To understand how touch acquires emotional value, Amaury François studies the neural circuits that link the sensory system to reward circuits. His work targets neurons sensitive to caresses: C-LTMR mechanoreceptors.
From sensation to emotion
"How can touch create a positive or negative emotion?
Touch not only transmits objective information about an external stimulus; it also has an enjoyable or unpleasant emotional dimension essential to the survival of mammals. Pain prompts us to flee from stimuli that are harmful to the body. Conversely, pleasant sensations stimulate social bonds.
While the neural networks that transmit objective tactile information are well known, those connected to emotion are more enigmatic. Dr. François aims to identify the neural networks that shape the emotional experience of touch.
Exploring the links between sensory information and reward circuits
Dr. François and his team have discovered neurons in the skin called C-LTMR mechanoreceptors which, when activated, create a pleasant sensation and thus strengthen social ties.
He and his team will explore the neural networks activated by petting mice, which link the neurons innervating the skin to reward circuits to trigger a positive emotion. They will focus on a part of the brain called the insular cortex, where certain neurons integrate the information transmitted by the skin’s C-LTMR mechanoreceptors, contributing to the emergence of the positive emotional dimension during a tactile contact.
Understanding sensory processing deregulation to treat chronic pain
Impulscience will allow Dr. François to mobilize innovative biotechnologies such as optogenetics, which uses light to change how neurons function or makes them glow depending on their activity. He will be able to manipulate touch neurons and monitor the neuronal activity of the cerebral regions responding to the stimulation in real time.
His research is crucial for understanding the various pathologies linked to a deregulation of sensory processing, such as chronic pain and anhedonia, which is the loss of interest in pleasant stimuli. Dr. François hypothesizes that these disorders are related to a detour of the neural pathways taken by the mechanoreceptors. C-LTMRs would be a potential way to reverse those pathologies, making them a promising therapeutic target.
Amaury François in a few words
Since obtaining his PhD in neuroscience at the University of Montpellier, Amaury François has explored somatosensory pathways to understand pain perception mechanisms.
During his post-doctorate at Stanford University Medical School, he designed innovative tools to track the activity of neurons involved in pain and manipulate them. As a CNRS researcher at the Montpellier Institute of Functional Genomics, since 2018 he has continued developing new molecular tools to manipulate touch neurons and behavioral tests to study pleasant touch in rodents.
Impulscience grant will allow Dr. François and his team to carry out an ambitious project: mapping the neural circuits that allow the emotional dimension of touch to emerge. This research is crucial for understanding and treating pathological deregulations of the sensory system, such as chronic pain.
By forming filaments and networks, actin is a key component in maintaining the shape of cells. In microfluidic chambers, Antoine Jégou recreates the constraints actin filaments are exposed to in cells to study how different actin networks are constructed and cohabit.
The actin network : a hors of forms for multitude of functions
Actin, a very abundant protein in our cells, can self-assemble to form filaments, which then form networks. This allows the cells to keep their shape, move, grow and divide as a kind of cell skeleton. Actin filaments have a wide range of shapes, sizes and mechanical properties. In addition, some proteins capable of associating with actin strongly contribute to defining the identity of each network. Lacking accurate measurements, researchers do not yet understand how the identity of actin networks is established and maintained. How can networks with surprisingly different structures and assembly dynamics coexist in a cell? How do actin-associated proteins target a particular network rather than the neighboring one?
Microfluidics to the rescue
The different actin networks have different properties because of their content, their combination with other proteins and their mechanical constraints. Interactions between these multiple factors are important in determining the identity and function of actin networks. How can they be studied?
One way is to recreate actin networks outside the cell in vitro by adding all the factors involved in their construction and function one by one. The factors must be sequentially and quantitatively studied, from the level of individual filaments to networks, while controlling many parameters. Antoine Jégou's team is preparing to meet this major technical challenge with microfluidics, a technology he has been developing in his laboratory for over 10 years.
Like in the cell
The microfluidic chambers Dr. Jégou proposes to use are very narrow, typically measuring one millimeter wide and only 20 micrometers high. In them he can place and observe one or more kinds of about a hundred actin filaments at the same time, subject them to various constraints and expose them to different proteins and forces. The filaments will grow more or less quickly and interact with each other and with different proteins that will change their shape and mechanical properties. Dr. Jégou's team members will leave no stone unturned to recreate the situations filaments encounter in a cell.
The team will study combinations of factors and use automated analytical methods to provide new insights into the intertwined/interdependent processes that govern actin network identity in cells.
Antoine Jégou in a few words
Antoine Jégou studied telecommunications engineering and worked for a mobile telecommunications company in Europe and Asia before turning to basic research in biophysics and obtaining a PhD in that field in 2008. During his post-doctoral fellowship at the structural enzymology and biochemistry laboratory on the Gif-sur-Yvette CNRS campus, he studied actin biochemistry and developed new tools to study actin dynamics at the single filament level.
In October 2014, together with Guillaume Romet-Lemonne he co-founded a research group at the InstitutJacques Monod in Paris. Since then, they have addressed key questions about how actin-binding proteins interact with actin filaments. Dr. Jégou received support from the ERC (Starting grant) in 2016.
Chunlong Chen and his team are trying to understand how our DNA duplicates itself with each cell division. Their new, cutting-edge approaches will shed light on why starting the process at the right time and place is fundamentally important to the proper functioning of cells.
The hard task of duplating the genome
When our cells divide, they must duplicate their DNA to ensure that both resulting cells have a copy of the same DNA sequence. To do that, duplication, called replication, begins at very specific sites in the DNA, in a remarkably organized and dynamic fashion. It depends on the type of cell and its state. A dividing human cell has over 30,000 replication origin sites to duplicate two meters of DNA (more than 6 billion base pairs!). While this vital process is incredibly well organized, deregulation can jeopardize the genome’s stability and lead to several diseases, such as cancers or some neurological diseases.
The origins of replication under the microscope
The individual origins of replication and their exact location and efficiency cannot be studied using current technology. It is also hard to study the order in which the replication origins are active, which is crucial to DNA duplication. Chunlong Chen aims to develop technology that can be used to study these key steps in DNA replication.
His laboratory has extensive expertise in the large-scale study of single DNA molecules. The team will combine imaging, mathematical modeling and bioinformatics analysis methods to observe replication as it has never been seen before.
DNA replication in two specific contexts: cancer and the formation of new neurons
In the project backed by Impulscience, Dr. Chen's team focuses on two conditions that are sensitive, each in its way, to the genetic instability caused by DNA replication.
On the one hand, he will study DNA replication in healthy and tumor cells and the link between replication and genome instability in cancer.
On the other, he will study the effects of replication errors on the formation of new neurons, or neurogenesis, to understand the vulnerability of the process, which can have consequences for brain function.
In addition, the team will develop tools to study individual replication origins to understand why some areas of the genome are more vulnerable to errors than others, and the importance of coordinating DNA duplication with other processes, such as reading genes to produce proteins (transcription).
Chunlong Chen in a few words
Chunlong Chen obtained his PhD in bioinformatics in 2007 from Université Paris-Sud and Sun Yat-sen University (China). In 2008, he joined the Molecular Genetics Center in Gif-sur-Yvette as a post-doctoral fellow and in 2011 as a permanent CNRS researcher. During this period, he became interested in the role of DNA replication in the appearance of mutations in the human genome and the stress associated with DNA replication and genome instability, which plays an important part in many human diseases. In 2016, he joined the Institut Curie in Paris, where he created the "replication program and genome instability" research team. His team uses genomic approaches and genome-wide data analysis to study DNA replication and how its deregulation challenges genome stability. Dr. Chen is recognized as a leader in this field. In 2012, he received the Academy of Sciences’ AXA Award for his contributions.
In cellular reprogramming, differentiated adult cells assume the characteristics of stem cells, thereby boosting the regeneration capacity of certain tissues. Fabrice Lavial is trying to understand the genetic mechanisms that might allow the benefits of cellular reprogramming to be kept while avoiding the risk of developing cancer. Understanding and limiting those risks would be a major advance for regenerative medicine.
The promise of cellular reprogramming
During development, stem cells differentiate into specialized cells characterized by genetic expression programs specific to each cell type. Those identities are expected to remain stable as cells divide. However, differentiation can be "erased" by using four factors (Oct4, Sox2, Klf4 and c-Myc) that act on genetic expression and give cells the characteristics of stem cells again. This process is called cellular reprogramming. We can imagine taking skin cells from a patient, reprogramming them to obtain stem cells, then programming them again into brain cells, for example. This type of process holds out tremendous therapeutic potential.
The dark side of reprogramming
These great therapeutic promises should be taken with caution. More research is necessary to understand the mechanisms and long-term consequences of reprogramming. Indeed, when carried out in animals (in vivo), reprogramming boosts the regeneration capacity of certain tissues but also causes a disease where cell multiplication is uncontrolled: cancer. Consequently, despite their revolutionary effects, the molecular mechanisms triggered by in vivo reprogramming must be understood better to avoid reaching the point where cells become cancerous.
The reprogramming process has similarities with cancer, such as giving cells the ability to renew themselves and resist aging and cell death. The genes involved in both processes have received little attention, mainly due to a lack of dedicated genetic tools, yet this research will be crucial to understanding interactions between reprogramming and cancer, which have diametrically opposite effects.
A mechanism in common with the development of cancer
Impulscience grant will allow Dr. Lavial's team to answer key questions before considering therapeutic prospects using cellular reprogramming.
He will compare and study the genetic expression profiles of reprogrammed cells and lung cancer cells. This will reveal the molecular program allowing cells to acquire the ability to reprogram themselves and determine the critical point at which they become cancerous.
The research program’s originality lies in using mouse models developed in Dr. Lavial's laboratory that allow him to accurately control when and in which cells reprogramming and tumor growth will be triggered. That way, the team can map genetic events and predict critical moments. Researchers will be able to pinpoint which genes need to be blocked to keep the reprogrammed cells from becoming cancerous.
Fabrice Lavial in a few words
In 2008 Fabrice Lavial obtained his PhD from the École Normale Supérieure de Lyon, where he explored the role of key pluripotency genes, Oct4 and Nanog, in chicken embryo development. During his post-doctoral stay at Imperial College London, he studied the functions of specific factors in stem cells and in reprogramming in the mammalian embryo. In 2014, he joined the Cancer Research Center of Lyon to create his laboratory thanks to an ATIP-Avenir grant. Since then, he and his team have contributed to the field of cellular reprogramming research, most recently focusing on cancer research.
Why are bacteria becoming increasingly resistant? Many researchers have tried to answer this question, without being able to fully resolve the enigma. Lydia Robert and her team are using a new multidisciplinary method to determine, for the first time, the environment’s impact on the appearance of mutations in bacteria DNA at the origin of the phenomenon.
An "arms race" in our bodies
A strange arms race is constantly underway in our bodies. It is a fight between our resistance to infectious diseases and the pathogens themselves. Mutations are the basis of this internal war, that allow pathogens to evolve. For example, they can enable them to develop greater resistance to antibiotics, or make them more virulent.
Similarly, some cancer cells accumulate mutations that allow them to escape chemotherapy. However, environmental factors also induce mutations. For example, sublethal doses of antibiotics seem to promote mutagenesis in bacteria.
A pioneering new method
However, these results are controversial. Classic experiments have limitations and are prone to bias. Dr. Robert and her colleague Marina Elez have developed a groundbreaking method to overcome those hurdles. They use a single-cell approach to accurately characterize mutagenesis in Escherichia coli bacteria in different environments. They combine genetics, molecular biology, microfluidics, optogenetics, deep sequencing, mathematical modeling, statistics and other disciplines to achieve the best results.
The Foundation’s support
The support from Fondation Bettencourt Schuller will allow Dr. Robert to clear the obstacles of the traditional experimental approach. Her main goal is to define the environment’s impact on the bacterial mutation rate for the first time.
She plans to study the effects of limiting the nutrients provided to the bacteria and adding sublethal doses of antibiotics. The idea is also to understand the impact of transient mutation rate variations on the evolution of bacteria, especially the emergence of resistance to antibiotics. In addition to being a key contribution to this field of research, the findings could have clinical implications as antibiotic resistance becomes a major health issue.
Lydia Robert in a few words
After her multidisciplinary studies at the Ecole Polytechnique, Lydia Robert turned to microbiology. In 2010, she obtained a PhD in life and health sciences the Hôpital Necker Enfant Malades, in Paris. During her PhD work, she developed powerful microfluidic tools to observe the development of bacteria dynamically under controlled conditions on the scale of a cell and over the long term for the first time.
She then immediately obtained a research position at INRA’s Micalis Institute, where she now co-leads the single cell mutagenesis and evolution team. Using a multidisciplinary approach, she has contributed many pioneering approaches and tools to her field.
Cells are continuously solicited by internal and external signals requiring a timely response. Nuclear magnetic resonance spectroscopy will allow Malene Jensen and her team to observe the details of how the task is organized in cells with extreme accuracy.
Scaffolding to organize signals in cells
Cells have efficient systems allowing them to turn internal and external signals into actions. Cells transmit signals by using groups of molecules that interact physically with each other. They can be pictured as a kind of relay leading to the signal’s effects. This is how, for example, a muscle cell can notice insulin in the blood and set up an appropriate response that will allow it to import glucose.
The high number of different proteins preesent in the cell organize themselves to correctly and faithfully process the vast array of information a cell continuously receive. To do that, the right proteins must be combined in the right place at the right time to send the right messages. This feat is accomplished in part by so-called scaffolding proteins, which serve as platforms for physically grouping the various components of a signaling pathway.
The messy life of scaffolding proteins
Scaffolding proteins are a very diverse group of proteins, but they have one thing in common: "disordered" areas in their molecular structure. This represent a real challenge to understand their function : they are so dynamic that it is hard to study them with the technology used to study other proteins with a more "ordered" structure. As a consequence, the molecular details underlying the function of scaffolding proteins are still very hard to understand.
Finding the modus operandi of disordered proteins
Malene Jensen's team is interested in a particular signaling pathway, JNKs, and the scaffolding proteins composing it. JNK pathways intervene in stressful situations in cells, such as UV exposure or inflammation, and organizes responses such as cell proliferation or death.
Impulscience supported project, aims to obtain a complete blueprint of the function of two scaffolding proteins in the JNK signaling pathway: POSH and JIP1.
Nuclear magnetic resonance (NMR) spectroscopy lies at the heart of this project, since it is the only technology that can provide an atomic resolution glimpse into the structural, dynamic and functional details of scaffolding proteins. It can be used not only to study the structure of POSH and JIP1 but also to know how they interact with other proteins of the JNK signaling pathway and how they combine with each other to form a super-scaffolding complex. This study could revolutionize the current view of the function of scaffolding proteins.
Studying cell signaling mechanisms is particularly relevant because the deregulation of many signaling pathways is associated with diseases such as cancer and metabolic disorders.
Malene Jensen in a few words
Malene Jensen, a chemist, received her PhD from the University of Copenhagen (Denmark) in 2006. She has extensive experience in using NMR to study protein structure and dynamics, especially proteins with disordered areas (intrinsic disorder). Her work has contributed to understanding the role of intrinsic disorder in various biological systems, such as the measles virus, and in certain proteins associated with neurodegenerative diseases. She joined the CNRS in 2010, and, with her team in Grenoble, contributes to understanding the role of proteins’ conformational dynamics involved in the life cycles of temperate bacteriophages. She also applies innovative NMR and X-ray crystallography methods to map the dynamics of disordered proteins in combination with their partners, illustrated by the JNK signaling pathway’s proteins. In 2015 she received the CNRS Bronze Medal for her contributions to research field.
Self-assembly is crucial for cells because it allows individual components to be assembled into functional biological structures such as proteins. Sometimes, poorly assembled proteins clump together and form fibers that contribute to disease. Martin Lenz wants to understand the physical principles underlying the frustrated self-assembly involved in the fibers’ formation, which remain largely unknown.
Self-assembly organizes proteins inside cells
Proteins in our cells constantly self-assemble to form functional structures. They can for example create the molecular machines responsible for new proteins production, form viral capsids as well as the components of the cellular skeleton, whose structures have been optimized over millions of years of evolution. In some diseases, such as Alzheimer's, proteins with complex non-optimized shapes also self-assemble. Surprisingly, given their disparate shapes and interactions, they form relatively well-defined structures: fibers. Martin Lenz will study the molecular mechanisms underlying this phenomenon, which he calls "dimensional reduction".
Understanding the origin of frustration in protein assembly
If the self-assembly of a set of objects (molecules or small particles ) that attract each other but do not fit together perfectly is observed, the resulting aggregates contain misaligned or distorted components. As they are assembled, the initially small misalignments between the first objects accumulate. Newly arrived objects encounter a more constrained environment than their predecessors. During the self-assembly process, geometric frustration accumulates, and further assembly is impeded. Preliminary work by Dr. Lenz's team suggests that the aggregates form fibers, "dimensional reduction," to escape frustration.
New theoretical and experimental tools must be developed to understand the role of frustration in the self-assembly of complex irregularly shaped objects, including proteins.
Discovering new principles underlying fiber formation in certain diseases
Impulscience supports Dr. Lenz and his team to prove that dimensional reduction is a general principle of self-assembly. To do that, they will develop new theoretical methods on the properties of complex particle assemblies. They will use high-resolution 3D printing and X-ray scattering to probe the self-assembly of colloids (microscopic particles suspended in a liquid) and proteins, allowing them to discover the formation mechanisms.
Their work will reveal new principles of how matter is organized. It is a fundamental step forward in the understanding of protein-like objects that will lead to a better understanding of biology and of certain diseases. It could also have an impact on engineering objects at the nano- and microscopic scale, contribute to better control of the manufacturing processes of certain drugs and optimize protein crystallography methods.
Martin Lenz in a few words
Martin Lenz, a physicist discovered biology during his master's studies. After a PhD in physics in 2009 and a post-doctoral stay in Chicago in 2012, Dr. Lenz obtained a CNRS research position at the Theoretical Physics and Statistical Models Laboratory at the Paris-Saclay University. Since 2018, he has also been a researcher at ESPCI in Paris. He became president of the Physics and Life sciences division of French Physics Society in 2022.
Although he defines himself as a theorist, he works closely with experimentalists, which allows him to make contributions that significantly describe biological systems. His work has been supported by the ERC (Starting grant, 2015) and recognized by prizes in both fundamental statistical physics (Young Scientist Prize of the International Union of Pure and Applied Physics) and molecular biology (EMBO Young Investigator Award).