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\DOI{10.5802/crbiol.156}
\datereceived{2024-05-15}
\daterevised{2024-06-05}
\dateaccepted{2024-06-17}
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\dateposted{2024-08-27}
\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{biographical-note}

\title{Tribute to Roger Guillemin, a pioneer in neuroendocrinology
(1924--2024), Nobel Prize in Physiology or Medicine}

\alttitle{Hommage au professeur Roger Guillemin, un pionnier de la
neuroendocrinologie (1924--2024), prix Nobel de physiologie ou
m\'{e}decine}

\author{\firstname{Christiane} \lastname{Mougin}}
\address{Department of Cellular Biology, University of
Franche-Comt\'{e}, France}

\author{\firstname{Jean} \lastname{Rossier}\CDRorcid{0000-0003-1821-2135}}
\address{Academy of Sciences, Institut de France, France}
\address{Royal Academy of Medicine, Belgium}

\author{\firstname{Bertrand} \lastname{Bloch}\CDRorcid{0009-0007-5404-7989}\IsCorresp}
\address{University of Bordeaux, France}
\email[B. Bloch]{bertrand.bloch@u-bordeaux.fr}

\keywords{\kwd{Neuroendocrinology}\kwd{Releasing
factors}\kwd{Hypothalamus}\kwd{Anterior pituitary}\kwd{Endorphins}}

\altkeywords{\kwd{Neuroendocrinologie}\kwd{Facteurs
hypophysiotropes}\kwd{Hypothalamus}\kwd{Ad\'{e}nohypophyse}\kwd{Endorphines}}

\shortrunauthors

\begin{abstract} 
Roger Guillemin discovered and characterized the hypothalamic factors
that control anterior pituitary functions. He consequently demonstrated
that these brain peptides regulate a large number of major body
activities through neuroendocrine mechanisms. This especially include
growth, fertility and reproduction, endocrine gland functions and
stress. These seminal works paved the way to major applications in many
fields of physiology and medicine for diagnosis, \mbox{pharmacology} and
therapy, far beyond the initial discovery and properties of these
molecules, including in \mbox{cancerology,} immunology, inflammation, drug
addiction and behavior.
\end{abstract}

\begin{altabstract}
Roger Guillemin a mis en \'{e}vidence et caract\'{e}ris\'{e} les
facteurs hypothalamiques qui contr\^{o}lent les fonctions de
l'ad\'{e}nohypophyse. Cette d\'{e}couverte majeure a permis de
d\'{e}montrer que ces peptides du cerveau r\'{e}gulent par voie
neuroendocrine un grand nombre de fonctions importantes de l'organisme.
C'est le cas de la croissance, de la fertilit\'{e} et de la
reproduction, des fonctions des glandes endocriniennes et du stress.
Ces travaux pionniers ont ouvert la voie \`{a} des applications
innovantes dans de nombreux domaines de la physiologie et de la
m\'{e}decine pour le diagnostic, la pharmacologie et la th\'{e}rapie,
bien au-del\`{a} de la d\'{e}couverte initiale et des
propri\'{e}t\'{e}s de ces mol\'{e}cules. Ces domaines comprennent en
particulier la canc\'{e}rologie, l'immunologie, les probl\`{e}mes
inflammatoires, les addictions et le comportement.
\end{altabstract}

\maketitle

{\vspace*{20pt}}

\twocolumngrid

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\xsection{}

\noindent
Roger Guillemin, Nobel Prize in Physiology and Medicine in 1977, died
at the age of 100 on February~21, 2024, in San Diego (California) where
he was living.

\begin{figure}
{\vspace*{3pt}}
\includegraphics{fig01}
{\vspace*{3pt}}
\caption{\label{fig1}Roger Guillemin at the Salk Institute in 2017
(Personal collection, Bertrand Bloch).}
{\vspace*{3pt}}
\end{figure}

Roger Guillemin was born in Dijon on January~11, 1924. He was a student
at the Carnot High School, and then began his medical studies in 1943.
His youth was nourished by the ``Franche-Comt\'{e}'' roots of his
father's family. A great-grandfather was an ironmaster in Vuillafans;
his father was born in Dole, and it was through this family that, as a
child, teenager and later medical student, he became very close to the
Duvernoy family in Besan\c{c}on. He strongly contributed to the French
resistance during World War~II, during the German occupation of
Besan\c{c}on, within a group of smugglers founded by Doctor Maurice
\mbox{Duvernoy.} It was from Maurice Duvernoy, director of the Besan\c{c}on
School of Medicine, that he later got his first anatomy lessons. By a
fair turn of events, Roger Guillemin's first works inspired some of the
neuroanatomical work of his son, Henri Duvernoy, on the vascularization
of the hypothalamic-pituitary arterial system.

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}Henri Duvernoy (left) next to the future Nobel
Prize in Medicine Roger Guillemin, himself next to his mentor Maurice
Duvernoy (Personal collection, C. Mougin; gift of H.~Duvernoy).}
\end{figure*}

Very early on his career, Roger Guillemin became passionate about
endocrinology. At the end of his medical course, he met Hans Selye in
Paris, a pioneer in stress studies. Fascinated by his lecture dealing
with the adaptation of the body to stress, Roger Guillemin left France
to work with him at the University of Montreal. His research work
allowed him to first defend his medical thesis in Lyon, then
subsequently his PhD in 1953 in Montreal. He then started to work for
several years at Baylor University College of Medicine (BUCM) in
Houston (Texas).

At the end of the 1940s, Geoffrey Harris, one of the pioneers in
neuroendocrinology at Oxford University, proposed that substances
present in the hypothalamus could reach the pituitary gland through the
portal vascular system, and control the release of pituitary hormones
and consequently many body functions, including stress. From this
concept, Roger Guillemin decided to isolate and characterize these
factors and synthesize them. This work will lead him to the Nobel
Prize. Between 1960 and 1963, he came back to the Coll\`{e}ge de France
in Paris where he developed his very first experiments devoted to
hypothalamic factors through innovative bioassays~\cite{1}. But according to
his words, the working conditions and administrative obstacles
encountered in France at that moment were at odds with his vision of
the ambitious and innovative research he wanted to develop. Roger
Guillemin then returned to BUCM in Houston in 1963. In his laboratory,
he created the material, technical, and  organizational conditions
necessary for the isolation of these molecules.

\begin{figure*}
\includegraphics{fig03}
\caption{\label{fig3}Roger Guillemin and his team at the Salk Institute
in 1983 (Personal collection, Bertrand Bloch).}
\end{figure*}

He hypothesized that these factors were small proteins (``peptides'')
produced by neurons in the hypothalamus. Even though his concepts and
his first results were strongly criticized by part of the \mbox{scientific}
community, he relentlessly developed innovative strategies to isolate
these substances present in minute quantities inside the brain. He
collected several tons of hypothalamic fragments from millions of sheep
in slaughterhouses. At the end of 1968, Roger Guillemin and his team,
including his students Roger Burgus, Wylie Vale, Catherine and Jean
Rivier, and Nicholas Ling, obtained 1~mg of the first hypothalamic
peptide from 300,000 sheep hypothalamus~\cite{2}. This peptide, called TRF,
stimulates the production of thyroid hormones through action on the
pituitary gland. Thanks to this first pioneering discovery,
neuroendocrinology became a major field in biology and medicine. The
structure of this peptide was established in 1969. Simultaneously, his
competitor Andrew Schally identified with his team the same TRF from
pig hypothalamic\break fragments.

In 1970, Roger Guillemin founded and directed the Laboratories for
Neuroendocrinology at the Salk Institute in San Diego (California), and
focused his research on the purification, isolation and
characterization of the hypothalamic peptide which stimulates the
release of hormones acting on the gonads (Gonadotropin-releasing
hormone or GnRH). He also tried to isolate the peptide that stimulates
the production of growth hormone. It took many years of sometimes
unexpected research results, because the first peptide he discovered
was an inhibiting substance, somatostatin. And it was a few years later
that GRF, the peptide activating the production of growth hormone, was
unexpectedly isolated from a pancreatic tumor responsible for
acromegaly~\cite{3}. This last discovery had direct consequences for
clinical medicine. The search for hypothalamic releasing hormone ended
in early eighties with the identification, by his former student Wylie
Vale, of CRF, the peptide that controls ACTH release~\cite{4}. 

Following the discovery of enkephalins, these endogenous morphines, by
John Hughes and Hans Kosterlitz in 1975, Roger Guillemin also
discovered several other opioid peptides, work to which one of us (JR)
contributed~\cite{5}.

\begin{figure}
{\vspace*{3pt}}
\includegraphics{fig04}
{\vspace*{3pt}}
\caption{\label{fig4}The Salk Institute for Biological Studies
(Personal collection, C.~Mougin).}
{\vspace*{3pt}}
\end{figure}

\begin{figure*}
{\vspace*{8pt}}
\includegraphics{fig05}
{\vspace*{8pt}}
\caption{\label{fig5}Hypothalamic neurons producing peptides
(Immunohistochemical detection) (Documents Bertrand Bloch).}
{\vspace*{16pt}}
\end{figure*}

Roger Guillemin therefore made a decisive contribution to the
understanding of the mechanisms by which the brain controls the
secretions of the pituitary gland and the endocrine system. The
consequences of his discoveries went quickly beyond the scope of
neuroendocrinology and are of particular interest for endocrine
physiology and pathology, control of fertility (contraception,
medically assisted reproduction, sterility\,{\ldots}), tumor and
inflammatory pathologies, regulation of mood disorders and psychiatry
and, of course, pharmacology~\cite{6}. These achievements also found
numerous applications in the veterinary field, something Roger
Guillemin liked to point out.

His work therefore led him to the Nobel Prize in Physiology or Medicine
in 1977, that he shared with Andrew Schally and Rosalyn Yalow. Roger
Guillemin also received the highest international honors. He was
elected as a member of the American Academy of Sciences in 1974 and as
a member of the Academy of Arts and Sciences in 1976; in France, he was
appointed foreign associate member of the Academy of Sciences in 1984.
His work has been recognized by numerous other prizes and honors. He
was \mbox{``commandeur} de la L\'{e}gion d'honneur''. Several universities
have conferred on Professor Roger Guillemin the title of Doctor Honoris
Causa, including the University of Burgundy (November 4, 1978) and the
University of Franche-Comt\'{e} (November~20,~1998).

Roger Guillemin has indeed trained and inspired dozens of students and
researchers around the world. Those who knew him have been impressed by
his ingenious mind combined with a sound science and willingness, and a
serenity associated with constant authority. Each of us had the
privilege to be part of his team in the late 1970s and early 1980s,
like several researchers from France, in this science paradise that is
the Salk Institute. His laboratory was a hive of world citizens, where
young researchers and skilled scientists of all origins were
interacting. Roger Guillemin's scientific demands went together with a
generosity and benevolence that permanently stimulated creativity.
Roger Guillemin was fully committed to promoting a science without
ideological or geographical borders; he has been involved on numerous
occasions with many other researchers in promoting this humanist vision
of science, open to the world and anchored in the needs of our
societies. This is evidenced by the numerous personal relationships
established with colleagues from all over the world, including in
France, throughout his life. Among many examples, let's remind his deep
ties of friendship and science with Professor Etienne Emile Baulieu,
inventor and promoter of RU486, the molecule for safe termination of
early pregnancy. Well beyond scientific discoveries and borders, his
personal influence allowed each of his students and collaborators to
create unwavering friendships and to promote his spirit and his values.

\begin{figure}
{\vspace*{6pt}}
\includegraphics{fig06}
{\vspace*{8pt}}
\caption{\label{fig6}Roger Guillemin during the ``Honoris~causa''
ceremony at the University of Franche-Comt\'{e} with Henry Duvernoy (on
his left), Bertrand Bloch and Christiane Mougin (on his right)
(Personal collection, Christiane Mougin).}
{\vspace*{15pt}}
\end{figure}

Roger Guillemin was also an elegant esthete, a very distinguished
oenologist, an artist and a lover of innovative art. He painted on
screen using his computer and basic softwares. No one knows what
painter he would have become if he had not decided to devote himself
completely to science.

He explained that the process leading to the creation of each of his
``computer paintings'', as he called them, was not very different from
the intellectual process of research carried out in the laboratory
about a scientific fact or a concept. However, according to him, there
is a major difference between the approach of a scientist and that of
an artist: ``There~are rules and laws from which the scientist cannot
\mbox{escape:} the laws of gravity, the fact that such a DNA sequence encodes
such a protein and not another, that gold melts at such and such a
temperature and not another, etc., while the rule for the contemporary
artist is precisely that there are no rules. It is \mbox{probably} a higher
level of what neuroscience and cognitive sciences call qualia.'' His
sculptures and pottery of pre-Columbian origin from Mexico, Vanuatu and
New Guinea, his relationships with numerous artists, including Nikki de
Saint Phalle, illustrate his refined interest for art. His six children
reflect this passion for art: a son who is a sculptor in Princeton, a
daughter who is a gallery owner, another a dancer\,{\ldots} and his late
wife Lucienne Guillemin, a talented pianist, and accomplished painter,
deceased in 2021 at the age of 100. With his family, Roger Guillemin
always enjoyed being on his farm in an outstanding natural site, in
Truchas, New Mexico, far from any urbanization; this haven of peace has
constantly been a specific location for him to think\break and work. \pagebreak

\begin{figure}[t!]
\includegraphics{fig07}
\caption{\label{fig7}Computer painting exhibit from Roger Guillemin in
Milano (1991) (Personal collection, Bertrand Bloch).}
\end{figure}

~\vfill\eject

\section*{Declaration of interests}

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

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