[Fis] NEW YEAR LECTURE (Youri Timsit)

[Pedro C. Marijuan]

Asunto: 	 NEW YEAR LECTURE
Fecha: 	Thu, 06 Jan 2022 15:09:26 +0100
De: 	Youri Timsit <youri.timsit at mio.osupytheas.fr>
Para: 	Pedro C. Marijuán <pedroc.marijuan at gmail.com>



Happy New Year to all!


First of all I would like to warmly thank Pedro Marijuán for having 
offered me to contribute to this New Year lecture. It is a great 
pleasure to exchange ideas in a context where “informational 
choreography” ^1 allows for imaginary encounters between Isadora Duncan 
and José Ortega y Gasset, to explore new ways of thinking about “what is 
life”. The topic of this new year lecture is “molecular brains”, a theme 
that has recently been developed on the basis of recent work on the 
ribosome ^2 ,  D. Bray's seminal paper published in 1995 ^3 and the 
recent papers about consciousness in non-neural organisms ^4

Are “molecular brains” a “vision of the mind” or a real property of 
matter and universe, born from the first forms of life? And as a 
corollary, did LUCA have a brain (molecular) and was he “intelligent”? 
And to go even further, is having systems capable of developing complex 
behaviours and cognitive faculties a fundamental property of living 
beings across scales? I hope that future works will shed light on these 
questions, but in the meantime, I present here briefly, the elements 
that led to the conclusion that systems equivalent of “neural networks” 
on a molecular scale could exist in the ribosome and that these systems 
most probably existed before the radiation of the three kingdoms.

The ribosome is indeed considered as window towards the earliest forms 
of life that predate the three kingdoms. While in astrophysics looking 
far away gives the opportunity to glimpse the fossil radiation of the 
universe, looking into the heart of the ribosome may tell us of what the 
first forms of life might have looked like. The ribosome evolved by 
accretion around a core that predates the radiation of the three 
kingdoms and were probably present in LUCA ^5–9 . The ribosomes are thus 
considered as a relic of ancient translation systems that co-evolved 
with the genetic code have evolved by the accretion of rRNA and 
ribosomal (r)-proteins around a universal core ^8,10–14 . They then 
followed distinct evolutionary pathways to form the bacterial, archaeal 
and eukaryotic ribosomes whose overall structures are well conserved 
within kingdoms ^15–18 . The complexity of ribosome assemblies, 
structures, efficiencies and translation fidelity concomitantly 
increased in course of the evolution.

The molecular brain’s story started with an attempt to understand the 
surprising electrostatic properties of the bL20 ribosomal protein 
(r-protein), a protein essential for the assembly of the large subunit 
of the bacterial ribosome ^19 . This r-protein had a kind of subversive 
and unique behaviour in deciding to crystallize in both a folded and an 
unfolded form within the same crystal ^20 . In trying to better 
understand its properties, we compared it to the other r-proteins 
located in the first high-resolution ribosome structures that had just 
been published ^21 ... and that's when something strange was noticed: we 
realized that uL13 and uL3, two r-proteins of the large subunit, were 
touching each other by a tenuous interaction between their two 
extensions, long filaments that weave between the phosphate groups of 
the rRNA. At that time, these famous r-protein extensions were a real 
enigma. It was thought that they could play a role in ribosome assembly 
by neutralising RNA phosphates with their positively charged amino acids 
^22 . But gradually it became apparent that all extensions of r-proteins 
systematically wove a gigantic network based on tiny interactions 
between them. In general, when proteins interact with partners, they 
form large interfaces (> 2000 Å^2 ) sufficient to stabilise their 
interactions. In this case, the vast majority of the interfaces did not 
exceed 200 Å^2 , which is all the more surprising given that they were 
extremely conserved phylogenetically ^23 .

Strikingly, it was found that the r-protein network also interacted with 
or “innervate” the ribosome functional centres such as tRNA sites, the 
Peptidyl Transfer Centre (PTC), and the peptide tunnel ^23,24 . Due to 
its functional analogy with a sensor-motor network, the r-protein 
network has been compared to a neural network, at the molecular level. 
Thus, it has been concluded that these tiny but highly conserved 
interfaces have been selected during evolution to play a specific role 
in inter-protein communication and they possess interacting residues to 
ensure information transfer from a protein to another. Thus, these tiny 
“molecular synapses" display a “necessary minimum” for allosteric 
transmission: a few conserved aromatic/charged amino acid motifs (fig. 
1). Moreover, it is possible that these minimalist “molecular synapses” 
reveal much more general principles in molecular communication. Indeed, 
these tiny interfaces, which appear in their simplest expression in the 
ribosome thanks to the spatial constraints of ribosomal RNA (rRNA), 
could be ubiquitous in macromolecular complexes, but drowned out by a 
'structural' background involving other amino acids for their 
stabilisation.


Figure 1. Molecular synapses and wires in the bacterial large subunit 
r-protein network. The tiny interfaces (the molecular synapses) between 
r-proteins are represented by surfaces

Data from the literature support our “vision of mind” that r-protein 
networks could contribute in both the ribosomal assembly and in the 
“sensorimotor control” during protein synthesis. Many experimental 
studies have indeed shown indeed that ribosome functional sites 
continually exchange and integrate information during the various steps 
of translation. As the numerous studies of the Dinman group have shown: 
“/an extensive network of information flow through the ribosome/” during 
protein biosynthesis ^25–32 . For example, several studies have also 
demonstrated long-range signalling between the decoding centre that 
monitors the correct geometry of the codon-anticodon and other distant 
sites such as the Sarcin Ricin Loop (SRL) or the E-tRNA site ^15,33 . 
R-proteins of the ribosomal tunnel also play an active role in the 
regulation of protein synthesis and co-translational folding ^34,35 . 
Ribosomes also perceive each other through quality sensor of collided 
ribosomes in eukaryotes ^36 . In addition, the ribosomes synchronize 
many complex movements during the translation cycles ^37–39 . The recent 
discoveries of “ribosome heterogeneity” ^40 also significantly expands 
the complexity of the possible ribosome’s network topologies ^41 and  
open new perspective on “network plasticity” that could also play a role 
its behavioural richness.

A recent interdisciplinary study with my mathematician colleagues Daniel 
Bennequin and Grégoire Segeant-Perthuis has shown how r-protein networks 
have evolved toward a growing complexity through the coevolution of the 
r-protein extensions and the increasing number of connexions ^42 . This 
study revealed that network expansion is produced by the collective 
(co)-evolution of r-proteins leading to an asymmetrical evolution of the 
two subunits. Furthermore, graph theory showed that the network 
evolution did not occur at random: each new occurring extensions and 
connections gradually relates functional modules and places the 
functional centres in central positions of the network. The strong 
selective pressure that is also expressed at the amino acid acquisition 
links the network architectures and the r-protein phylogeny thus 
suggesting that the networks have gradually evolved to sophisticated 
allosteric pathways. The congruence between independent evolutionary 
traits indicates that the network architectures evolved to relate and 
optimize the information spread between functional modules (fig. 2). In 
summary, graph theory, without knowing the function of the ribosome, can 
blindly detect the central functional centres of the ribosome. 
Conversely, ribosomes have learned graph theory during evolution, by 
placing the PTC and important functional centres at nodes corresponding 
to the maximum centrality of the network.



*Figure 2. r-protein and functional centres  networks in the large 
subunit of the eukaryotic ribosome. *The r-proteins and their extensions 
are represented according to their evolutionary status. Universal 
(common to bacteria, archaea and eukarya): red; Archaea: cyan; Eukarya: 
yellow. Lines between two circles symbolize an interaction between two 
globular domains. The colours of the lines follow the code for the 
evolutionary status described above, except for eukarya specific 
connection that are represented with black lines, for clarity. “N” or 
“C” indicate if the seg or mix are N-terminal or C-terminal extensions. 
NC indicates proteins without a globular domain (uS14, eL29, eS30, eL37 
and eL39). Functional sites (PTC, Tunnel, tRNAs and mRNA) are 
represented in light blue. The names of bacterial proteins which, by 
convergence, occupy a position similar to that of Eukaryotic or Archaeal 
r-proteins, are shown in blue below the circles.

Moreover, a network archaeology study has also revealed the existence of 
a universal network, that consists of 49 strictly conserved connections 
that was probably present before the radiation of the bacteria and 
archaea ^43 . This primordial network is much more developed in the 
small ribosomal subunit suggesting that the large subunit network 
complexity developed in later evolutionary stages. These findings 
therefore suggest that LUCA already possessed such type of molecular 
networks, with long wires and tiny interfaces. Interestingly, these 
networks also mix the i-systems of rRNA and aromatic amino acids of 
proteins for forming conserved structural motifs probably involved in a 
still unknown mechanism of signal transduction (probably involving 
electron or charge transfer). It is therefore possible that this 
ancestral mode of communication has then not only evolved in modern 
ribosomes but in other macromolecular systems for information transfer 
and processing. These results therefore suggest that the ribosome opens 
a window on the first information processing networks, which appeared at 
the origin of life. They probably diverged towards other cell systems 
that have been compared to brains such as the multiple nano-brains. 
These works provide the molecular basis to decipher how non-neural 
unicellular organisms may display complex behaviours such as associative 
learning and decision-making^1,2,44 .


Waiting for your comments and opinions,

Best regards to all!

Youri



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