day (or early in the
night). I was very impressed, but surprisingly, I discovered an
extremely humble human being who was eager to see what results I could
get in the field of muscle development (I was not completely convinced
that I would get anything worth it at that time{\ldots}).

Even though the presence of Fran\c{c}ois on the 6{th} floor was
unpredictable, his spirit was always present, and there was a familial
atmosphere in the lab. Most of the people working there did not count
the amount of time they spent in the lab. This scientific community was
extremely rich for a young student like me, with the group of Margaret
Buckingham at the other end of the floor, that of Bob Whalen and
Gillian Butler-Browne next to us, and the smaller groups of Michel
Cr\'{e}pin and of Josette Rouvi\`{e}re-Yaniv. Different families
coexisted on the 6{th} floor: Dani\`{e}le, the wonderful wife of
Fran\c{c}ois, was working in our group, Catherine (also from our group)
and Adrian Minty from Margaret's, Gillian Butler-Browne and Bob Whalen,
Arlette Cohen, another wonderful woman, who was Fran\c{c}ois' niece and
worked with Margaret, to quote some examples. I quickly learned that
the 6{th} floor was now my house, as it was for many others, and that
Fran\c{c}ois was the godfather and the guardian angel of this wonderful
group of people. I realize now the incredible luck I had to cross
Fran\c{c}ois' path: most of the people I worked with in the next years,
I met them while they were visiting Fran\c{c}ois' lab, which was one of
the main centers for research on muscle worldwide! And I had also the
opportunity to be sent to international meetings where I could easily
realize that my ``scientific family'' was a leader in the muscle field!
Margaret and Bob were often keynote speakers, and always fighting with
all the biggest labs working on muscle worldwide. This is how I met
leading scientists in the muscle field, such as Helen Blau from
Stanford University, Woody Wright from the University of Texas, South
Western (who was to become a close friend), Bernardo Nadal-Ginard, a
cardiologist from the Children's Hospital in Boston, or Hans-Henning
Arnold from Hamburg, and so many others. These, along with Margaret,
were pioneers in the newly emerging field of myogenic transcription
factors. Belonging to Fran\c{c}ois' lab was the true valid passport to
be accepted in that community, and to be invited to the beer sessions
where the people I considered as world leaders were exchanging
information! Of course, there was some pressure since the average
scientific level on the 6{th} floor was very high, but that pressure
never came from Fran\c{c}ois, who was always encouraging and finding
interests in every single piece of scientific information that was
brought to him. As an example of that pressure, I still remember
participating to what was presented to me as an informal meeting in
Concarneau, where Fran\c{c}ois asked me to present my PhD project (you
did not say no to Fran\c{c}ois). I realized that this was a common lab
meeting between the 6{th} floor and the lab of\break Sydney Brenner, who was
to become soon Nobel Prize. I also made my first oral short
communication in Keystone at midnight, while still a young PhD student,
presented by Steve Hauschka, from the University of Washington in
Seattle, who pioneered the field of myoblasts during development which
was the topic of my PhD~\cite{5}! Seminars were also impressive at the
bottom of the Monod building, which also housed at that time
Fran\c{c}ois Jacob and Jean-Pierre Changeux (who later moved to the new
Biotechnology building). Nicole le Douarin, who was heading the
Institute of Development in Nogent, was visiting sometimes, and I was
sent to her lab to bring my ``expertise'' (I certainly did not think I
was an expert in anything at that time) in 2D-gels and western blots
(they call that proteomics nowadays), which I used to study tropomyosin
isoforms~\cite{6,7,8}. One day, a young (but older than me) Italian
scientist visited Marc, and I had to explain to him what I was doing
while he was waiting for Marc. I was petrified to realize that this was
Giulio Cossu, from La Sapienza University in Roma, another main actor
in the field of classes of myoblasts during development and one of our
strongest competitors with Franck Stockdale, from Stanford University
(whom I also met in Keystone). The people who had joined the 6{th}
floor before me, or did after, also became close friends at that time
(I remember Marc's next student after me, Domenico Libri, who later on
played a major role in the RNA biology field, David Sassoon as a
postdoc in Margaret's, and Gary Lyons, another postdoc who became a
very close friend, and so many others), and we also had discussions
with Fran\c{c}ois' other lab in\break Coll\`{e}ge de France.

\advance\baselineskip by -.2pt
The second difficulty after convincing the University that my PhD
contained some elements of virology, was to find a date for the defense
of my PhD! I wanted to have Nicole le Douarin as part of the jury and
finding a common slot between Nicole and Fran\c{c}ois took over a year
(but that was worth it, and I offered Nicole a piece of cake (a somite)
especially made by a friend and representing a chick embryo!) I will
never thank enough Fran\c{c}ois and Marc for allowing me to meet all
these impressive scientists and to be able to join such a community.

Some changes in my personal life confirmed that Fran\c{c}ois was really
a gentleman. I had met Gillian Butler-Browne and we became partners in
science and in life. Needless to say, this introduced some
perturbations in the 6{th} floor atmosphere, but Fran\c{c}ois (and
Marc) was always supportive in these hard times, as he has always been
since. The next step was what to do next. My personal situation was
complicated (I already had two boys, and Gillian had two girls), and
Marc offered me to stay after my PhD to work part-time on his projects
and to develop mine during the rest of the time, with the blessing of
Fran\c{c}ois. I realize that if I got a position at CNRS in such a
configuration, this was certainly due to the constant support of
Fran\c{c}ois and of Nicole le Douarin.

\section*{Our common path with Fran\c{c}ois' support}

We had developed interest for human muscle pathology, and Fran\c{c}ois
was then the head of the scientific board of AFM (the French muscular
dystrophy association). He was deeply involved in this new role (on top
of the numerous ones he was playing in French and international
science) and introduced us into the AFM circle which we never left
since. AFM had already supported the last year of my PhD, and we
decided to engage into research on human muscle and dystrophies.
Through Fran\c{c}ois, Gillian had already met Michel Fardeau, deeply
engaged into this field, and Fran\c{c}ois encouraged us to go in that
direction. I joined Gillian in her new location at the medical school
in rue des Saints-P\`{e}res, where we started a small group on human
muscle development and pathologies. This is when Woody Wright came back
into the picture by encouraging us to work on\break telomeres in human
skeletal muscle stem cells. Woody had been a brilliant postdoc in
Fran\c{c}ois' lab, before coming back to the aging field and creating
his own lab in Dallas (he made his PhD with Leonard Hayflick, a pioneer
in the aging field). Fran\c{c}ois never forgot us, and always supported
us after our departure from the 6{th} floor. I remember he invited us
to a meeting in the M\'{e}rieux property, and, as he often did, asking
me at the last minute to present the telomere subject. I thought I had
a good excuse: no slides (this was the time when slides were real
slides, not PowerPoint). No problem, Fran\c{c}ois told me, you will use
filter pen and transparencies! Again, you don't say no to Fran\c{c}ois,
even though Jim Watson was there. He also introduced us into the field
of stem cells through dedicated meetings and networks at the
Acad\'{e}mie des sciences (we even wrote a paper together on this
topic~\cite{9}), where we met many collaborators with whom we set up
the INSERM stem cell network (including Thierry Jaffredo whom I had met
when he was in Nogent, Marina Cavazzana from Necker who was a pioneer
in the field of cell therapy for blood diseases, Georges Uzan from Paul
Brousse Hospital, Laure Coulombel from Gustave Roussy Hospital who
initiated the \textit{m\'{e}decine/sciences} journal, and many others).
I now realize that I started working on cellular senescence and
immortalization when I started my PhD in Fran\c{c}ois' lab, although
Woody and I managed to publish overcoming of senescence in myoblasts
only in 2007~\cite{10} (a project we started when I visited him in
Dallas in 1998). Fran\c{c}ois was never very far from us, we visited
him every now and then (not often enough) at the Acad\'{e}mie, and he
offered us to join a research unit in Piti\'{e}-Salp\'{e}tri\`{e}re in
1998, a lab directed by Marie-Madeleine Portier, one of Fran\c{c}ois'
collaborator in Coll\`{e}ge de France. She was retiring, and
Fran\c{c}ois thought Gillian could take over. Once again, Fran\c{c}ois
was offering us an opportunity to move forward in our career, and to
set up our own lab next to the Myology Institute founded by Michel
Fardeau and Ketty Schwartz, and where Marc Fiszman had moved. This
represented an important step in our scientific journey, since we now
could dedicate all our efforts to human muscle pathologies and
regeneration, with the constant support of AFM. We then joined the
Myology Institute when Thomas Voigt took the head, and Gillian joined
the scientific secretary of AFM while I joined the scientific board of
AFM. Fran\c{c}ois was still deeply involved in AFM and
T\'{e}l\'{e}thon, and I am convinced that he was involved in the
invitation we had with AFM by the President at Elys\'{e}e. Gillian
Butler-Browne retired in August 2018 from being director of the newly
created Centre of Research in Myology situated within the Myology
Institute in the GH Piti\'{e}-Salpetri\`{e}re. Fran\c{c}ois came as an
old friend to the meeting we organized for Gillian's retirement, when
so many of the friends we had met through him came. Gillian is now an
emeritus scientific director, while Vincent Mouly is still co-heading
their group with Capucine Trollet, and is also involved in managing
research bodies at Sorbonne University.

During all these years, from the family of the 6{th} floor to that of
AFM and to the Institute of Myology, Fran\c{c}ois always supported us
with kindness. He opened many doors for us, and without him, we
strongly doubt we could have even imagined what would be our scientific
career. He was a fascinating human being, who combined extreme
intelligence with human understanding of what other people could do. We
consider meeting him was the best thing that ever happened in our life,
both scientifically and personally. We learned so many lessons from
him, including working hard, but also scientific and human integrity.
He was a true scientific gentleman who pushed the limits of knowledge,
imagination, and scientific honesty to an extent that few people have
reached. Within his brilliant career, he helped so many people that it
is hard to understand how he found time to still push these limits. And
he did that with a humility that only extremely talented people can
afford. Thank you Fran\c{c}ois for all your help and support, for all
the wonderful time we had with you, but mainly for being such an
example to the following generations.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could\unskip\break benefit from this article, and have
declared no affiliations other than their research organizations.

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