Event report by Jesus Victorino, PhD student at the Universidad Autonoma de Madrid, Spain.
Four Novembers ago, I arrived in Heidelberg on my 24th birthday which I celebrated carrying my first poster as a freshmen PhD student. Back in those days, a hypothesis with an outline of my future experiments was all I captured on that A0 laminated fabric poster. Four years and a PhD later, there could not be a better place to show my results right before defending my thesis than at the very same EMBL conference: From Functional Genomics to Systems Biology. Well, not exactly the same. This time we could not enter the ATC building and walk through its double-helix bridges, since the event took place virtually.
The organising committee managed to set up an online conference, enabling more than 270 participants to share their thoughts and results about genomics, proteomics and imaging. And we got to see everybody’s living room! Although the schedule differed from usual conferences in Europe (13:00-20:00 CET), it broadened the audience by allowing people from other countries to attend. And all that without taking a plane or paying for a hotel room, which significantly decreased the required budget to attend the conference and the carbon footprint we left behind.
I found several additional aspects of attending a virtual conference very exciting. On the one hand, the lack of big crowds in a large room with a single microphone and a line of researchers waiting for their turn, encouraged me to ask questions to the speakers. I simply felt more comfortable. Zoom allowed a record of the many questions asked, and those that were not answered due to time constraints were posted on a Slack channel created to coordinate the meeting. The Slack channel was incredibly helpful not only to increase the feedback with more scientific questions & answers but also to improve networking, especially for the poster session. I hope we keep using a similar virtual space that enables participants to contact other scientists even for onsite conferences.
At least in my experience, the poster session worked out way better than expected, which was a pleasant surprise. I found myself talking with researchers (mainly PhD students) for most of the session, which I never experienced before. I took advantage of the Slack channel to advertise my poster and also to interact with the presenters of other posters I was very interested in. Magically, people were showing up in my Zoom room and I found that breaking the ice virtually was easier than in a real room, since there was no awkward moment in which you hesitate to interact with the presenter, or the presenter does not know whether you might want to know more about his/her research or are just passing by.
On the other hand, I found the platform where we should upload the posters very inconvenient. Instead of uploading our posters in PDF and being able to chat through Slack, Zoom or similar, we had to use ‘iPosterSessions’ and re-shape our posters to fit the virtual and very rigid format of the website. I found the platform non-intuitive and there were incompatibilities, at least with my computer, for the ‘chat’ and ‘contact author’ options within it. Besides, we had to provide a way to virtually meet other participants and present our posters on our own (e.g. a Zoom room or similar), which was not very straight-forward,, and not everyone might have had access to it. Having said that, this was basically the only issue I experienced during the entire meeting – the lectures worked perfectly, we discussed exciting projects and the poster sessions were very fruitful.
Another great choice from the organisers was to schedule ‘meet the speakers’ sessions. I enjoyed meeting three of the speakers together with other early career researchers where we could exchange thoughts and impressions. I think this is very important to train students on how to interact with more senior researchers and I have rarely found a dedicated spot for this at international conferences.
During the conference, all lectures and short talks were divided into four main thematic areas: quantitative genomics, quantitative proteomics, quantitative imaging and single-cell genomics. Here’s my pick from the panel of speakers that I feel represents the essence of each area.
Transcriptional enhancers were the main characters of the quantitative genomics sessions, where different labs addressed the question of how the control of gene regulation affected phenotype in a different way. The fruit fly embryo was one of the preferred model organisms and was used by the team led by Thomas Gregor to study how the spatial organisation of the chromatin affects transcription at the eve locus. Justin Crocker also showed beautiful Drosophila embryos that they used as a test tube to understand the logic of a developmental enhancer and the phenotypic impact of its mutations. With respect to this study of the genotype-to-phenotype impact but in the context of human genome variation, Bart Deplancke told us about how non-coding variants affect gene expression in immune cells unveiling implications in leukemia.
Following with genomics, we witnessed the power of sequencing technology but at the single-cell level to understand physiology and disease. In this thematic area, we learnt with Antonio Lentini about gene expression and silencing at the X chromosome and Dana Pe’er talked about its uses to study development and cancer. The work presented by Henrik Kaessmann was very impressive and stood out not only for the use of thousands and thousands of cells, but for studying spermatogenesis in twelve different mammals providing a valuable resource to study this process across evolution.
The quantitative proteomics sessions taught us about the promising years that we face since improved technology might quickly move the field forward. Bernhard Küster showed how proteomics and in vitro models can be used to investigate drug response to cancer treatments. Although the massive characterisation of the proteome is yet not comparable with the performance of sequencing technologies in the genomic field, Michiel Vermeulen’s talk illustrated how to combine genomics and proteomics to understand cancer biology and identify new important players and therapeutic targets.
The fourth thematic area was quantitative imaging in which Emma Lundberg talked about high-throughput imaging and its use to dissect the human proteome. We could appreciate the potential of the analysis of massive amounts of imaging data in the work presented by Professor Lundberg where they involved hundreds of new proteins in cell cycle and identified new putative roles for proteins they found to localise in multiple subcellular compartments. Super-resolution microscopy could not be missing at this conference and Suliana Manley nicely showed how to use it to study mitochondrial organisation and dynamics.
Outstanding science and fresh data in a very interactive environment summarises the experience at the conference, where I was glad to see that many of the projects presented were shared in the form of preprints. I collected them and included in this list of preprints at the #EMBLOmics for attendees who might want to know more about some of the talks and for those who did not attend and might want to have a flavor of this conference.
Of course, it would not have been a proper EMBL meeting without the final gathering and concert. The event ended with a fantastic concert by Lazy Fur which really put the icing on the cake –the concert is recorded here, so you can listen to their nice voices while you prepare for your next experiment. I really thank the organisers for all the effort to make the screen disappear and feel like in a non-virtual event.
Since 2020 has shaken the way we interact with people, scientists, like everyone else, have had to quickly adapt to the new circumstances. In the academic world, conferences play an important role for scientists to share their recent advances and build their contact network. While it was already under debate how to reduce the ecological impact of such a tremendous flow of researchers travelling all over the world, virtual conferences did not seem to launch. All of a sudden, the global pandemic situation has rapidly turned this will to a necessity, leaving us no other option but to evolve. The good thing is that virtual conferences seem to be reasonably meeting our expectations, providing with a more sustainable way of sharing our data and interacting with each other. They offer both advantages and disadvantages with respect to in-person events but undoubtedly have accelerated our steps towards including more virtual conferences in the calendar once we go back to a ‘normal situation’.
About the author
I’m Jesus Victorino, PhD student working in gene regulation and member of the preLights community, a platform to disseminate science and the role of preprints in Biology.
From our virtual event reporter Magdalena Wutkowska, The University Centre in Svalbard / UiT – The Arctic University of Tromsø, @m_wutkowska
The EMBL conference on Molecular Mechanisms in Evolution and Ecology took place from 30 September to 2 October 2020. The meeting – which had its first iteration in 2008 as a workshop on Evolutionary and Environmental Genomics – has gained a broader context over time not limited to evolution and yeast, which was reflected in this year’s program.
This year for the first time the conference was held virtually. Six sessions over three days encompassed vast topics such as Evolutionary Systems Biology, Systems and Synthetic Biology, Assembly and Evolution of Microbial Communities and Experimental Evolution and Evolution of Complex Traits. Between the sessions, participants could join ‘meet the speaker’ coffee breaks, poster sessions and short talks. Below are just some of the highlights from the main sessions.
SESSION 1 – Evolutionary Systems Biology
The first session on Evolutionary Systems Biology was chaired by Gianni Liti (University of Nice, France), who first outlined the history of the meetings since 2008.
Matthew Goddard (University of Lincoln, UK) spoke about the nature of interactions between yeasts and other organisms through traits. Saccharomyces cerevisiae, just as any other organisms, evolved in the presence of other species. The existence of a trait does not have to be adaptive, and evidence of increased fitness is required to make such a statement. Goddard presented a case study of interactions between yeasts and fruit flies. Yeast produce ferments and volatiles that attract fruit flies, whereas yeast could benefit from dispersal capabilities provided by fruit flies. Some experimental evidence support the notion that the yeast – fruit fly association is mutualistic. However, recent studies showed no supporting evidence, i.e. no clear individual volatile correlated with general attraction of fruit flies. Moreover, the dispersal advantage for yeast is most likely a stochastic by-product of this interaction. Thus, the interaction is not driven by adaptation, but more likely by exaptation, which is a shift in the trait function during evolution. This talk urged us to examine the evidence for increased fitness closely, while looking for adaptive traits.
Anastasia Stolyarova (Skolkovo Institute of Science and Technology, Russia) posed the question whether epistasis shape variation within populations. Many natural populations are characterised by relatively low genetic variability; therefore, it is not possible to see strong epistatic selection between polymorphisms. Thus, to study non-random associations of alleles (linkage disequilibrium), she used the world’s most variable eukaryotic species Schizophyllum commune, which differs by up to 20% of nucleotide diversity at neutral sites. Based on 54 genomes from two distinct populations, she found that in both populations between nonsynonymous mutations were higher than between synonymous ones. Additionally, within-gene linkage disequilibrium between nonsynonymous mutations was higher when compared to that between the genes. Model simulations suggested that this phenomenon resulted from abundant epistasis.
Toni Gabaldón (Barcelona Supercomputing Centre, Spain) talked about ‘origin and evolution of hybrid yeast pathogens’. Novel hybrid lineages may display innovative traits that could facilitate successful colonisation and growth in new settings, including human hosts. Emergence of pathogenesis in hybrids was studied by genomic comparisons of closely related pathogenic and non-pathogenic species within Candida clade that differ in virulence. Hybrids turned out to be not only common among some clades, but they can also survive for a long time.
Aaron M. New (Centre for Genomic Regulation, Spain) spoke about deciphering how genetic variants quantitatively change protein characteristics in a long evolutionary perspective. Predicting the outcome of mutation combinations is high in additive models, but drops in sign epistasis, which is crucial for evolution. This problem was explored in a model paralog pair of yeast genes involved in galactose metabolism and signalling: GAL1 and GAL3, that differ in their biochemical properties. The study identified a mutation in GAL3 that was responsible for sign epistasis by modifying existing destabilising effect to a stabilising one on protein folding. These mutational changes in sensing/signalling proteins are of evolutionary importance for the emergence of new phenotypes.
In his talk, Antonis Rokas (Vanderbilt University, USA) focused on ‘the evolution of the buddying yeast biodiversity’. His lab members and collaborators used buddying yeast (Saccharomycotina subphylum) to decipher genetic bases for metabolic diversity at an unprecedented scale. This research revised current understanding of drivers of evolution in eukaryotes, both in genomic and phenotypic aspects. As it turned out, the gene conservation was shown to be not universal. Losses of genes or traits were pointed out as important evolutionary forces, whereas horizontal gene transfer, although identified only a few times, had an essential effect on evolutionary trajectories.
Pedro Beltrao (EMBL-EBI Hixton, UK) shared novel insights on ‘evolution and functional relevance of protein phosphorylation’. Phosphorylation uses enzymes to catalyse reversible attachment of phosphoryl groups that (de)activate many types of molecules, including proteins. Phospho-regulation is of fundamental importance for post-translational protein modifications, that impacts the decision process in the cells and can be an underlying mechanism in many diseases. His research on ~500 phosphorylation-deficient mutants across 100 stress conditions explained that roughly half of them had no phenotypes and the contribution to fitness is not equal between phosphosites. Relevance of these sites for phenotypes can’t be predicted by using only one variable or feature. Advancements in understanding evolution of function of protein phosphorylation requires more insights from cell biology and mechanistic understanding.
SESSION 2 – SYSTEMS AND SYNTHETIC BIOLOGY
Kiran Patil (EMBL Heidelberg, Germany) held the second session on Systems and Synthetic Biology.
Claudia Bank (Gulbenkian Science Institute, Portugal, and University of Bern, Switzerland) discussed considerations and challenges in the process of using empirical data in fitness landscapes models in predicting evolutionary outcomes. The fitness landscape theoretical framework was proven to be a platform for testing evolutionary hypotheses. Large discrepancies in experimental data have been identified in fitness arose from single-mutations and epistasis across environments. However, it is still not clear how to reliably predict mutation effects across different environments using these models.
Jens Frickel (VIB–KU Leuven, Belgium) explained issues and uncertainties connected to mechanisms buffering mutations and its role in organisms fitness. Some gene products blur the effect of many mutations; therefore, they can act as buffer against genetic variation. The most studied buffering gene is HSP90 that assists accurate folding of mutated proteins. Genome-wide screens of yeast genes in 5000 strains allowed for identification of the gene ontology categories of genes involved in buffering activities that increase the average relative fitness. The most potent categories include chromatin binding, chromatin remodelling and unfolded protein binding. He presented directions of current and future research aiming to understand buffering mutations.
In his talk, Angad Mehta(University of Illinois at Urbana-Champaign, USA) focused to experimental explorations of mitochondria and chloroplast evolution. The endosymbiotic theory has been backed by molecular evidence from sequencing studies. However, the process of entering the cell by endosymbionts and coevolution with the host are not understood. He used synthetic biology tools to test experimentally investigate and evaluate evolutionary scenarios of bacterial endosymbiont evolution and transformation into organelles. Engineered S. cerevisiae (lacking mitochondrial DNA) and E. coli (thiamin auxotroph) were used as host (providing required metabolites) and endosymbionts (providing the ATP). Further research focused on the evolution of yeast – E.coli chimaeras and number of mitochondria maintained within the complex. At the moment he is involved in similar studies modelling the evolution of cells with chloroplasts using S. cerevisiae and cyanobacteria.
Kyle Fowler (University of California, San Francisco, USA) spoke on how regulons can change across evolutionary time. Transcription networks are a source of evolutionary novelty and contribute to plasticity; therefore, research in this field is crucial to understand evolutionary processes. In this talk, Fowler presented some of the results from studies on gain of function in interactions between two transcriptional regulators MATα2 and MXM1. Results showed that functional, cooperative interactions could most likely evolve with ease and explain diversity in structures in regulatory networks. Common intra-molecular epistasis expanded the permissive sequence space allowing for 9% of all sequences to be functional.
Chang Liu (University of California, Irvine, USA) presented ‘synthetic genetic systems for continuous protein evolution in vivo’. Liu Lab and collaborators developed an error-prone orthogonal DNA replication system called OrthoRep. In this system, preselected genes can be mutated at rates 100,000-fold above the genomic mutation rates. In practice it can be employed to carry continuous in vivo evolution of the preselected genes with no off-target genomic mutagenesis. OrtoRep provides countless applications to evolve useful biomolecules (enzymes, biosensors, antibodies and many more), study adaptation (governing rules, uncovering pathways of adaptation) and perhaps predict evolution in natural systems.
SESSION 3 – ASSEMBLY AND EVOLUTION OF MICROBIAL COMMUNITIES
Sara Mitri (University of Lausanne, Switzerland) chaired the first session of the day on Assembly and Evolution of Microbial Communities.
She continued with a lecture, in which she explored co-evolutionary dynamics within small bacterial communities inhabiting highly stressful environments (metal-working fluids). In particular, Mitri elaborated on interactions and stability of these communities as well as the evolution of established interactions. High toxicity promoted positive interactions between species. These interactions, however, were not constant and could be moderated by the addition of amino acids, and interactions of toxicity with food availability. Series of experiments revealed that evolving alone led to competition and genome preservation, whereas co-evolution with other species led to neutral interaction and genetic loss. Species interaction highly depend on the environmental conditions. As species adapt to each other’s presence, these interactions may weaken over time.
Daniel Machado (EMBL Heidelberg, Germany) talked about two distinct strategies developing in co-occurring microbial communities explored by genome-scale metabolic modelling. Microbial communities showed striking polarisation at the trade-off landscape between cooperation and competition. With increasing size of microbial communities, members displaying one of these strategies differed in multiple aspects such as number of metabolic genes, nutrient requirements, metabolic dissimilarity, abundance and phylogenetic distance. Moreover, competitive and cooperative communities were shown to have distinct habitat preferences. Communities displaying either of these strategies respond differently to both abiotic and biotic perturbations in their environment.
Isabel Gordo (Gulbenkian Institute, Portugal) explained some aspects of gut bacterial communities evolution in mice models. She focused on two main topics: evolution of a single dominant strain of E. coli and evolution of an invader strain in the coexistence with resident E.coli. Studies on the first case revealed that both balancing selection and clonal interference were wide-spread within the guts. Coexistence of populations of bacteria with increased mutation rate and population without them can last for a long time. The effect of deleterious mutations in vitro was higher than from in vivo experiments, that lead to a conclusion that probably the deleterious effect of mutations was reduced by biotic interactions and is even lower in species-rich setting. Experiments on the second scenario showed that in the initial stages of the evolution of an invader was dominated by phage-mediated horizontal gene transfer. At later stage, mutations started to accumulate. In the last part of her talk Gordo emphasised the need of long-term evolutionary studies of these scenarios and presented selected unpublished results from her lab.
Jona Kayser (Max Planck Institute for the Science of Light, Germany) described mechanisms in which mechanical forces can affect evolution in dense cellular populations. These populations are found in yeast colonies, but also biofilms, embryos or tumours. Collective motion of cells in the dense colony moves other cells with them. Slow-growing mutant populations with drug resistance can be carried to the rim of the colony by fast-growing yeast that are sensitive to drugs. In case of a treatment during infection application of the drug could stop the growth of neighbouring wild populations and caused resurgent growth of the mutants that were drug-resistant and not outcompeted by fast-growing wild types. These mechanisms may lead to increased understanding of treatment design in antibiotic resistance infections and tumours.
Wenying Shou (Fred Hutchinson Cancer Research Center, USA) talked about disentangling molecular mechanisms causing rapid evolution of new metabolic interactions in cells undergoing nutrient-growth dysregulation. Through conserved mechanisms in eukaryotic cells, nutrients control eukaryotic cell states promoting or ceasing growth. During unnatural auxotrophic limitation(s) this regulation might fail, resulting in nutrient-growth dysregulation. In this state cell growth is not arrested despite of limitation in resources. Shou presented experimental evidence that cells in this state release unusual metabolites. As a consequence, these released metabolites may provide an unforeseen way of rapid evolution of new metabolic interactions with other organisms.
Tami Lieberman (Massachusetts Institute of Technology, USA) spoke on adaptive evolution of skin commensal bacteria. In Liberman’s research tracking evolution, instead of sampling over a long period, many colonies were sampled from different pores in a single time point. Some bacterial species can adapt by de novo mutations in healthy people while in other bacteria inhabiting human face there were no signals of adaptive evolution. Mutational rate was much lower compared to rapid spreading on the face skin. Pores can be seen as separate islands, where location within the pore can predict success more than fitness does. Populations within pores most likely are descendants from a single ancestor. Some of the strains expanded and diversified rapidly on individual humans. People are colonised by multiple lineages, probably coming from multiple independent colonisation events.
In her talk, Rachel Dutton (University of California, San Diego, USA) focused on the ecological interactions in cheese-rind communities. Dutton’s Lab uses cheese rind biofilms to deconstruction and reconstruction of the system in order to understand microbial communities. They found many species-specific effects within these communities; however, some effects were found conserved across species. Over the years, the lab brought evidence for fungi being essential players impacting bacterial biology by releasing enzymes, siderophores, volatiles, antimicrobials and by increasing bacterial mobility.
The next session was a roundtable discussion on Assembly and Evolution of Microbial Communities moderated by Jun-Yi Leu (Institute of Molecular Biology, Taiwan). The participants Maitreya Dunham (University of Washington, USA), Isabel Gordo (Gulbenkian Institute, Portugal), Gianni Liti (University of Nice, France) and Nassos Typas (EMBL Heidelberg, Germany) discussed the past, present and future of the field. They emphasised that although there have been many substantial advancements in high-throughput sequencing, there are some issues that are still lacking full understanding, for instance, mutations, gene copy numbers and its consequences for the fitness of organisms. Experiments on laboratory strains of organisms explore only a small proportion of mechanisms and genetic diversity. Thus, future research should focus beyond that. The complexity of microbial systems is high, they are impacted by many factors, and they themselves impact their surroundings and other organisms. Therefore, there is a profound need for collaboration between different scientific disciplines to produce novel cross-disciplinary approaches, efficient data integration methods and solutions to long-lasting problems. Some of the significant challenges in the field include developing efficient training programmes that would enable students to receive well-rounded education encompassing a variety of disciplines. Finally, current knowledge should be more efficiently transformed into real-life solutions and applications that could potentially tackle some of the critical global issues.
The third day of the conference started with a career development session. Guests Claudia Bank (Gulbenkian Science Institute, Portugal, and University of Bern, Switzerland) and Daniel Machado (EMBL Heidelberg, Germany) discussed critical issues in carrier development and its maintenance. Career paths can be very different and can involve switching between disciplines, between academic and non-academic sectors. Much of the discussion was focused on the application process, its stochasticity and not being discouraged by rejections. They highlighted the importance of mindful and self-compassion approach towards work, especially in academia. Keeping a work-life balance might be often overlooked, although it is an important issue that can affect well-being and also motivation.
SESSION 5 – EXPERIMENTAL EVOLUTION
Chaired by Jun-Yi Leu (Institute of Molecular Biology, Taiwan), the session opened with a presentation on yeasts’ synthetic genomic applications by Lars Steinmetz (EMBL Heidelberg, Germany). The talk started with a summary of discoveries and advancements in genome editing. Manipulating regulation of transcription factors were used to increase understanding of adaptation to heat in yeast. Extensive work on engineered yeast cells able to on-demand reorganisation of their genomes helped to study selection changes in transcript isoforms that can occur after these reorganisations. However, many questions in genome editing and design regarding the location of genes and design principles still remain open.
Sarela Garcia-Santamarina (EMBL Heidelberg, Germany) shared her research on current understanding the interplay of drugs and gut microbiome in vitro. Experimental evidence showed high prevalence of drugs affecting growth of bacterial strains, whereas bacteria can significantly alter concentration of many drugs. It is not clear if these effects observed in monocultures are consistent in communities. Comparing responses of monocultures and communities in response to different drugs showed emerging community behaviours, such as sensitisation of drug-tolerant strains and protection of drug-sensitive strains. These emergent behaviours were concentration-dependent and disappeared when concentrations increased. High levels of these stressors disrupt community protective traits. The protective properties can be partly explained by drug metabolisation.
Sinéad Collins (University of Edinburgh, UK) spoke on the use of experimental evolution to understand microbial response to climate change. Oceans’ phytoplankton is composed of diverse organisms that act as “tiny adaptor plugs” between organic and inorganic worlds. These two worlds undergo shifts due to climate changes, and by using one methodology, it is impossible to predict how would they react in short and long-time perspective. She employed microcosm experiments that provide direct links between cause and effect in manipulation studies mimicking climate change, i.e. temperature and CO2 concentrations. Using these tools, the studies explored epigenetic transmission in adaptation to changing and fluctuating environmental conditions.
Christopher Large (University of Washington, USA) spoke on genomic stability and adaptation of beer brewing yeasts during serial repitching in the brewery. Repitching (using yeast many times over multiple fermentations) serves as a method to perpetually maintain yeast populations in breweries, and it is a suitable procedure to study adaptation to the brewery environment by looking at copy number variation, mitotic recombination single nucleotide polymorphisms and insertions/deletions of bases in the genome. In these conditions brewing yeast continuously underwent domestication at a fairly rapid rate. Many related strains in different breweries adapting over time displayed the same structural variations that included mitotic recombination of specific chromosomes and aneuploidy.
Gilles Fischer (Sorbonne University – French National Centre for Scientific Research, France), talked about transient hypermutator subpopulations in yeast colonies. A continuum model of genomic evolution of cancer predicts three main ways in which aberrations (including mutations) accumulate a gradual, punctuated and catastrophic modes. Often, we think about genome evolution as a gradual accumulation of mutation. Yeast populations contain hypermutator subpopulations that originate from transient phenotypic mutator cells. These subpopulations increased in size under stressful conditions such as oxidative stress and could lead to systemic genome instabilities illustrating the possibility of the catastrophic mode of genomic evolution.
Virginia Cornish (Columbia University, USA) spoke on ‘expanding the synthetic capabilities of yeast’. Cornish Lab uses engineered yeast capable of carrying out in vivo mutagenesis and selection steps of directed evolution. These yeasts have been engineered to perform new functions that made them useful in many applications. For instance, they were used as synthetic biosensors to create cheap colorimetric essays that can be used for detecting pathogens. This and further work in this area can lead to many therapeutic applications in the future.
SESSION 6 – EVOLUTION OF COMPLEX TRAITS
Maitreya Dunham chaired the last session of the conference, which focused on the evolution of complex traits.
Joseph Schacherer (University of Strasbourg, France) talked about S. cerevisiae-wide survey of the evolution of complex traits. Existing knowledge on architecture, inheritance and phenotypic expressivity of complex traits is still poorly understood. Genomes and phenotypic resources generated for over a 1000 isolates of S. cerevisiae served as a platform to select strains for pairwise crossing and examination of complex traits in resulting hybrids. These hybrids were grown under 50 growth conditions in order to obtain phenotypic distribution of the offspring. Most of the cross/condition combinations were shown to have complex inheritance. The complexity across traits was found highly variable. The expressivity of complex traits was both variable and dynamic across strains in different conditions.
Melania Jennifer D’Angiolo (Institute for Research on Cancer and Aging, IRCAN, France) talked on the origin of genomic introgressions from a yeast living ancestor. Introgressive hybridisation is an important mechanism in evolution of species across kingdoms. They were frequently identified in many yeast populations; however, it remains unclear how they appeared in reproductively isolated species. In her research, D’Angiolo found a coexistence of hybrid ancestor and its descendants inhabiting the same ecological niche. It was proposed that the underlying mechanism involved genomic instability that made possible for the hybrids to overcome sterility.
Irene Stefanini (University of Turin, Italy) spoke about research on buddying yeasts’ associations with insects. S. cerevisiae are important components of grape berries microbiota; however, their numbers depend on presence of the grapes and fluctuate according to the seasons. They are rarely found on unripe grapes, but their number rapidly increases towards the end of the season. For a long time, it was not clear where do these organisms overwinter and how do they get back on grape berries. Yet, a complete local variability of yeasts was found in insects’ guts where they could overwinter and be transported back on the grape berries when they formed in a new season. Rarely observed yeast mating in nature was promoted in insect guts, including wasps. Recent genome-wide association of S. cerevisiae from wasp guts started to shed light on mutations important ecologically relevant fungal phenotypes.
Lucy Xie (Stanford University, USA) spoke on a newly described drug resistance mutation-independent mechanism found in Candida albicans. In contrary to mutation-dependent, the new high-frequency drug resistance called pararesistance involves epigenetic modifications. Common antifungal (fluconazole) in low doses induced pararesistance in up to 10% of cells. These numbers increased after addition of other substances. The induced pararesistance was still observed after more than 100 generations cultured in the absence of the drug. Understanding the intricacies of this mechanism could decrease medical treatment failures in fungal infections.
Tatiana Giraud (Evolution et Systématique Laboratoire ESE, Université Paris- Sud XI, France) spoke on “multiple convergent events of mating-type loci linkage through different rearrangements”. Giraud focused on smut fungi beneficial gene linkages called supergenes that provide adaptation advantages. Presented studies on prevalence, formation and evolution of supergenes increased understanding of this little-explored field.
Adam M. Feist (Denmark Technical University) spoke on an ongoing cross-disciplinary automated project for understanding adaptive laboratory evolution. The project consists of two main components hardware for high throughput culturing and complex experimentation procedures to obtain information on mutations and conditions in which they arise and with a customised software for processing the output data. Acquired experimental data are subsequently organised, described, analysed and become part of a database (ALEdb). A multi-scale annotation framework aims to identify critical mutations at different conditions and scales (from binding sites to large aggregated features such as COGs). Feist also explained the current focus on using the data for design and engineering purposes, as well as expanding the breadth and scope in the database. ALEdb is available as a web-based platform https://aledb.org/
After the last session, Kiran Patil held a speech with closing remarks and future outlook. Attendees were given access to all the conference materials, including posters and pre-recorded talks for two weeks after the conference had ended.
Event report by Suzanna Prosser, Lunenfeld-Tanenbaum Research Institute, Canada
Gender imbalance is a longstanding issue in academia, with men still more likely to progress to the highest levels. Institutional and individual biases, attitudes, and self-limiting beliefs are only some of the factors that allow this situation to persist. The Gender Roles and their Impact in Academia virtual conference served as a timely reminder of these issues, whilst also highlighting current thinking, research and practices surrounding gender, diversity, equality and academia. It was only fitting that the conference commenced on the second Tuesday of October, which is designated as Ada Lovelace Day, an annual celebration to raise the profile of women in STEM.
The opening lecture was delivered by Melvin Konner (Emory University) whose 2015 book ‘Sex, Evolution and the End of Male Supremacy’, upset a lot of people if the vitriolic reviews and commentaries it received are anything to go by. The premise Melvin presents in his book is a very simple one: “women are not equal to men; they are superior in many ways, and in most ways that will count in the future”. He explained that the similarities between men’s and women’s brains are far greater than the differences, but historically women have been believed not to have the capacity to lead. The consequence of this is that their voices have been excluded from the places where they would be most beneficial. We are now, however, living in a time where women are managing to trickle up to prominent leadership roles throughout the world, although sadly the tides of change continue to move slowly.
The notion that men are superior to women has perpetuated in part due to biological evidence perceived in such a way so as to support this thinking. Against this, Gemma Puixeu (IST Austria) very eloquently argued that while biology can justify the differences between the sexes, it cannot justify gender binarism nor gender inequality. Acknowledging that there are many other players aside from chromosomal sex defining systemic sex, allows us to appreciate that gender expression is multifactorial, leading to a continuum that is influenced by non-biological factors. Indeed, gender binarism can only be explained by cultural enforcement. For gender inequality, traditional evidence states that sexual selection is stronger in males, as male traits are superior and that evolution is male-driven. On the other hand, alternative evidence says that there is no power inequality between the sexes, and questions what are male and female traits, and why we value them differently. Furthermore, one sex does not evolve in spite or at the expense of the other. So, if male supremacy is not explained by biology, why has science failed us? First, it is subjective – if performed by men, it is for men and suffers from unconscious bias. Second, arguing women are subordinate by nature justifies socio-politico-economic interests.
Talks by Cordelia Fine (University of Melbourne), Ijeoma Uchegbu (University College London) and Stephen Curry (Imperial College) covered why gender diversity matters in the work place, strategies to approach equity and diversity in academia, and how to ensure science is built by men and women. Evidence provides overwhelming support for diversity on teams and panels leading to better decision-making processes, outcomes and productivity. Indeed, diverse teams make superior decisions as they focus more on facts and process them more carefully. Depending on field, over 50% of graduate students are female, however often less than 10% of professors are women. Reasons why women fall out of the academic pipeline are varied but, as Heather Metcalf (Association for Women in Science) explained, intersectionality is a crucial dimension, with reasons being very different for women of different backgrounds.
Women are frequently encouraged to adopt more male-associated traits, such as confidence. However, Suzanne Doyle-Morris (InclusIQ) informed us that women that display overt confidence tend to be penalized with negative labels such as bossy, difficult, and strident. And the inherent confidence women possess to occupy space in fields dominated by men often goes unacknowledged. Furthermore, over-valuing confidence disadvantages people from groups, genders and cultures in which self-promotion is criticised, and risks hiring and promoting the wrong people. Instead, panels need rigorous training in preparation for conducting evaluations so as to see through confidence to get to competence. It is important to value competence over confidence, as competence as a trait works for a wider range of people when looking for leaders in academia. In addition to hiring committees, this is particularly important in research funding decisions, as obtaining funding serves as an indicator and requirement for career success. However, systemic inequality also exists in grant allocation, to the detriment of women. Claartje Vinkenburg (CJ Vinkenburg Advies) described how panel members believe in their own ability to objective evaluate proposals based on merit, but that panel members’ implicit associations and explicit expectations around the ‘ideal scientist’ and ‘ideal career’ affect how they evaluate and discuss applications. In addition, the requirement to ‘sell science’ (high risk, high reward) creates an additional layer of gendered complexity to the decision process.
In the final keynote lecture of the conference, Jo Handelsman (Wisconsin Institute for Discovery) discussed gender bias in academic science. Unconscious bias describes the underlying attitudes and stereotypes that people unconsciously attribute to others that affect how they understand and engage with them. Unfortunately, many scientists believe they don’t display unconscious bias as they are trained to be objective, however study after study proves this to be untrue. In one such study, participants were more likely to hire whichever application had a man’s name on it, then provided post-choice justifications, like citing whichever strength was present, for their biased behavior. Worryingly, those who believe they aren’t biased are those that apply biases the most. Fortunately, there are tangible steps that can be taken to overcome unconscious bias, including: promotion of self-awareness of biases, understanding the nature of bias, providing opportunities to discuss bias to create accountability, and the provision of training sessions to promote bias literacy. Indeed, earlier in the meeting, Ansgar Büschges had described the use of unconscious bias training as a prerequisite for participation in faculty search committees at the University of Cologne for the active recruitment of women. In addition, the identification of hiring criteria before the evaluation of candidates can abolish bias in selection participants. Jo also advised female scientists to give their referees as much information as possible about themselves (accomplishments, career goals etc.), as the less information people have available the more likely they are to fall back on biases.
Gender imbalance in science hasn’t occurred due to not having suitably qualified women, but rather the structures that are in place which prevent them from taking their rightful place in the higher echelons. Instead of helping women do better, we need to eradicate the barriers that prevent them from succeeding and provide them with the same level of support and mentorship that men receive. We need affirmative action, targets and quotas to reach gender equality, alongside a rethinking of criteria and assessment. While the problem is a chronic under-representation of women in research, men need to be part of the conversation. Indeed, the drive for gender equality is not an attack on men to prevent them from succeeding, but the provision of space to allow women to succeed as they deserve.
Despite the coronavirus pandemic, EMBL’s BioMalPar conference could still take place online. Nearly 400 participants from around the world attended the virtual meeting to share the latest research into Plasmodium, the malaria-causing parasite.
From onsite to digital
There were both benefits and drawbacks to hosting the conference online. On the plus side, the conference’s barrier to entry was significantly reduced, allowing for a higher-than-usual number of participants to attend, from all over the world and at different stages of career. There was more interaction between speakers and the audience and those who would not normally feel comfortable asking a question in a conference hall could do so more comfortably online. The conference was slightly shorter than usual – just two half days – so there were fewer talks overall and no possibility for workshops; however ‘special interest’ lectures were held instead. Poster sessions could still take place with posters remaining online after the session for more leisurely viewing. On a more specific note, Dr Julian Rayner, a member of the BioMalPar Emeritus Steering Committee, remarked that he missed the asparagus stalls in the streets of Heidelberg, where the conference normally takes place. Asparagus or not, it’s remarkable that, in the face of real challenge and uncertainty, the EMBL BioMalPar conference could still take place, now sixteen years in the running.
The conference began with opening remarks from co-chairs Alfred Cortes of ISGlobal in Spain, Silvia Portugal of the Medical University Heidelberg in Germany and Sam Wassmer of the London School of Hygiene and Tropical Medicine in the UK. They emphasised the novelty of the online conference and outlined some ground rules.
Emerging Challenges and New Tools
The first session of the day was on ‘emerging challenges and new tools’ and was chaired by Andy Waters.
Laurent Dembele of the University of Bamako, Ghana, spoke on the subject of artemisinin resistance. Mutations to a protein called Kelch13 prevent the antimalarial from working, allowing the parasite to become dormant in the blood and to ‘reactivate’ when the drug is no longer in the system. Dembele evaluated two antimalarial drugs (KDU691 and GNF179) in vitro which target P14K, a protein that mediates the aforementioned dormancy. He concluded that KDU691 can selectively kill the dormant Plasmodium rings after treatment with artemisinin, but that GNF179 can kill both dormant and non-dormant rings and was active at multiple stages of the malaria parasite life cycle. A combination of artemisinin and GNF179 could mitigate the risk of artemisinin resistance, it was suggested. This has direct applications to SE Asia, where artemisinin resistance is particularly prevalent.
Simone Reber of the Humboldt University of Berlin spoke about her research into Plasmodium tubulin, a potential target for drug development. Tubulin is a ubiquitous protein that controls cell proliferation and so has direct applications to the treatment of malaria, a disease that depends upon cell replication. Simone characterised tubulin in the malaria parasite and considered drugs that could inhibit it and compared Plasmodium tubulin to a similar shaped human tubulin. A concentration of 2.5 micromoles of inhibitor could kill the Plasmodium tubulin but not the human tubulin, for which 20 micromoles were needed. Tubulin is a promising target for malaria treatment but research into it is limited by the protein’s small size. For 150 micrograms of tubulin – in itself, a rather small sample – 5 litres of blood is needed.
Regina Rabinovich of ISGlobal gave her special interest lecture on COVID-19 and its impact on ‘research and beyond’. She took a step back from the specific biology of malaria to consider global public health in general; ‘from the mitotic spindle to global malaria strategy’, as she called it. She offered a concise history of malaria eradication and addressed recent developments in strategy: a shift away from blanket solutions to region-specific programmes. She also shared the broad public health lessons that we can learn from COVID-19, with particular emphasis on accelerating R&D efforts and cultivating a sense of urgency. She concluded with remarks on the potential impact of the coronavirus in Africa both socially and epidemiologically, with reference to data modelling from the WHO and Imperial College London.
Alfred Cortes introduced the second session on ‘parasite biology’.
First to speak was ManojDuraisingh of the Harvard TH Chan School of Public Health. He spoke on how the P. falciparum egresses from red blood cells. He detailed that the PfPP1 protein is essential for such egress and that it coordinates multiple signals early in egress. He also outlined the role for Hect E3 ligase in egrees and that PfPP1 regulated cGMP levels through PLT-GCalpha.
MathieuBrochet of the University of Geneva spoke on his work into the Plasmodium protein, PKG. This protein was previously known to control calcium signals called Ca2+ which, in turn, are critical for Plasmodium life cycle stages in the human and mosquito, namely erythrocytic egress and gametocyte development. How PKG influenced these Ca2+ signals was previously unknown, however, so his research sought to identify a partner protein. He identified ICM1 as this partner protein, finding that when ICM1 was distributed, so was egress, invasion and Ca2+ mobilisation.
FranckDumetz of the University of Cambridge spoke about his investigations into the presence of ‘G4’ proteins in the P. falciparum genome and whether they play a role in post-transcriptional regulation. He first identified 681 ‘rG4s’ in the transcriptome and used both in vitro and in vivo approaches to find that rG4s can have a regressive impact on translation when they appear on the transcribed strand of a gene. He continued to suggest that there may be novel RNA-binding proteins in Plasmodium that are involved in regulating rG4 motifs.
Venessa Zuzarte-Luis shared her research into why Plasmodium replication in the liver of mammals is particularly high, producing tens of thousands of parasites, compared to replication in reptile and avian species, which only produce dozens of parasites. Vanessa states that this disparity is caused by the parasite’s utilisation of liver-specific methionine adenosyltransferase enzyme (MAT1), and the capacity of that enzyme to generate unlimited amounts of S-adenosylmethionine (SAM). SAM is capable of reverting the impairment of infection, suggesting that the parasites use this abundant resource.
“Omics” Approaches and Evolution
After a poster session on Slack, Julian Rayner began the third session on “omics” approaches and evolution.
Franziska Hentzschel of the University of Glasgow presented her research into the parasite-host interplay in vivo at the single-cell level. She used flow cytometry and single-cell RNAseq to characterise parasite and host cells in circulating blood, bone marrow and the spleen of P. berghei-infected mice. She found that the spleen was preferred as the extravascular site for Plasmodium reservoirs, with the earliest ring stages enriched in putative reticulocytes found there.
LianneLansink of the Queensland University of Technology and the University of Melbourne detailed her research into how the malaria parasite adapts in the human host to changes in the environment. She created an environment of lipopolysaccharide, a condition which causes low blood pressure. She reported that this impaired the maturation of the parasites in vivo. The condition also affected parasitic gene expression; ribosome genes were down-regulated and other genes were perturbed in single parasites in a life-stage dependent manner.
Epidemiology and Surveillance
The second day of the BioMalPar conference began with a virtual pub quiz. Sam Wassmer then introduced the fourth virtual session of the event: ‘epidemiology and surveillance’.
ChrisDrakeley of the London School of Hygiene and Tropical Medicine gave a talk on the use of serology in understanding malaria transmission dynamics. He outlined several use cases of serology in malaria-endemic regions and emphasised the advancements in serological technologies; multiplex bead assays and protein/peptide microarrays allow for the assessment of proteome-wide immune responses which allows for greater granularity of analysis, looking at specific antigens or antigen combinations that cause specific immune responses.
MarioRecker of the University of Exeter spoke about understanding individual-level variations in malaria susceptibility and acquisition of clinical protection. His study sought to identify robust inferences of individual-level protection or susceptibility to malaria by analysing a longitudinal systems-immunological cohort study of Junju, a region of Kenya. He found that one of the most important risk factors to malaria is the number of previously experienced episodes which correlates positively with probability and number of clinical episodes during the upcoming transmission season. He also found that birth year can also have a significant and lasting impact on a child’s susceptibility to clinical malaria, due to the child’s exposure to Plasmodium early on in life.
ManuelaCarrasquilla spoke about her research into genome sequencing in Colombia to determine the history of P. falciparum. She analysed 151 clinical samples of the parasite collected in a regional hotspot during a 2016 outbreak linked to mining activities. She determined that the Colombian P. falciparum populations show high levels of genetic structuring and confirmed the presence of five major parasite lineages overlapping in time and space which have been shown to have important functional variation, including drug-resistance genes. Then, combining epidemiological data over a two-year period, she found that almost a third of infections show evidence of shared recent common ancestry, suggesting that increasing mining activities created an opportunity for polyclonal infections and outcrossing.
SimonKigozi of the London School of Hygiene and Tropical Medicines presented the results of his analysis of outpatient surveillance data from four health facilities in Uganda. The malaria burden had shifted from younger to older individuals as a result of malaria control methods including long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS).
Pathogenesis and Immunology
SamWassmer began the fifth virtual session of the conference on ‘pathogenesis & immunology’.
BrittanyRiggle of the NIH was first to speak on the subject of pathogenesis and her work into CD8+ T cells as a potential avenue for treating cerebral malaria. Using multiplex immunohistochemistry in post-mortem brain samples from children with or without cerebral malaria and with HIV. Diagnosis of cerebral malaria increased the number of CD3+CD8+ T cells engaging the cerebrovasculature. HIV co-infection further increased this engagement. Riggle suggests that CD3+CD8+ T cells could be a promising target for adjunctive therapy for cerebral malaria.
HannahFleckenstein of Heidelberg University Hospital spoke about her research into how P. falciparum malaria parasites persist at low parasitemia for months in the human host in the absence of the Anopheles mosquito vector, a poorly understood phenomenon. In the dry season in Mali, the parasites spent longer in circulation before adhering to the endothelium. This adhesion is mediated by knob-like structures on the surface of infected red blood cells which allows for the avoidance of splenic clearance. She found that, in dry season parasites, decreased adhesion resulted in higher levels of splenic clearance which was sufficient to maintain low parasitemia.
Speaking on the subject of monoclonal antibodies, LawrenceWang of the NIH presented his findings into a sporozoite-neutralising monoclonal antibody called L9. The mAb could immobilise sporozoites in the skin and the liver and cause a phenomenon called ‘dotty death’. When asked why monoclonal antibodies would be preferred over mass-market drugs, which are cheaper and less laborious to produce, Lawrence responded by saying that some mAbs can offer potentially life-long protection and are a halfway house between a drug and a vaccine.
EmiliePollenus of KU Leuven spoke about the role of CCR2 in the resolution of MA-ARDS (malaria-associated acute respiratory distress syndrome). This condition is one of the health complications that malaria can cause, contributing to its 400,000 annual death toll. Those with the condition who do not have access to mechanical ventilation have an 80% risk of death, while those with it have a 10-40% risk. Pollenus found that the number of CCR2 monocytes increased during resolution after treatment with antimalarial medicine. In mice where the CCR2 protein was silenced – known as CCR2 KO (knock out) mice – there was a reduction in the number of inflammatory monocytes in the lungs and the spleen, however, this did not affect the resolution of the alveolar edema. Eosinophils – a type of white blood cell – completely disappeared from the lungs upon infection and reappeared with resolution but not in CCR2 KO mice.
CarolaSchaefer of the Seattle Children’s Research Institute spoke about creating a laboratory model for P. vivax infection to test interventions against the disease. Using the P.vivax liver humanised mouse model, with the addition of human reticulocytes, parasites were able to invade and replicate Schaefer could also observe gametocytes that were transmitted to mosquitoes in preliminary experiments.. She then tested the in vivo model with P. vivax Duffy Binding Protein (PvDBP) antibodies, an antibody that could potentially inhibit parasite invasion of red blood cells. 95% protection was observed, providing evidence that PvDBP is a promising target for future therapies.
SilviaPortugal opened the final virtual session of the conference on transmission biology.
DennisKlug of Inserm in France presented his research into the function of the protein TEP12 in antiparasitic immunity in Anopheles mosquitoes. When the protein was silenced, there was an increased parasitic load in P. berghei infections in An. gambiae and An. stephensi mosquitoes. However, there was a lower parasitic load with P. falciparum infection, suggesting an unknown adaptation of this parasite species.
AureliaBalestra of the University of Geneva discussed her identification of CDK-related kinase 5 (CRK5) as a critical regulator of atypical mitosis in the gametogony[KC1] which is required for mosquito transmission. This kinase interacts with a single Plasmodium-specific cyclin (SOC2), suggesting this cyclin/CDK pair controls DNA replication and M-phase progression.
InesBento of the University of Texas Southwestern Medical Centre presented her findings into mosquito-human sporozoite transmission. She found that sporozoites in the salivary glands of the mosquito are in synchrony with the vector’s behaviour, leading to lower parasitic load in the day compared to the night, when the mosquito is more prone to bite.
Bento’s talk concluded the session and was the last talk of the conference. AndyWaters then gave a memorial presentation on Shahid Khan, a malariologist who passed away in late 2019. He began his career with a degree in Parasitology from the University of Glasgow and then worked as a technician at the University of Oxford. He completed a PhD at Cambridge and a Postdoc at NIMR in London. Tributes were made to Shahid by his colleagues; he was described as the ‘sunshine’ of the laboratory and recently wrote a children’s bedtime story entitled ‘There’s a mosquito in my room’, which is available to download here.
The conference was formally closed with remarks from AndyWaters and JulianRayner. They called the virtual meeting a successful and ‘wonderful experiment’.
About the author
I’m Thomas Locke, the Editor of Fight Malaria, a website that aims to distil the science of malaria and make it more accessible to the public. Every week, we summarise some of the malaria research highlights in a sixty-second podcast called ‘Malaria Minute’ and also interview various stakeholders in the fight against malaria. You can learn more about the initiative here. I was fortunate to work as an ‘Event Reporter’ for this year’s BioMalPar and offer a summary below. I’d like to offer thanks to EMBL for covering the cost of my ticket.