Lab move to ETH Zurich, the job search and fixed term PI positions

ETH Zurich (credit) 

Next January, after 9 years at the EMBL, I will be joining ETH Zurich as a tenured faculty of the Department of Biology with my research group hosted at the Institute for Molecular and Systems Biology (IMSB). I am really excited about this move and I think the IMSB is a perfect fit for the type of research that we do. We primarily use computational approaches to study the relation between genotype and phenotype with a specific focus on post-translational regulatory systems (more on the EBI website or my GScholar page). IMSB has a long tradition of method development in large scale measurements of biological systems with a current interest in mechanistically explaining trait variation. The smaller experimental component of our group uses yeast genetics which is also a great fit for the groups around including our future neighbours in the Institute of  Biochemistry. Research wise the group will remain focused on: studying the evolution and functional importance of post-translational regulation; determining the regulatory networks of a cell, and how they change under different conditions including disease. More broadly we also study the mechanisms that underlie trait variation across individuals of the same species. In terms of methods it will remain primarily computational with around 30% of the group devoted to lab work. The lab will be fully equipped for large scale yeast genetics with the exciting addition of having funding for a MS instrument for the proteomics. 

Teaching, scientific integration and group structure

With any move there is always some thoughts about the challenges ahead. Professionally, the types of things on my mind are that I will need to setup the group, integrate myself scientifically and prepare myself for teaching. Setting up the group and integrating myself within the local environment won't be new experiences. I feel I was too slow with both of these things when I first joined EMBL-EBI so I am curious if I will be able to move things along faster this time. Coming from EMBL and the local EBI/Sanger campus I have the impression that ETH is less collaborative but there were clearly many people interested in collaborating just from the small sample I got during interviews. There is an interesting difference in group structure between EMBL and ETH where at ETH a group can have sub-groups with junior PIs that can have varying degrees of independence as per the decision of the more senior PI. Organising a lab in this way will be something new. Finally, I will have to teach at the undergraduate level for the first time. I have always said that students coming out of biology or related topics need to have better training in bioinformatics. While daunting this will be my chance to contribute to this training directly.  

The interview process and decisions

For those less familiar with the EMBL, group leaders are hired for a maximal period of 9 years with only a few exceptions (around 10%) that end up having an open-ended contract. We get generous core funding and get to tap into a great scientific network which more than compensates for the lack of tenure. This means that around year 7 your thoughts start moving into the future. At faculty presentations I would often write how many years I had left in the tittle slide as a personal reminder.  Towards the end of year 7 I started applying and spent most of year 8 applying and interviewing. The first time I applied for PI positions it was all very unidirectional, with myself looking broadly for possible places. This time it felt more like dating a potential future university/institute with expressions of interests on both sides. One of the issues in going into this is that I didn't really know what my value would be in the market. I knew I had a good CV and would certainly find a job, I just didn't know where I could aim for in terms of seniority and resources. That become clearer only after the first interview and the expression of interest of places I felt were really fantastic. 

The second half of 2020 became then about trying to find the best place professionally and personally. I ended up applying to 10 places, interviewed in 8 and received 5 offers. I tried to find a job in my home country (Portugal) but from the two places I was interested one picked another candidate and the other could not make an offer that was not fixed term. The decision ended up being among 3 places with the major differentiation factor being between 2 offers that had less core funding but higher management responsibilities and ETH with incredibly generous core funding and the best scientific fit (but less seniority). Personally the decisions were about staying in the UK or moving to France or Switzerland. There is quite a lot to be said about this choice (safety, adventure, integration, kid friendly, jobs for partner, etc) and in the end we went with Switzerland. While excited I am also anxious about yet another move to what will be my 5th home country, the now almost familiar sense of uprooting and new beginnings. But this is not yet time for goodbyes.

Non-tenure group leader positions (in Europe)

I don't know who invented the fixed term, non tenure track, group leader positions in academia. It may have been EMBL and this model has clearly spread across Europe with many research institutes having some form of junior positions that have a variable number of years (5 to 12) to set up a group and then necessarily need to move on to a different place. EMBL does this because it is funded by many member state countries to train the next generation of "academic leaders" that will lead research groups across the member states. The obvious advantage of hosting these positions is that it keeps the institute forever young if you manage the turnover well. I think these positions can work well if they remain a relatively small proportion of the total PI/faculty positions; there is some level of support to at least kick start the group; and the positions last a sufficient number of years. Having gone through this at EMBL my impression is that 7 years would be the bare minimum and 9-10 years would be ideal. This also depends on the level of support beyond the PI salary. If conditions are not met then it is not worth setting up people for failure with the selfish goal of using the higher turnover to bring in new ideas/methods. Don't give people super postdoc positions for 3-5 years with no funding and no chances of tenure just because you want fresher ideas around. If there is some mechanism for tenure or open ended contract then it should be crystal clear from the start how (un)likely this is and what are the transparent criteria for achieving it.

Group member profile - Omar Wagih

The latest instalment of this blog post series is by Omar Wagih (@omarwagih, Gscholar) who has just last month successfully defended his PhD. Along with Marco, Omar has been part of the group working on studying how DNA variants relate to phenotypes. He developed the mutfunc resource and the fantastic guess the correlation game.

What was the path the brought you to the group? Where are you from and what did you work on before arriving in the group?
My love of genetics is, in more ways that one biologically ingrained. Growing up in a family of scientists, I was always surrounded by a wealth of information which I instinctually sought to organise. For this, I pursued my undergraduate and masters degree at the University of Toronto, majoring in computational biology and computer science, respectively. Along the way, I was fortunate to work in some of the leading computational biology labs in Canada including those of Gary Bader, Philip Kim, Charlie Boone, Brenda Andrews, Andrew Fraser and Andrew Emili. I worked on a range of projects which ranged from analysing images of genetic screens of yeast to determining the impact of disease mutations on kinase-substrate phosphorylation. These experiences led me to develop an interest in understanding how changes in the genome translate to variability in cellular physiology, and ultimately phenotype, which prompted me to pursue my PhD.

What are you currently working on?
My current project involves working towards a deeper understanding of how changes in the genome propagate to phenotypic variability by predicting which cellular mechanisms are likely to be impacted. For the past several years I have been developing and using computational methodologies to assess the mechanistic impact of natural and disease-causing mutations. I have been applying these to yeast, human and bacteria models in hopes of streamlining hypothesis-driven variant annotation. I have also been utilising these predictions to assess the overall burden these mutations impose on gene function and putting such information towards conducting gene-phenotype associations.

What are some of the areas of research that excite you right now?
I'm intrigued by novel mutagenesis technologies that are allowing us experimentally assess the impact of genetic variants on cellular fitness and function in a massively parallel fashion. Technologies like deep mutational scanning CRISPR are becoming increasingly common in achieving this and their off-target effects are steadily being reduced.

With such massive amounts of mutagenesis data, I'm also interested in how machine learning methodologies such as deep learning can be applied to learn how mutations collectively impinge on cellular function and ultimately phenotype. This would significantly improve the precision of variant impact predictors and, in my opinion, will have crucial roles in shaping the development of novel and personalised drug therapies.


What sort of things do you like outside of the science?
Whether I'm skiing, hiking, camping or exploring the city, or you'll more likely than less find me outdoors. I often partake in sports. During my time in Cambridge, I rowed for my college and was part of the university boxing team.

I have been fascinated by drones for a while and own a DJI Phantom 3, which I often use for aerial filming. I also enjoy landscape and portrait photography, particularly with my 50mm lens. If I still have extra time on my hands, you'll find me implementing silly ideas that come to mind into apps or games. Here are a few I've made: genewords, pubtex, and guess the correlation.

Group member profile - Marco Galardini

Marco Galardini (webpage, Gscholar, twitter, EMBL-EBI page), a postdoc in the group, is the next member that kindly volunteered to write a group profile page. He is currently one of the few people in the group that is not working directly with protein PTM regulation but is looking instead more generally at the consequences of mutations on cellular growth phenotypes.

What was the path the brought you to the group? Where are you from and what did you work on before arriving in the group?

I like to think of my career so far as a simulated annealing process, where the temperature parameter is substituted by curiosity. I started by studying applied chemistry in high school; we had to spend lots of time in the lab and we got plenty of opportunities to get our hands dirty with both inorganic and organic chemistry. The latter is probably the reason why I then pursued a bachelor degree in biotechnology at the university of Florence, with a focus on industrial and environmental processes; during that time I also got interested in microbiology, mostly by the great diversity and versatility of the bacterial kingdom. When I discovered that the University of Bologna was offering a masters degree in Bioinformatics I jumped into it with great enthusiasm, eventually combining it with the interest in microbiology during an internship at the Nijmegen university.

After a short break as a software developer in a company I started a PhD in Florence, carrying on a comparative genomics study in the nitrogen-fixing plant symbiont Sinorhizobium meliloti (PhD thesis). Since this project combined computational biology, microbiology and the impact on the environment, I can say that it succeeded in combining the various academic interests I had developed during the years. Following the simulated annealing analogy I can say that I sometimes felt like I was in a local optima. Under the supervision of Marco Bazzicalupo, Emanuele Biondi and Alessio Mengoni (lab page) I was lucky enough to ride the wave of genomics in a moment where getting bacterial genomes was becoming increasingly easy; I was therefore able to describe the interesting functional and evolutionary features of the (relatively) complex genome of S. meliloti, while developing some computational methods on the side.

What are you currently working on?

I'm currently two years into a very exciting project that aims to develop models
to predict phenotypes for the Escherichia coli species, in close collaboration with Nassos Typas (EMBL). Bacterial species are known to harbor striking genetic variability between strains, both in the form of point mutations, but also with respect to their gene content (the so-called pangenome), due to recombination and lateral gene trasfer. Understanding how this variability translates to differences in phenotypes has been therefore the focus of this project. This has proven to be both a challenging and valuable experience, as we had to build a strain collection from scratch, phenotype it on different growth conditions and sequence a large fraction of those strains.

For this I owe a great deal of gratitude to various members of the Typas group who have helped me out in running the wet-lab experiments, namely Lucia Herrera and Anja Telzerow. I am now in the process of testing the predictive models, who have proven to show very promising results, with potential applications to other species, in and outside the bacterial kingdom.

What are some of the areas of research that excite you right now?

Despite the common claim that no great discoveries are made anymore, I think that science is moving faster and getting bigger every day; if we want to be optimistic it should only be a matter of time before this will start to have an impact on our everyday lives. Some examples involving microbiology include real-time tracking of infectious diseases (e.g. WGSA, or NextFlu) and microbial communities as environmental sensors (e.g. Smith et al. mBio 2015). I'm therefore very excited to see how the lag time between a discovery and its application shrinks; there are legitimate concerns of course (e.g. laws not catching up, democratization of new technologies), but I can't help being thrilled about it. I also enjoy reading about how human activities are becoming a new powerful selective pressure in evolution; antibiotic resistance is the best known example, but there are also positive examples like the reports of bacterial species evolving the ability to degrade plastic. This shows that the natural world is still worth exploring and that evolution can also act on very short time-scale.

What sort of things do you like outside of the science?

I used to be quite active in photography, with a preference for analogic media
such as black and white films and polaroids; despite not being very active right now, I'm still packing my camera when going for a short trip. I also have an interest in small DIY projects involving music; I have built some experimental synths running on Arduino, which were used in a band I used to play in. Apart from that, I enjoy reading and watching movies, going to contemporary art exhibitions, and a bit of cycling.

Group member profile - Romain Studer

Next up on this series of group member profiles is Romain Studer (blog, scholar profile, twitter), a postdoc in the group that is very interested in protein evolution combining sequence and structural information.

What was the path the brought you to the group? Where are you from and what did you work on before arriving in the group?

My main interest in biology is the study of proteins in a broad diversity of organisms. My PhD work, as well as my postdoctoral research, was focused on protein evolution, at the primary sequence level and at the tertiary structure level.

I did my undergraduate studies and PhD work at University of Lausanne, Switzerland. My undergraduate studies were focused on immunology and biochemistry, with a dash of bioinformatics.  My PhD research, with Prof. Marc Robinson-Rechavi, was more on evolution and mainly focused on the comparison between paralogs (i.e. genes that diverged after a duplication event) and orthologs (i.e. genes that diverged after a speciation event). Positive selection can be used as a mechanism to fix advantageous mutations between paralogs, as well as between orthologous genes. The conclusion of my analyses was threefold: (1) positive selection affects diverse phylogenetic branches and diverse gene categories during vertebrate evolution; (2) positive selection concerns only a small proportion of sites (1%-5%); and (3) whole genome duplication had no detectable impact on the prevalence of this positive selection (Studer RA et al. 2008, Studer RA et al 2010).

After my PhD, I stayed a few months in Lausanne to work with Prof. Bernard C. Rossier to explore the evolution of sodium pumps and channels, involved in the regulation of blood pressure. I found that the sequential emergence of the different subunits of these proteins could be directly linked to the emergence of multicellularity in animals (Studer RA et al. 2011; Rossier BC et al. 2015).

In 2010, I then obtained two successive fellowship grants from the SNSF to move to UK. I worked in the group of Prof. Christine Orengo, where I have explored in more details the influence of structure on protein evolution. I contributed to the evolutionary aspect of the CATH database, a classification of protein domains. I also explored the evolution of RubisCO, the enzyme responsible for photosynthesis. I reconstructed the ancestral 3D structures of RubisCO and estimated the stability effect (ΔΔG) of mutations during evolution. The essential conclusion of this work was that mutations providing an increase in catalytic rate tend to be destabilising, but are rapidly followed by stabilising mutations during the course of evolution (Studer et al 2014).

My SNSF funding finished by the end of Summer 2013 and I then started to work as a senior postdoctoral fellow with Pedro Beltrao at the European Bioinformatics Institute (EMBL-EBI).


What are you currently working on? 

My current project is to estimate the level of conservation of posttranslational modifications (PTMs) in proteins, in particular phosphorylation. Phosphorylation is an important mechanism to quickly regulate protein function. Combining phylogenomics methods and experimental phosphoproteomics data, I am evaluating the replacement rate of phosphorylated residues during the evolution of multiple yeast species. I found that (1) most phosphosites are quite recent, (2) ancient phosphosites are very likely to be important for function and (3) motif preference have diverged across species.


What are some of the areas of research that excite you right now?

One interesting field is the application of experimental analyses on ancestral characters, such ancestral amino acid mutations, phosphorylation state or whole ancestral proteins. Evolutionary frameworks allow the prediction of ancestral sequences with good accuracy. Such sequences can then be modelled in 3D structure by homology modelling, or can be even resurrected in vitro by protein synthesis. These ancient proteins can be submitted to the same analysis as their modern counterpart and explore the difference over the time. This framework has the potential to reveal important properties.

Group member profile - Haruna Imamura

Here is the second entry into what I hope will be a very long series where I introduce our lab's members. Next up is Haruna Imamura (pubmed), an interdisciplinary postdoc with experience in mass-spectrometry and informatics.

What was the path the brought you to the group? Where are you from and what did you work on before arriving in the group? 
I first joined the biological network analysis group in my undergraduate course in the lab of Masaru Tomita at Keio University (Japan). I launched a project, which applied the concept of network analysis to a dataset of phosphorylation dynamics. Because of this experience, I grew increasingly interested in resolving the biological importance of phosphorylation in the context of signal transduction and began to study phosphoproteomics. From my master’s course, I joined the proteome group led by Yasushi Ishihama, in the same university, and learned proteomics-related experimental skills, including phosphorylation enrichment and mass spectrometry (MS) manipulation. As Prof. Ishihama moved to Kyoto University (Japan), I also moved and started my PhD course there. My PhD project was to determine the protein kinase selectivity towards their substrates (Imamura et al. 2014, Imami et al. 2012, Imamura et al. 2012)  . We analysed lysates after in vitro kinase reactions and identified phosphorylation sites with MS to obtain kinase/substrate relationships in a high-throughput manner. The information obtained in the study would allow connecting already accumulated phosphorylation data to kinases.

As MS has been improved dramatically, nowadays there are more research studies coming up with a long list of identified phosphopeptides. However, it is revealing that only a small fraction of modification sites seem to have an important function in biological systems. So the next challenge in this field is mining functionally important phosphorylation among the pool of ‘junk’ phosphorylation. In this context, I mainly had three wishes for my post-doc project: (1) to be able to contribute through proteome experience, (2) to learn more about informatics, and (3) to reveal important phosphorylation in biological systems. I found Pedro’s group to be a great environment for it, and I asked him for position availability. Fortunately, there was a project that matched my background, and here I am.

What are you currently working on? 
I am working on a project to study how phosphorylation in host cells is changed by the infection of Salmonella. Salmonella is a facultative intracellular pathogen that is one cause of diarrhoea in humans. The process of infection is like a series of offensive and defensive battles between Salmonella and the host cells. Salmonella tries to hijack and utilise the host’s cellular system for its proliferation, while the host cells tried to eliminate them by activating an immune response. Among various changes happening in the cells, post-translational modifications, including phosphorylation, play important roles.

We use Salmonella enterica serovar typhimurium as a model system and study host cell-lines that have been infected in a time-course. Their phosphoproteome are analysed using MS, and the experimental dataset was combined with other publicly available information by informatics to find out key regulations for Salmonella infection. I am an EIPOD fellow, which is a programme from the EMBL Interdisciplinary Postdocs (EIPOD) initiative, promoting interdisciplinary research at EMBL. This work is a collaboration with the Typas lab in EMBL-Heidelberg, which is an expert of microbiology and genetic interactions. The MS analysis has been done with the help of the Proteome core facility led by Jyoti Choundhary in the Sanger institute.

What are some of the areas of research that excite you right now? 
With the current technology, phosphoproteome analysis with MS still requires a group of cells. It means the outcome would be averaged among a variety of cell populations. So I am interested in some projects attempting to do single-cell whole-proteome (or even phosphoproteome). Also, cellular imaging interests me, as it would be a complementary technology to MS. For example, mass cytometry could capture and quantify phosphorylation at the single-cell resolution in a systematic way, which enables the study of phosphorylation signalling on intercellular communications.

Besides, out of curiousness, I am interested in research which raises doubt regarding ‘self-consciousness’. For example, in molecular-scale, ‘behaviour epigenetics’ is one of the attractive topics for me, which describes how nurture shapes nature. Also, ‘gut-brain axis’ is gaining more attention, as it is shown that the gut microbiota communicate with the central nervous system and influence the brain. How true is ‘you are what you eat’? Finally, in macro-scale, one of my favourite videos from TED (Suicidal crickets, zombie roaches and other parasite tales) talks about some surprising incidences where parasites control the host brain and can change its behaviour.

What sort of things do you like outside science? 
I have fun horse riding since a year ago. I have always wanted to do it since I was in Japan, and the environment here inspired me to start. The stable is about 15 mins by bike from the institute, so I can go there to have class once a week after work. It is good exercise and riding horses is relaxing. Also, it is fun to talk with people there who love horses and learn hands-on biology. I am trying to build a better relationship with the horses, who have a variety of personalities. In daily life, I usually go to the gym for running. It is becoming a routine in my life after I began when I was a PhD student. It helps me to clear my mind and gives my brain a chance to refresh. Running a marathon is one of the things on my bucket list, but I have to put more effort in to achieve it.

Group member profile - Brandon Invergo

I had mentioned previously that we should do a better job of using the web to describe our group and work. As part of this effort I will try to have a recurrent blog post series to introduce the lab members more extensively. The first group member to give this a try is Brandon Invergo (website, twitter, GScholar) who is currently doing a postdoc in the group with an ESPOD fellowship. Here follows Brandon's answers to a few questions I asked him.


What was the path the brought you to the group? Where are you from and what did you work on before arriving in the group?

I originally studied Computer Science, but by the time I was finishing my degree, I was more interested in doing something Biology-related than in working for a software company. Not sure yet what I wanted to do specifically, after receiving my degree I was fortunate to get a job working in the lab of Lawrence H. Pinto at Northwestern University (Evanston, IL, USA). There, I performed electrophysiological and behavioral assays of the mouse visual system, in the context of a functional genomics program. After a few years, I decided that it was time to go back to school and to start on the path towards a career in academic research. So, I moved to the Netherlands to pursue a master's degree in Biology at Leiden University. I specialized in evolutionary and ecological sciences and I did my primary research project under the supervision of Bas Zwaan. I investigated how the dynamics of hormonal signaling during pupal development of a tropical butterfly change in response to environmental conditions (temperature) and how those changes give rise to distinct adult phenotypes (polyphenism).

For my PhD, I wanted to perform research where I could combine my backgrounds in computer science and evolution and a nascent interest in systems biology (bonus points if I could also tie in my background in vision research). For this, I moved to the Institute of Evolutionary Biology (Pompeu Fabra University / Spanish National Research Council) in Barcelona, Spain, where I joined the group of Jaume Bertranpetit and worked under his supervision with the co-supervision of Ludovica Montanucci. My thesis, which I successfully defended in November 2013, was entitled "A system-level, molecular evolutionary analysis of mammalian phototransduction". In it, I combined techniques from bioinformatics and computational biology for molecular evolution with network- and modelling-based tools from systems biology. I sought to uncover the influence of the structure and dynamics of the visual phototransduction pathway on the evolution of the proteins that comprise it. The work also resulted in the improvement of the most comprehensive mathematical model of the system produced to date (currently under review at Biomodels), as well as a Biopython module for working with codeml and other programs from the PAML package (which are notoriously annoying to work with in analysis pipelines).

What are you currently working on?

I joined the EBI and the Sanger Institute in December 2013 as an ESPOD fellow, one week after my thesis defense. Here, I am continuing to explore how complex signaling systems function and evolve, except now I'm working in the context of malarial parasites (Plasmodium spp.).

In particular, I'm studying post-translational modifications (PTMs) on a proteome scale in the parasites, with an eye towards how the parasite uses reversible PTMs (mainly phosphorylation) for cellular signaling during key transitions in its complex lifecycle. This work involves performing both the mass-spectrometry experiments to collect the data and the computational analyses on these and other datasets. I'm finishing up a rather big experiment now and in a few weeks I expect to be neck-deep in data.

What are some of the areas of research that excite you right now?

Really anything at the intersection (well, more generally, the union) of molecular evolution and systems biology immediately catches my attention, such as the evolvability of pathways or the patterning of natural selection across systems. Of course, I'm reading a lot right now about detecting and describing PTMs at the proteomic scale. I'm also excited by developments in biochemical system modelling, particularly right now in methods for bayesian inference of parameters from large-scale datasets. Finally, though it's not directly my field, I like to keep an eye on what's happening in complexity research at the most fundamental, mathematical level.

What sort of things do you like outside of the science?

I'm very active in the Free Software community and within GNU in particular. I help out a lot behind the scenes: working with (read: pestering) GNU software maintainers, evaluating new software that has been offered to us, and being on the advisory board. I also maintain some GNU packages (GSRC & pyconfigure) and some of my own software projects in my free time. My other main passion is music. I have written many mediocre electronic music songs over the years, some of which have even been released, and I was a moderately successful DJ for nearly a decade. Sadly, my music-writing died off as my PhD thesis gained steam and I haven't written anything recently. When I decide to take a break from all that or to be social, I like to play boardgames.