PIs of Tomorrow

Proudly presenting the winners!!!

Public prize: Joachim Moser von Filseck (University of Geneva). Prize sponsored by MDPI biology and F1000Research

Jury prize: Thomas Auer (University of Lausanne). Prize sponsored by opnMe and Nikon

We thank as well the support of SCNAT which covered the travel and accomodation of all our finalists.

 

Eleonora Porcu, University of Lausanne

A statistical approach for dissecting the causal molecular underpinning of complex diseases

Genome-Wide association studies (GWAS) identified thousands of variants associated with hundreds complex traits, but in most cases their biological interpretation remains unclear. Many of these variants overlap with expression quantitative trait loci, indicating their potential involvement in the regulation of gene expression. Recently, I have proposed a transcriptome-wide Mendelian Randomization (TWMR) approach that uses multiple SNPs jointly as instruments and multiple gene expression traits as simultaneous exposures to pinpoint likely causal genes for complex traits. In Porcu et al (Nature Communications, 2019) we showed how TWMR outperforms previous approaches, resulting in the identification of hundreds of genes playing causal role in the predisposition to dozens of common diseases.
Given the sexual dimorphism in many human phenotypes and gene expression as well, I am currently applying TWMR to explore the genetic basis of sex-biased trait associations and search for sex-specific expression-trait causal effects. The preliminary findings of this study have been selected for platform presentation at the last American Society of Human Genetics Conference (Houston, October 2019). As I am interested in complex traits, no single molecular analysis is expected to fully unravel their biological mechanisms. While so far I have been using gene expression data only, TWMR requiring only summary statistics can be applied to other “omics” (e.g. methylation, metabolomics, proteomics) data. My plan for the near future is to adapt TWMR to a methylation-wide Mendelian Randomization approach to assess the role of methylation in complex traits.

I strongly believe that in this postGWAS era and with the urgent need to understand how the thousands of GWAS associated loci contribute to the variation of human phenotypes, my comprehensive analyses will harness the advantages of a carefully combined analysis of “omics” data to illuminate biological mechanism underlying complex traits and help the design of functional experiments.

Thomas Auer, University of Lausanne

The making of an olfactory specialist

Past work

The evolution of animal behavior and its genetic and neural basis are poorly understood. In my postdoc, I have established Drosophila sechellia, a close relative of D. melanogaster as a neurogenetic model species. While the latter feeds on a variety of fruits, D. sechellia is specialized on a single host (noni), which is accompanied by changes in olfactory, gustatory, mating and other behaviors. In a first project I could, via reciprocal allele transfer, physiological and behavioral experiments, establish a causal link between tuning changes in one olfactory receptor and differences in host-attraction between species. This is one of very few examples were a defined genetic modification directly explains a change in behavior. These receptor changes between species are accompanied by alterations in receptor expressing cell numbers. Following a quantitative trait mapping approach, I identified causal loci in the D. sechellia genome that are implicated in neuron number variations in this species. This work provides fundamental insights into how neural circuit architecture is modified and impacts sensory perception.

Future research

Feeding is fundamental for the survival of each animal but we know little about how gustatory circuits change in evolution. As D. sechellia is highly attracted by and feeds on noni while D. melanogaster is repelled, I will employ these species to investigate peripheral and central changes in the underlying sensory circuitry. This will allow me to test the role of individual receptors/neurons or connectivity differences between species in feeding decisions. Secondly, I plan to investigate how multisensory integration between olfactory and gustatory channels is orchestrated in this species and how this impacts social behaviors. The gained mechanistic insights into behavioral evolution will increase our understanding of brain function and its control of behavioral output.

Olga Murina, MRC Human Genetics Unit, Edinburgh, UK

The Enemy Within: Mapping Cellular Responses to Endogenous DNA Damage

Maintenance of genome integrity is fundamental to cell survival and proliferation, whereas genome instability is a hallmark of cancer and developmental disorders. While exogenous agents, such as ionizing radiation and chemotherapeutics, are well-established causes of genome instability, the sources of endogenous DNA lesions spontaneously arising from physiological cellular processes remain to be determined. The goal of my future research is to gain a comprehensive understanding of how such cell-intrinsic DNA damage arises and its resolution to provide new insights into disease mechanisms and therapeutics. Central to my work will be using unbiased genome-wide CRISPR screens, an emerging opportunity enabling innovative forward genetic experiments in mammalian systems. Building on my expertise in employing large-scale chemogenomic screens in human cells I will use CRISPR screens to identify synthetic lethal and epistatic interactors of disease-associated genome stability genes. These genetic findings will be used to establish molecular mechanisms underlying endogenous damage and should additionally yield novel DNA repair network components. Furthermore, to monitor formation of endogenous DNA lesions and damage signalling upon genetic perturbations I will use advanced cell biology techniques, including high-content imaging, and combine them with proximity labelling to study the protein-protein interaction dynamics at the damage sites. Informed by my past research, my primary focus will be on the key endogenous lesions induced by aldehydes, abundant by-products of normal cellular metabolism, and DNA-embedded ribonucleotides, the most frequent aberrant nucleotides in replicating cells. Initially, targeting key network nodes (e.g. RNaseH2; ALDH2), I will apply the above methodologies to cancer and embryonic stem cells, rapidly proliferating cells particularly susceptible to replication-associated damage. In the longer-term, I will extend these studies to (patho)physiologically relevant cell and tissue contexts, using disease-relevant primary cell and organoid systems, to dissect the cellular responses to intrinsic DNA damage paving the way to new strategies for targeted treatment.

Joachim Moser von Filseck, University of Geneva

The ESCRT-III-mediated membrane deformation reconstituted in vitro

I have always wanted to know how life functions on the molecular and atomic scales and have therefore worked in structural biology and biochemistry/biophysics labs, mainly in vitro. In vitro reconstitutions are the perfect fit for my scientific questions, allowing for a controlled environment yielding molecular insight in the chemistry and physics of living systems.

During my PhD, I studied how lipid transfer proteins from the ORP/Osh family transport lipids between membranes and found that they counterexchange their lipid ligands (ergosterol, cholesterol, phosphatidylserine) for the phosphoinositide PI(4)P. Harnessing cellular PI(4)P gradients, these proteins can mediate the formation and maintenance of cellular lipid gradients [1-3]. As a postdoc, I have reconstituted membrane deformations mediated by the ESCRT-III proteins that sever membranes in a variety of cellular contexts. Using Cryo-EM/-ET and subtomogram averaging (STA) on membrane-bound ESCRT-III heteropolymers, with or without membrane constraints, I have shown that heteropolymerization leads to mechanical and topological changes in the polymer, expanding previous and suggesting exciting new mechanisms for membrane fission [4, 5]. 

In my future lab, I will follow a unique interdisciplinary approach, based on integrated structural biology, biochemistry and membrane biophysics, in order to elucidate the mechanisms of the physiological and pathological functions of ESCRT-III proteins in vitro and in vivo using different EM techniques: 

1. Study the molecular architecture of ESCRT-III (hetero-) filaments on the atomic scale using Cryo-EM on polymeric assemblies formed from different ESCRT-III subunits. 

2. Investigate ESCRT-III subunit stoichiometry and lipid composition in membrane deformation using Cryo-ET and STA. 

3. Compare the budding of virions and virion-like particles from cells and artificial membranes and understand ESCRT-III recruitment at their neck using CLEM. Ultimately, I want to use an in situ structural approach on ESCRT-III polymers at viral necks with Cryo-CLEM on FIB-milled lamellae, completed by Cryo-ET and STA [6]. 

 

Bibliography 

1. Mesmin, B., et al., A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell, 2013. 155(4): p. 830-43. 

2. Moser von Filseck, J., et al., A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes. Nat Commun, 2015. 6: p. 6671. 

3. Moser von Filseck, J., et al., INTRACELLULAR TRANSPORT. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science, 2015. 349(6246): p. 432-6. 

4. Mierzwa, B.E., et al., Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodelling during cytokinesis. Nat Cell Biol, 2017. 19(7): p. 787-798. 

5. Moser von Filseck, J., et al., Anisotropic ESCRT-III architecture governs helical membrane tube formation. bioRxiv, 2019: p. 716308. 

6. Bykov, Y.S., et al., The structure of the COPI coat determined within the cell. Elife, 2017. 6. 

Confirmed Jury Members

Michele de Palma (EPF Lausanne)

Stefanie Jonas (ETH Zurich)

Raffaella Santoro (University of Zurich)

Guillaume Diss (FMI Basel)

Marlen Knobloch (University of Lausanne)

Beat Fierz (EPF Lausanne)

Jean-Léon Maitre (Institut Curie, FR)

Where are past winners now?

Sponsors of the session

  • SCNAT supports travel and accommodation of the finalists
  • opnMe.com sponsors a cash prize for the jury winner
  • MDPI biology sponsors a cash prize for the public prize winner
  • Nikon sponsors a camera for the jury winner
  • F1000Research sponsors
    •  A free subscription to F1000 Workspace and F1000Prime
    • A free article worth $1000 in F1000Research