Our group uses Drosophila and its powerful genetics to dissect the Drosophila immune system. In addition we have started projects in reproducibility and psychology of science. Find below a non-exhaustive description of our projects (updated June 2024):
- Drosophila immunity
- The reproducibility Project
- Psychology of science
1) Drosophila immunity
|
|
||
| Figure 1. Adult fly injected with GFP expressing bacteria. This mode of infection triggers a systemic immune response consisting of the production of antimicrobial peptides by the fat body, phagocytosis by blood cells and melanization at the site of injury. |
A. Layers of immunity: Deconstructing the Drosophila effector response
Yao Tian (antimicrobial peptides), Thomas Esmangart de Bournonville (immune effectors and tumor),
Asya Dolgikh (Nimrod).
Following decades of neglect where adaptive immunity captured most of the attention, innate immune mechanisms have become central to our understanding of immunology. However, the recent emphasis on innate immunity has focused on the first two phases of the immune response: recognition and signaling. In contrast, the contribution of immune effectors individually or collectively to host resistance has not yet been investigated to the same extent. We are currently dissecting the Drosophila innate immune response with a focus on effectors. Since immune effectors are members of multigene families, their function cannot be adequately addressed by the single mutant approach that still prevails today. Thus, we are generating flies carrying single and multiple mutations of immune effectors in a defined genetic background, which will allow comparative analysis of gene function either individually or collectively at the level of gene families. Our study is done both at the level of individual effectors and immune modules. Recently, we have characterized how antimicrobial peptides individually or collectively contribute to host defense. Our studies reveal an unexpected level of specificality at the effector level as a single antimicrobial peptide can determine survival or death to a defined pathogen. We also address the role of immune effectors beyond immunity in contexts that have been implied but not well demonstrated, notably in the control of the gut microbiota and the elimination of tumor cells, neurodegeneration, and aging. By deciphering how immune effectors combat infectious microbes and impact non-immune processes, our work will illuminate critical aspects of Drosophila host defense, and will be instrumental in comprehension of innate immunity in general.
 |
Key references
Hanson et al., (2023) Ecology-relevant bacteria drive the evolution of host antimicrobial peptides in Drosophila. Science: 381(6655):eadg5725.
Hanson and Lemaitre (2023) Antimicrobial peptides do not directly contribute to aging in Drosophila, but improve lifespan by preventing dysbiosis. Dis Model Mech. 16(4):dmm049965.
B. Exploring auto-immune damage and protection in the Drosophila host
Siqi Wang, Samuel Rommelaere, Kenan Krakovic (immune effectors and brain).
Innate immunity is the first barrier to infection in vertebrates and the sole mechanism of host defense in invertebrates and plants. Eliminating threats without causing excessive host damage (immunopathology) is a delicate challenge. Our projects focus on recent results implicating antimicrobial peptides (AMPs) as causative agents of immunopathology, and newly-characterized molecules that appear to mitigate these effects.
AMPs are small, cationic, usually amphipathic peptides display potent antimicrobial activity in vitro by disrupting negatively charged microbial membranes. However, AMPs can be cytotoxic to host cells, which have more neutrally charged membranes, in certain contexts and have been associated with neurodegeneration. AMPs may target host cell membranes that become negatively charged due to translocation of the phospholipid phosphatidylserine to the outer leaflet upon stress. Phosphatidylserine exposure is classically associated with apoptosis but has now been observed in other contexts. Our laboratory has recently shown that cells of some Drosophila tissues, notably the respiratory trachea, constitutively expose PS and as a result are sensitized to cationic peptide activity. Crucially, we identified that secreted proteins of the Turandot family protect these tracheal cells from AMPs. Turandots bind to exposed phosphatidylserine and shield host cells from cationic peptides, preventing autoimmune damage by AMPs. These are the first eukaryotic proteins known to protect host cell membranes from AMPs.
Collectively, these results indicate that contrary to the common view, AMPs can cause immunopathology by targeting host cells that expose PS. We are currently exploring the significance of non-apoptotic phosphatidylserine exposure in relation to the innate immune system, notably, the mechanisms by which Turandots protect PS-enriched cells from innate effectors.
 |
| Impact of antimicrobial peptide and Turandot activity on bacteria and host cells AMPs are small cationic and amphipathic peptides that interfere with the negatively charged membranes of microbes (far right). Eukaryotic cells are usually insensitive to AMPs as their membranes contain cholesterol and are less negatively charged than microbes (far left). Recent studies have shown that some eukaryotic cells including certain cancer cells and Drosophila tracheal cells expose phosphatidylserine (PS) at the surface, making them more negatively charged (middle right). Turandots can bind to the surface of PS-enriched host tissues to mask PS Adapted from Westlake, Hanson Lemaitre, 2024, The Drosophila Immunity Handbook. EPFL Press |
Key references
Rommelaere S, et al., (2024) A humoral stress response protects Drosophila tissues from antimicrobial peptides. Curr Biol. 34(7):1426-1437.e6.
2) The reproducibility Project
An extensive mapping analysis to assess reproducibility in experimental life sciences
Hannah Westlake (Annotation and verification, currently at Exeter), Fabrice, David (IT), Désirée Polpeka (metascience), Blandine Ribotta (metascience).
Confidence in published results is critical to sustain trust within a scientific community and to allow new research to build on previous findings. While recent reports have sparked intense discussions on the existence of a reproducibility crisis in life sciences, most scientific claims are rarely verified. Those known to be incorrect are either discretely contradicted by subsequent articles, criticized during informal discussions, or simply ignored. These invalid claims are generally acknowledged by experts, but often create difficulties and waste time for those new to the field. In addition, many more scientific claims are simply never replicated.
Hence, we have started an ambitious project in 2019 that aims to assess the replicability of articles published between 1980 and 2010 in my research field, Drosophila immunity. Our ultimate goal is i) to provide a database open to the public that allow us to better estimate the extent to which discoveries in the life sciences can be reproduced and trusted from the perspective of an experimental biologist, ii) to decipher the characteristics of unreproducible articles such as their bibliometric patterns, their distribution among teams and scientists, and their stage of occurrence in a scientific career. This project should be fully completed at the end of 2024.
A. Annotation of 400 articles and bibliographic verification (completed)
400 articles focusing on Drosophila immunity published between 1980 and 2010 were selected after Pubmed retrieval and manual selection. The main, major (usually 3-4) and minor claims, and the methods of each article were extracted as well as the evidence supporting them. For this, the reliability of each claim was then evaluated by analyzing subsequent published studies from the same laboratory or other laboratories that confirmed or contradicted the claim. Many claims referred to as ‘unchallenged’ have not been followed up on. A web interface called ‘ReproSci’ was opened to the public on July 5th, 2023. The scientific community working on the Drosophila immune system was contacted by email and was invited to access and comment on the results. The link to the website is https://reprosci.epfl.ch (an ORCID is however required to access the web interface).
B. Experimental validation of unchallenged claims (in progress)
Among the many unchallenged claims analyzed in our survey of the field, we have identified 100 claims that could be experimentally tested. We selected a subset of them for experimental validation. With the help of colleagues with the relevant expertise, we have already tested 24 of these claims. We are still completing the experimental tests for 4-6 additional claims, hoping for a total of about 30 tested claims. Our results indicate that a significant portion of unchallenged claims, notably those published in high profiled journals, were not replicable.
C. The metascience side of the reproducibility project (ongoing)
Preliminary analysis estimates that about 65% of claims in the field of Drosophila immunity are strongly verified by the literature and that 5-8% were strongly challenged. This percentage of unreproducible claims is much lower than many other estimations (e.g. top articles in cancer biology: 50% unreproducible), but not fully unexpected for a research field that relies on genetics. Strikingly, about 20% of studies never had published follow-up studies. Through collaboration with the community, we have launched a questionnaire to determine whether scientists in the field are aware that some claims have been disputed. A preliminary analysis reveals that most scientists are not aware of unreproducible or controversial data, including some claims that are overtly contradicted in the literature. This behavior goes in line with notion that once a statement, even though it was wrong, has been published, data contradicting this statement are rarely take in consideration. Using our dataset, we will try to estimate whether verified or challenged claims are more likely to be published in high-profile journals. We will also explore whether there are hubs of irreproducibility, that is whether irreproducibility affects certain authors and certain labs more than others. We will also explore whether the permanence of the author in the field (established or transient) or their career stage varies with the proportion of verified or challenged claims.
3) Psychology of science
Blandine Ribotta, Désirée Popelka.
Considering the impact of science on society, developing a better understanding of the social and psychological factors shaping the scientific community is important. Such a project requires bringing experts together, who truly understand academia and have experience in different fields, such as life sciences and social sciences. In this framework, we aim to explore three sets of psychological and sociological factors that are not usually associated with science that could however influence career success in academia. In particular, we aim to better understand how romantic relationships, personality, and thinking styles shape the scientific community and influence career progression in science.
Among the many studies analyzing factors contributing to scientific success, romantic relationships are rarely considered. Yet observations show that scientists tend to form homogamous relationships, which are especially common among high-achieving scientists. We previously observed that homogamy contributes to career success, most notably for mothers. Our first objective is to identify the crucial factors in romantic relationships that specifically contribute to success. Moreover, we will characterize the factors that favor the formation of collaborative couples and decipher how homogamy affects satisfaction in romantic relationships.
Our study will have a large impact on the community, considering the prevalence of homogamy among academics. The findings of this study have implications beyond academia, as homogamy is also common in other professions, where visibility and passion are essential, such as the arts, politics, and sports.
Lastly, we will investigate the relationship between personality types and success in science. We will explore whether personality traits can predict scientific achievement and try to identify specific traits that are associated with eminence. We will explore whether there are differences in personality types of scientists working in different fields, and whether additional factors such as divergent and convergent thinking and other cognitive styles influence career success.
For this, we will use validated tools and measures to assess personality and cognitive traits and launch large-scale surveys as well as semi-structured interviews to gather and analyze data. By bringing together experts in social and psychological research with scientists working in experimental life science laboratories, we hope to generate a rich data set that will have a significant impact on the growing field of metascience. Our project has the potential to provide critical insights into implicit factors that drive the emergence and success of leaders, and thus has significant implications for the scientific community and beyond.
Key references
An essay on science and Narcissism (2016) B. Lemaitre EPFL Press