Dr Bernard THISSE,
Directeur de Recherche au CNRS, France
Professor of Cell Biology and Biology, Cell Biology Department, UVA, Charlottesville,
USA
In memory of Bernard
December 30th, 2021
Dear All,
This is the saddest letter I ever wrote in my life. Bernard passed away recently. He was
diagnosed the last day of 2020 with a very aggressive lymphoma. He fought during 16 months,
trying every treatment that was available. He took this journey, fighting without complaining.
But he did not win the battle. I miss him terribly. All of us (friends, family, trainees, colleagues)
miss him. He was passionate by about many topics in Science, but also has strong interests in
Philosophy, Astronomy, Physics, History, Art, Operas and … Politics. Where he felt the best
was outdoor. He was a serious biker and hiker, in love with mountains and forests.
Bernard always challenged himself and us all around him. He had to answer his
questions, he never gave up, worked like crazy and wanted perfection in all he was doing. No
way he would accept a poor image or a crapy gel. He had a bright mind and was able to get
out his field (e.g.: circadian rhythm, morphogenesis in vitro using a mouse embryonic stem
cell model) with the same success that the ‘home’ topics he was studying.
When Bernard started in Science, it was in the early days of Molecular Biology and
Developmental Biology started to emerge as a new field of investigation. Bernard did his PhD
in Strasbourg (France, LGME, Director: Pf. P. Chambon) using Drosophila melanogaster as a
model organism, focusing his study on the molecular characterization and analysis of the
function of a gene essential to the formation of the mesoderm at gastrulation, the twist gene.
After its cloning (a very long walk in the 80’s) and analysis of its expression, he both sequenced
the twist gene and generated antibodies to visualize its expression. He then studied the
interaction of twist with the maternal transcription factor known to be required for the
formation of ventral domains of the fly embryo, the dorsal gene. He found that the
transcription of twist is directly activated by dorsal and therefore that the transfer of the
maternal information to the zygote involves a cascade of transcriptional activation.
Just after getting his PhD, he got a CNRS position (very rare to get it at this step of a
career). Bernard then moved to University of Oregon for his post-doc (under the supervision
of Pr J. Postlethwait, University of Oregon, Eugene) to evaluate the potentialities of a novel
and very promising animal model, the zebrafish. Prof P. Chambon had already offered us lab
space at our return to France to start the zebrafish model in his new institute: at the IGBMC
(Strasbourg, France). Everything had to be built (e.g.: cloning genes, getting markers, genetic
tools, developing various protocols for injection, transplants…). Convinced that the zebrafish
model would be the perfect model to study early patterning events, Bernard decided to
approach the question by studying first the establishment of the dorso-ventral axis and then
to elucidate the formation of the antero-posterior axis.
As a PI in IGBMC, his major contribution has been to establish that the dorso-ventral
patterning depends on the morphogenetic activity of an heterodimer of bone morphogenetic
proteins (BMP2b/BMP7) regulated by three antagonists Chordin, Noggin1 and Follistatin-like
1b and on the activity of the FGF signaling pathway that restrict BMP gene expression to the
ventral part of the embryo. We found that this FGF activity is negatively regulated by Sprouty2,
Sprouty 4 as well as by Sef (Interleukin 17 receptor D).
A second major contribution to the field of early zebrafish development was to
demonstrate that the Nodal signaling pathway is responsible for the graded establishment of
cell fates along the antero-posterior axis of the zebrafish embryo and to identify Antivin/Lefty
to be a competitive inhibitor of Nodal that limits its activity. Bernard also reexamined the
concept of dorsal/Spemann Organizer in the organization of the embryo. We discovered that
the organizing properties are not restricted to the dorsal margin of the embryo as previously
described but instead are distributed all along the embryonic margin. At the molecular level,
we found that these organizing activities depend on the ratio of activity of two morphogenetic
gradients, BMP and Nodal. We demonstrated that two opposing gradients of BMP and Nodal
are sufficient, both in vivo and in vitro, to instruct uncommitted cells of the zebrafish blastula
animal pole and to become organized into a well-developed embryo.
Based on his very sharp in situ and intact embryo morphology, Bernard realized that
maternal Wnt8a mRNA was deposited at the vegetal pole of the embryo. From there, we
identified that the maternal Wnt8a mRNA was the zebrafish dorsal determinant. The lab
showed that this mRNA is transported from the vegetal pole to the blastomeres on one side
of the embryo that becomes the dorsal side. We also demonstrated that the extent of Wnt8a
domain of activity at blastula stage is restricted to the dorsal margin by the activity of two
maternally provided Wnt antagonists, Sfrp1a and Frzb.
Finally, we also discovered a novel mechanism for the regulation of the transcriptional
outcome of the canonical Wnt/β-catenin signaling pathway that involves a modulation of the
activity of the TCF corepressors Groucho/TLE through their sequestration by interaction with
the transcription factors Lbx2.
Even very successful (number of papers, high impact journals, awards, grants), Bernard
wanted to get out of his comfort zone, in being exposed to other ways of approaching
questions in Science and to interact with people having a different background than his own.
The obvious choice for us was to go back to the US, and we moved in 2007 to be relocated in
the School of Medicine, University of Virginia, Charlottesville.
The main adventures there were of 2 folds: leave the early patterning questions to get
interested in Left-Right asymmetry with a transcription angle and second, build a mammalian
embryo-mimetic system using a new model system for us (mouse embryonic stem cells)
instructed with spatially localized morphogen activity gradients.
We found that the transcription factors and transcription cofactors mediating or
regulating the transcriptional outcome of the Hippo pathway control the development and
differentiation of the progenitors of the Left-Right organizer and therefore left-Right
asymmetry. These factors regulate all transcription factors known to be required for the
function of the organizer as well as the expression of essential ligands and receptors of major
signaling pathways (Nodal, FGF, non-canonical Wnt and Notch) previously shown to be
essential for the formation of the Left-Right organizer. Finally, one of the transcription
cofactor Vgll4l regulates spatially and temporally the expression of de novo DNA
methyltransferases and methylbinding proteins: writers and readers of DNA methylation
marks. This was the first example demonstrated in a living and wild-type embryo of a
regulation of epigenesis through the transcriptional control of DNA modifying enzymes.
Based on the discovery we made showing that two opposing gradients of BMP and
Nodal are sufficient, both in vivo and in vitro, to instruct uncommitted cells of the zebrafish
blastula animal pole and to become organized into a well-developed embryo, Bernard had the
excitement to explore inducing embryonic development from aggregates of mouse embryonic
stem cells. We have been able to induce in vitro formation of the 3 germ layers through a
process of gastrulation and their differentiation in various tissue and organ primordia,
mimicking the development of the mouse embryo up to mid-gestation. Moreover, we
observed formation of a notochord, vasculature and a neural plate folding to form a neural
tube. This was the last paper Bernard published. In between heavy cycles of treatments, he
insisted to mount all the figures himself. You can easily recognize Bernard’s style. Science was
Art for him too.
More than anything, he loved interacting with other scientists and developed many
collaborations, most of them within the Zebrafish community (e.g.: working on novel
primordial germ cell specific genes, the origin of embryonic macrophages, left-right
asymmetry of the brain, made a library of expression pattern of the whole family of zebrafish
nuclear receptors, studied the family of fatty acid binding proteins, Na/K ATPases and
adenosine and dopamine receptors, or a family of blood markers). He had the crazy idea and
the gut that took every evening of his life during years to build an in situ database, as a
resource for the scientific community. This database is still heavily used and he (I) still get
many requests for sending clones or asking for advices. Bernard provided the scientific
community with more than 50,000 pictures.
Because of his health condition and heavy care plan, we decided to get retired 09.01.
2021 and closed the zebrafish lab. Bernard was excited by the idea of going back to the bench
early January 2022 to perform experiments as a volunteer scientist and to continue on the
mouse stem cell project focusing on the formation and development of the brain in
embryoids. This did/will not happen.
Altogether, Bernard could be proud of what he achieved. He answered most of the
questions he raised, used a mix of technologies to answer them (e.g.: molecular biology,
genetics, genomics, imaging, dissections, transplants, injections…). He published a number of
studies in prestigious journals and would always want to publish when he would have a
complete story to tell, the best possibly documented.
He was a great mentor and conveyed his passion for Science and Philosophy. Students
and post-doctoral fellows he trained took with them his optimism and hard worker attitude.
Marie & Agathe were with me the last weeks of Bernard’s life. This was very special.
I miss him so much.
Christine