State of the lab 12 - Becoming an established scientist

This blog post is part of a (nearly) yearly series on running a research group in academia. This post summarizes year 12, the 3rd year after moving to ETH Zurich. In the last blog post I wrote down some of our overall research directions for the first 5 years of the group at ETH and I will wait another year or two before reflecting back on those commitments. This time, I wanted to try to write down some thoughts I have been having about essentially becoming more established in academia. This includes a longer term perception of group turnover, the time and resources needed to achieve research objectives and some activities that go beyond the management of the research group.

Group member turnover cycles

With 12 years of managing a research group, I have gotten used to some of the broader rhythms of turnover of the lab. Our lab is now almost totally renewed with just 1 lab member that came with the lab from EMBL. While this turnover was somewhat enforced by the move from EMBL to ETH, the turnover of lab members is a constant in academia given the short term nature of the lab members’ positions. In our group PhD students have typically stayed for around 4 years and postdoc have typically stayed for up to 5 years. Since there is some degree of clustering of the hires there tends to be some periods of higher turnover. We have had something like 2 to 3 periods where the lab has seen a large change. In the group, I try to hire from diverse backgrounds (e.g. biology, CS and math) and we work with a range of experimental and computational approaches, including for example yeast genetics, proteomics, structural bioinformatics, machine learning, etc. This creates a nice dynamic of group members building up their projects, while at the same time learning about the capabilities of the rest of the lab. The projects are usually meant to be somewhat synergistic, trying to address bigger goals from the individual problems (see past blog post on this). This means we have had windows of around 3 years when things click together before the turnover starts again. We are just around that exciting stage in the cycle and I am really looking forward to making the best of it. I still don’t enjoy what comes next, when the group will inevitably turnover again. I have accepted that it is an opportunity to steer the ship into new directions but sometimes it is disappointing to change the group just around the time it feels like we can take on almost any challenge.

Longer term view of science

One thing that has been on my mind is that I am sometimes weary about the time it can take to achieve a research goal. I am not talking here about an individual research project which tends to take on the order of 2 to 3 years on average. In our group we have tried to address some bigger research goals, such as trying to understand the evolution of protein phosphorylation or the functional relevance of individual phosphosites. These kinds of challenges take multiple independent projects and over 10 years of time to make a meaningful dent on. These days I will look at a potential long term research goal and I will think about the many different types of methods and steps that will be needed and this can distract me from the excitement of figuring those things out. I should say that I am by no means jaded about doing research. I still get such a thrill discussing the day-to-day results with lab members, being at the frontier and trying to figure things out. It is just when I pause to think about the longer term view, either in the past or trying to project into the future that I sometimes wish things could just move faster. I have taken part in a couple of large multi-PI projects that have moved very quickly and from these I can see the temptation of trying to have large labs. 

From junior to “established” PI

There is no point in time when a switch happens and someone is no longer considered a junior PI but after 12 years I can safely assume that label no longer applies to me. This has brought some relatively small changes in my job, one simple one being that I no longer think about tenure. For most of my career I was on fixed term positions, including my first group leader position at EMBL which had a time limit of 9 years. I joined ETH 3 years ago on a tenured contract and not having to think about my next job has left me with a tiny post-tenure slump - what am I aiming for ? Related to the previous section, I have considered that I could enjoy overseeing science at a higher level than as a group leader. As one example, I organized an application for a National Centre of Competence in Research (NCCRs) with 19 PIs interested in human genetics in Switzerland. While the application failed, I was really keen and excited to co-direct the center if it had been funded. 

Another aspect of my job that has changed somewhat is a higher commitment to activities outside the lab, such as taking part in committees, advisory panels or formal and informal mentorship of junior PIs. I don’t feel particularly overwhelmed by these activities but that might change if I am required to take part in more committees within ETH. Not everything is an additional burden to an already busy job. I have felt that being more visible and connected in international science comes with benefits, including being easier to at least discuss collaborations or having labs interested in joint grant applications.

Scientists that have worked in academia for longer than I have might find some of these things funny and I am certainly curious about what it will feel like reading this 10 years and more from now. In fact, the blog is now a bit over 20 years old with posts starting in my PhD. While I don’t post much these days I aim to continue at least this yearly series while I feel there are some new things to say beyond the progress in our science.

 

State of the lab 10 and 11 - the first years at ETH Zurich

Yet another lake by a mountain in Switzerland

This blog post is part of a (nearly) yearly series on running a research group in academia. This post summarizes years 10 and 11, the first 2 years after moving to ETH Zurich. It also marks the end of the first decade as a research group leader, which is meaningful only because we have ten fingers and use 10 as a base for counting but I digress. There has been a lot to adapt to in moving to a new country including all the basics of moving, re-building the group and starting teaching. It was a lot easier than the first time around since I didn't have to set up the group from zero. Some people came with me, some stayed at EMBL-EBI with funding that couldn't be moved and generally speaking we could continue several computational related projects without much interruption. If we were primarily lab based then I think the interruption would have been more dramatic. Unexpectedly, there were more periods of high stress than I typically have. There was no particular reason for the stress but just a combination of multiple small things and probably due mostly to the adaptation to a new place. I will cover here some of the biggest things I am having to adapt to and also some of the research directions planned for the first 5 years of the group at ETH. One aspect that I will not cover is networking and getting to know the Swiss research landscape, but I will come to it in a later post.

The Swiss style of leadership

The EMBL, where I was before, has a very top-down leadership. EMBL is funded by different counties that are represented in the EMBL council. There is a director general who is appointed by the council and has a lot of control. Of course, there is a hierarchical support structure with a senior management team, heads of research units and a group of "senior scientists" that support the director in decision making. I am still figuring out ETH but there is a very different feel to it, both in size and style of leadership. EMBL employs around 2000 people while ETH has around 12,000. Organizationally, ETH is divided into 16 departments, and each department is further split into different institutes. For example, I am in the Department of Biology, which has 6 institutes, and I am in the Institute of Molecular Systems Biology (IMSB). As leadership, there is an executive board, including the president of ETH, then the Department heads, and in each department there is the meeting of heads of institute and the professorial conferences (i.e. all votes from professors). At least in the Department of Biology the heads of the institutes and the leadership of the Department are meant to rotate every 2 years. At these levels - institute and department - the leadership feels highly representative with lots and lots (!) of voting. This representative rotational leadership feels very different from EMBL and I think mirrors more broadly a Swiss way of doing things. The obvious consequence of this is that any change requires deep consensus and therefore radical change is less likely but it is too early to say much more.  

Teaching at undergraduate level

During 9 years at EMBL I had almost zero teaching duties. I voluntarily taught some classes in the GABBA PhD program in Portugal and not much more. At ETH teaching is now an important part of my job. I am teaching courses in Bioinformatics and Systems Biology, primarily to biology students, which are all very familiar topics and close to my area of research. I don't particularly enjoy the act of teaching, in particular standing in front of 70-100 students and trying to explain things. As an introvert I am more comfortable with 1-on-1 or small group discussions and I get very tired with the interaction of teaching in a classroom setting. I have always said that Biology students should learn more computational skills so at least I have the opportunity now to influence that at ETH. In fact, the biology curriculum was changed right when I was joining to add more bioinformatics and they do have the chance to learn it with multiple lectures that cover bioinformatics and machine learning. Despite it being a mixed bag for me I am privileged in that I have a very low teaching load in topics that I like. Teaching is an area that I feel I could do more for and it could have an impact, in particular if we made it open to anyone. However, it is still something that I find difficult to fully devote to given the research role. 

Our research at ETH during the first 5 years

The start of the research group at ETH has been fantastic. There was another big turnover of the group members during the transition, the second major turnover since the group started 11 years ago. I am really happy with the team we have here and having done this sort of turnover before, I can already see the growing potential of many projects that have started here. So the next 2-3 years is going to be about building up these projects and trying to coordinate them such that they interact and feed off each other. We have very generous stable funding as all other tenured prof positions at ETH  - so called endowed professorships in the US or positions with core funding for the European researchers.  Surprisingly, there is not a lot of oversight on this research funding which is a big difference from EMBL where the units, and their group leaders, are reviewed every 4 years. So I thought I could at least write down our commitment for research over the first 5 years here, in the spirit of disclosing what we are doing with this public research funding.

Human genetics research - mechanisms linking genotype to phenotype

Human genetics is an area that we started working on in the last 3-4 years or so of EMBL. Some of these things are already visible in recently published articles, including some protein-interaction network-based analyses of trait-associated genes. We continue to actively work on this and one direction of focus is to try to build interaction networks that are specific to different tissues or cell types.  We are working on a manuscript on this and it is an area to continue to build upon, to be able to study the differences in cell biology of different cells/tissues and how genetic changes manifest differently in these. A second direction of focus here is to study the relation between common and rare variants linked to related traits using networks.

From cells to proteins - we are finishing a project where we are using protein structures to annotate functional residues in proteins to study mechanisms of pathogenicity.  One aspect of this that will need further development is expanding on the prediction of structural modelling of protein interactions with other proteins and other molecules. Finally, we are interested in how genetic variation controls protein levels and ideally how to build computational models that can integrate the impact of genetic variation through control of protein levels, interactions, organs and organismal traits, ideally without a black-box modelling approach. All of these things are actively ongoing and I expect to have progress to report in the coming years. 

Post-translational regulation - large scale studies of kinase signalling

There are over 100,000 phophosphosites discovered in human proteins and over 20,000 found in budding yeast proteins. We don't have good methods to study the functional role of these phosphosites nor to reconstruct the kinase/phosphatase-substrate signalling network of different cells.  About half of the group is continuing to work on these problems and here at ETH we managed to consolidate the computational and experimental parts of our group which used to run in different locations while I was at EMBL. Because we are doing more of the experimental work now, this part of the group had a slower start but things are now moving along very well. Some of the problems that we are working on include the prediction of the biological process regulated by phosphosites; studying the impact of phosphorylation on protein conformational change; experimental methods to map kinase-substrate interactions and large scale mutational studies of PTMs. The thought has crossed my mind to phased-down a bit this area of research, or at least to move more into mammalian systems in our experimental work to make it more complementary to the human genetics side of the lab. 

Structural bioinformatics, protein evolution and other

We have been having a lot of fun with AlphaFold2 ! With the current fast pace of change in protein related bioinformatics methods I am sure we will continue to play with these methods as they come. It is not likely that we will do a lot of method development ourselves, it is not our way, but I think we are very good partners for method developers to help make the bridge to applications. Protein structures, protein design and evolution models are all things we will likely be playing around with in the coming years. 

State of the lab 9 - an informal report on the 9 years of EMBL-EBI

This blog post is part of a yearly series (or close to yearly) on running a research lab in academia. 2021 was the last of 9 years as a group leader at EMBL-EBI, which is the standard time given to group leaders to establish and run their labs at EMBL. For this year's blog post I thought it was a good time to look back at the full 9 years and I am going to (briefly) cover the time at EMBL with some numbers including giving an approximate account of the finances. This is something that I do with the group at the start of every year but it still feels strange to make financial numbers public. 

The scientists

A lot has happened during 9 years. Starting with the people, we have had 7 PhD students, 1 of which co-supervised, 13 postdocs and 10 interns/visiting lab members. The total group size was around 10 for the majority of the time which, as a manager, feels about right in what I can do as a direct line manager. It is fair to say that science is a very social activity and working with different people with different personalities, through the good and bad, is really enriching. Not to get all corny but the personal interactions are some of the things that stick with me the most over the time. It is always in those extremes - the "unfairly" rejected paper or unexpected positive response, individual personal and work difficulties that are overcome or sometimes not. Mental well being is an example of such difficulties that across the broader society we are not good at dealing with and that have also not always been easy as a manager. 

From these 30 lab members there are 7 that will continue with the group over the next few years: Cristina (senior scientist), Jurgen (postdoc) and Miguel (postdoc) have joined me at ETH and Eirini (PhD student), David (postdoc), Inigo (postdoc) and Danish (postdoc) will remain at EMBL-EBI with funding that cannot be moved. From the PhD students and postdocs that have left all but 2 have left with published papers as first or co-first authors. One PhD student decided not to continue the PhD and one postdoc left after several years without a first author paper. In both cases I feel some blame as the project ended up being difficult and the results were just not very positive.  

The publications and science

In total we published 45 original research papers, 3 review articles and 2 news&views over the course of 9 years. This includes only research that was really done after starting the group and also includes 8 preprints that have not yet been published in a journal after peer-review. This is split into 27 papers where I am listed as co-corresponding author and I also think our group played an important role in the final outcome, plus 18 on which our group had some input into. I am showing on the figure the distribution of these papers along the 9 years. The first paper from our group only came at year 3 with the first real significant set of publications coming at year 4 and 5. In regards to the non-tenure track system, even by this crude metric it is easy to see how different it would be if I had to apply to the job market at year 6-7 vs year 8-9. Of course, note that the numbers for 2021 in particular are inflated by preprints that will ultimately be published in a journal most likely in 2022. Another clear trend that feels true to me is the increase of small collaboration efforts where our group just helped out in some modest way. I think this is a reflection of just being more integrated into the local and broader academic networks.

I am not going to go into the scientific outcomes of the 9 years in any detail. I think some of the strongest work we did was on the evolution and functional importance of protein phosphorylation with multiple publications that have built on each other and where I think our contributions move this field forward. There was also a smaller line of research on the genetics of trait variation that I wouldn't consider to be at the cutting edge but it has been fun to work on. In particular it has been interesting to step closer to the fields of human genetics and genetics of human disease where making advances requires the interactions between people with such different ways of viewing science. Just the language barriers between human genetics, cell biology, biochemistry and chemical biology have been fascinating to get into. 

The funding

So now something that feels less comfortable or at least less common to discuss - the funding. Before going into any numbers, I should caveat this by saying that these are very rough approximations that of course should not be considered an actual financial statement. These numbers also don't take into account the money spent on the whole infrastructure (administration, grants, IT, etc) but are just the funding spent on research lab members, including my salary, and consumables. With that out of the way, over 9 years we spent approximately 5.7 million euros as broken down per year on the figure. Although we have had a small wet lab running in the last 6 years, I would say that 90% of this was on salaries. Of these around 2.7 million were from external grant funding, plus ~450k from competitive internal postdoc fellowships. This of course just shows how amazing it is to work in a place with core funding. I ended up being very successful early on with 2 million funded in years 2 a 3 and this made me too careless about applying for grants later on which I now consider a real error on my part. I applied in total to 13 external grants with 6 being successful. 

So a number that immediately is easy to get but that is probably quite meaningless is the money spent per research paper. We spent a total of ~127k euros per paper or 210k if we only count those where I am listed as co-corresponding. Of course this varies so much per paper really with my very rough estimates on bounds to be something like between 25k to 1 million.  Given that we mostly spend the budget on salaries this simply reflects the amount of people time spent on a project. 

To new beginnings 

This is a somewhat dry recap of the 9 years of EMBL but I thought it would be interesting, at least to me, to have these things written down. Even if these are just numbers, I am curious to see what the next 9-10 years look like. I am sitting in my new office at ETH, just close to two weeks after arriving in Zurich. There is a lot to adapt to, including teaching material that I should be preparing right now. I am curious to see how long it will take me to get into the local academic network and how much the move will impact on our capacity to do work. The lab work is really the part that will take the longest as I don't think we will run any experiment before middle of the year and although we have the budget for an MS instrument that will take even longer to get going. In any case, I am excited about the new beginning here.  

State of the lab 7 & 8 - The last years at EMBL

This is usually part of a yearly series of posts where I note down thoughts related to managing a research group in academia over the years. This post covers years 7 and 8 and it brings me now to the start of year 9, my last at EMBL. While I usually do one of these posts every year, with all of the craziness of 2020 I ended up skipping one. 

Year 7, group turnover 

2019 was the year where the group fully turned over all lab members that were with us since the earlier years with 2 postdocs (Haruna Imamura and David Ochoa) and 3 PhD students (David Bradley, Claudia Hernandez-Armenta and Marta Strumillo) leaving. Haruna is now a Research Scientist at the Systems Biology Institute in Japan, David O is a the platform coordinator at Open Targets and Claudia and David B are now doing postdocs. Marta is finding her way through consulting. We were joined by 2 postdocs (David Burke and Miguel Correa) and 2 PhD students (Eirini Petsalaki and Rosana Garrido). This constant turnover of group members is quite difficult to manage both personally and professionally. Year 7 was really the year with largest amount of changes in the group and there is something to be considered about trying to make sure that changes remain gradual. However, it is not always possible to plan for this to happen. While I think that this change in academia is generally positive for science, I do wonder what could be achieved if this was not a requirement (see earlier post).   

Managing research focus over the years

Over the last few years, the research in the group had some dispersion in terms of the group research topics. At the start, the group was named "Evolution of cellular interactions" with a primary focus on the evolution and functional relevance of protein phosphorylation. While this remained the central focus there were other areas we worked on including cancer genomics and genetics of human disease and microbial trait diversity. We also have work that is not yet visible on drug mode-of action predictions. This led me to change the group name to "Cellular consequences of genetic variation" which could better serve as umbrella to the different topics. This is, at least in part, a simple reflection of funding opportunities but also a reflection of true movement in my research interests and the environment I have been working in (Genome Campus). On one hand I feel this dispersion is detrimental in that we could do more with a single minded focus, but on the other hand these extensions have not really been the majority of our work and also act as way for the group to explore new directions. My visual reference for this is a cell sending out protrusions in some directions to feel out the environment around. On some of these new areas (e.g. microbial trait diversity) I feel we have done enough, even with a small total investment, to make the work stand on its own. 

I have to say that the without explicitly planning for it, the dispersion worked to my advantage when applying for position last year as it allowed me to present the group through slightly different lenses depending on where I was interviewing in. Of course, this is only beneficial if there is sufficient research progress made by the group not to appear superficial or unfocused. I suspect that this movement in research topics is normal but I haven't had many deep conversations with others about how this has happened to them in their research groups. In some cases, the changes in topics for some groups seem more abrupt from the outside but it could be just a perception. I will soon have an opportunity to rethink where we put most of our research efforts and likely cut back on some of these extensions. 

Year 8 - A new group, the pandemic and the job market

At the start of last year, I was finally getting comfortable with the idea that the group had changed so much and I was truly excited about the new beginning. Just as the year was starting and I was enjoying this excitement the pandemic hit. As I had described before, we ended up devoting some effort in the group to work on SARS-CoV-2 projects which I think was also good for group morale. However, the changes in working conditions, the effort on the SARS projects and my need to go back to the job market made me less capable of keeping up with some of the projects in the group. While most of the work has kept going there are at least 3 projects/manuscripts that have been neglected simply for my own lack of time/effort. We all know these stories of PIs that let work pile up on their desk and I feel it as a failure although I can rationalise why I really didn't have the time to fully keep up. 

Finally, over last year I was fully back on the job market and I am so relieved that this is now over. Since there nothing official that I can announce I will wait to write up in detail what the process was like and compare it to my first attempt to secure a PI position. I can at least say that I will leave EMBL-EBI at the end this year and I will certainly write more about the 9 years of EMBL. I do want to look back to all that has been good (mostly) and bad, make a summary of what I feel were the biggest advances we made, perhaps discuss the finances, and more broadly go over the issues of this lack of tenure for junior PIs now implemented in so many European research institutions. 

State of the lab 6 – group turnover and getting back in the job market

This blog post is part of a yearly series and marks the end of the 6th year as a group leader at EMBL-EBI. Continuing on the theme of the last post of this series, 2018 was a year of wrapping up projects. We finished and made available 4 preprints (plus a few collaborations) in 2018 with 4 more manuscripts ready to be submitted early this year. As in 2017 the group continued to work at full potential with most lab members having been in the group for several years. Some of the turnover I was expecting last year was postponed for the current year. This will make 2019 particularly challenging both personally and professionally with 3 postdocs and 3 PhD students leaving. I have had a few conversations about lab turnover with more senior colleagues. Their typical responses have been that while it is hard to imagine how the group can survive when experienced people leave the incoming lab members bring new ideas and are a great opportunity to start new directions. Being an optimist I look forward to this new chapter in the group although it will be certainly sad to say goodbye to so many people.    

We often talk about the issues in academia that are not great: the publish-or-perish mentality, chasing the big journals, the job market, etc. Looking back through the last 2 years I really want to make the point of how great it has been to manage this team of scientists. We got to hit that sweet spot where most team members have been in the group for a few years, know each other’s’ capacities and there are synergies in skill sets and projects. With group members doing a mix of computational and experimental work and a knowledge base ranging from structural biology to genetics. It feels like we could aim our collective capacity to almost any problem and we would make progress. I guess this is what is expected but for me it was the first time seeing it build up within the group. I am sure the group will hit that sweet spot again with a different configuration of people and ideas but the next few years will be a period of reconfiguration. 

Group leaders at EMBL typical have a maximum of 9 years and I am currently left with 3 years to move to a new position. Although it is still some time, 3 years means I am now making the last set of hires. We will have 2 postdoc and 1 PhD positions open this year and the group size will start to decrease. Besides focusing on the start of the new projects I will be very actively applying for funding with the idea of taking that funding with me when I move. Given the time it takes to interview and have decisions made for academic posts I will start applying this year if I find interesting places that will consider hiring me in a joint position or with a delay in the start time. I aim to move the group in 2021 but could start sooner as a joint appointment which would give me time to start the new group and apply to and/or move funding. The job application period at the end of the postdoc was one of the most stressful in my life so I am not looking forward to doing it again.  

Scientifically there is much to write about but instead of trying to summarise what we have finished in 2018 I think it is the right time to write a few separate blog posts with a summary of what we have achieved over the last 6 years. There have been a few separate threads of research that have resulted in multiple manuscripts so I will group them,  describe the work, the people that did it all and what I think are some of the open questions that we may work on in the future. 

State of the lab 5 – in the flow with 4 years to go

This blog post is part of a yearly series and marks the end of the 5th year as a group leader at EBI. In March we had an external evaluation of all research groups at EMBL-EBI. It was an interesting experience and overall it was judged a great success for EBI. For our group it was also part of the evaluation towards the standard renewal of contract where I got the 4 year extension. Since there is essentially no tenure at EMBL this also means that I have 4 years until I have to find a senior PI position. This is still a long time but it will increasingly be on my mind going forward. I am not particularly worried but I feel like there are many more places now in Europe with fixed term junior group leader positions. The postdoc bubble will turn into the junior PI bubble and we will have another big barrier and competition in the transition between junior and senior positions.

Personally it is almost strange to stay in the same place after 5 years since I have been typically staying 4-5 years in each place during university (Coimbra), PhD (Heidelberg) and postdoc (San Francisco). It looks like I will have to find some other excuse to thin out my pile of papers on the desk instead of simply moving to a new country and trashing everything.

The end of a cycle
Last year was our most productive year so far, as measured by the number of publications. This year is going to top it based on the manuscripts that I should be working on at the moment instead of writing this post (sorry guys). The research in the group is just flowing with more synergies among the group members. Just when everything is working so well is when so many in the group are leaving. Last year our first PhD student finished (Omar, now at DeepGenomics) and two postdocs have left (Romain moved to benevolentAI and Sheriff is now a project leader at EBI). This year there will be even more people potentially leaving. It is going to be a new challenge to try to keep the science going through the turnover. On the other hand, new arrivals signal the start of new projects and are an opportunity to move the group in new directions. Just at the end of the year, we had 3 new members starting: Allistair (PhD student), Inigo (postdoc) and Abel (visiting PhD student). Abel and Inigo will be working on the impact of mutations in protein interactions and control of protein abundance while Allistair will likely work on the evolution of regulatory networks.

Highlight from 2017 – Predicting condition specific phenotypes from genomes
Most of the work in the group is focused on understanding the function and impact of genetic variants on protein post-translational regulation, in particular for phosphorylation and ubiquitin. However, we have been also working more generically on the genotype to phenotype problem. I think these analyses could use more prior knowledge information and we are trying to contribute in this direction.

Part of this work, led by Marco (GScholar, Twitter) and in collaboration with the Typas lab in Heidelberg was finally published at the end of this year. The question we wanted to address was to what extent we can predict condition specific phenotypes of a strain of E. coli based on its genome and what we know from the well-studied E. coli K-12 lab strain. This is inspired by work that Rob Jelier and Ben Lehner did in S. cerevisiae but on larger scale. To set the project up, imagine we know that a given gene X of E. coli is required for growth under high heat. Then, if that gene X is not present or severely mutated in a strain of E. coli, we would expect that this mutated strain should not survive well in high heat. To test this in large scale we assembled a panel of hundreds of strains of E. coli for which we obtained genomes and fitness measurements under many conditions. We modelled the consequence of mutations using different methods and we collected prior knowledge of which genes are supposed to be important for each condition. In the end we could only predict which strains would tend to grow poorly for around 40% of conditions. This level of success may not be surprising since we didn't take into account for example issues like gene expression levels or compensation by new genes. It could be that gene function may be a lot more plastic than currently assumed but to prove this we will need different experiments.

Besides testing the central question expressed above this collection of E. coli strains with associated data will hopefully serve as resource for future studies. Any additional layer of molecular data (e.g. gene expression) or phenotype (e.g. motility) we measure can make use of all of pre-exiting information. We could ask if motility correlates with the growth under several drugs we tested for example. All of the resources for this collection are freely available and of course this would not be possible without the hard work of the scientist that collected the strains to begin with (listed here).

Highlights for the year ahead
We have 3 different projects that are close to completion that relate to the functional relevance of protein phosphorylation. This is probably going to be our biggest contribution of 2018. We continue to work with the cancer related datasets, primarily using these data to study protein post-translational regulation. Not necessarily to better understand cancer but making use of the large genetic and molecular variation that exists in cancer to better understand the regulatory processes of normal cells. Additionally we will have some progress to report on the evolution of protein kinases and potentially the evolution and regulation of ubiquitylation.

State of the lab 4 – the one before the four year review

It has been 4 years since I started as a group leader at the EMBL-EBI (see past yearly reports – 1, 2 and 3). This year the group composition has been mostly stable, with the exception of interns that have rotated through the group. We had Bruno Ariano (twitter) visiting us for 6 months working on a project to build an improved functional interaction network for Plasmodium. Matteo Martinis has joined the group for a few months and is working with David Ochoa on comparing in-vivo effects of kinase inhibitors with their known in-vitro kinase inhibition effects. Finally, Areeb Jawed has joined Cristina and Bede, for some months, in their efforts to develop genetic methods to study protein modification sites. I think we had a great year in terms of publishing and I had the luxury of not trying to apply for additional funding. That luxury is short lived as we have funding that is ending this year that I will try to replace.

The one before the four year review

All EMBL units are evaluated every 4 years by a panel of external reviewers. The next review for the research at EMBL-EBI is coming up now in March and we have been preparing the required documentation for this. Naturally this forced me to think about what we have achieved as a group for the past 4 years and what we aim to do for the next 4. It is impossible not to go through this process without being drawn into some introspection and without comparing our performance with that of those around me. I think we did well in this period of time, we got two significant grants funded (HFSP and ERC) and published some articles that I feel have been significant contributions towards the study of kinase signaling. I remember my interview for this position when they asked me what I would expect to achieve in the next 5 years. My first though was: “Really ? That question ?”, but I think we did achieve we I had hoped at the time. Still, at EMBL-EBI we are surrounded by some fantastic colleagues that keep the bar really high. It is hard to be satisfied and I am certainly motivated by our research environment to try to help our group to keep up the good work. This review will also determine if our group receives a 4 year extension after the first 5 years. I am confident but still apprehensive and curious about what the reviewers will say.

Studying cell signaling states using phosphoproteomics

During the past four years we have worked on several aspects of kinase based cell signaling. I mentioned before our work on trying to describe the evolutionary history of protein phosphorylation (blog post) and to predict the kinase specificity from interactions networks and phosphoproteomic data (blog post). I haven't described yet our work on studying cell signaling states that has been published a few months ago When David Ochoa started in the group around 3.5 years we reasoned that, by collecting information on how phosphosites abundances change across a large number of conditions, we would be able to use the profile of co-regulation across conditions to learn about how cell signaling systems work. This is copying by analogy what has been done in gene expression studies since Mike Eisen's work. David made use of published conditional phosphoproteomic studies to compile a very large compendium of different conditions. There are issues related to the incomplete coverage of mass spectrometry measurements and potential batch effects of the different studies. David tried to work around these, primarily by focusing the analysis on groups of phosphosites (e.g. targets of the same kinase) instead of individual positions. Using this data he derived an atlas of changes in activities for around 200 human kinases across nearly 400 different conditions. We show in this work how this can be used to advance our knowledge of kinase signaling (Ochoa et al. Mol Sys Bio 2016, and the phosfate webserver).

For me this work was the fist time we could measure a large number of cell signaling states. To see what is the structure of this state-space and what we can learn from this. What kinases are most often regulated ? What kinases define particular signaling states ? What states act as “opposing” states and how may we use this information to promote or inhibit specific states or transitions through the state-space ? These are all questions that we can address with this atlas. The fact that the data was collected from different publications, using different protocols and machines will certainly have an impact on the accuracy and resolution of this atlas. However, the quality and coverage and these types of experiments will only improve and I think this direction of research will continue to be exciting for long period of time. 

Since this work we have also tried to benchmark different approaches to predict the changes of kinase activity from phosphoproteomic information (preprint). In collaboration with Julio Saez-Rodriguez's lab we also used some of the same concepts to relate the changes of metabolism with predicted changes in kinase, phosphatase and transcription factor activities (Gonçalves et al. PLOS Comp Bio 2016).

Onto the next four years

If I do get my contract extension, we will continue our current main research focus on studying cell signaling  through the next four years. Although we will certainly continue to study long term evolutionary trends, such as the evolution of kinase specificity, we will complement this with trying to understand the impact of genetic variation for individuals of the same species with a strong focus on E. coli, S. cerevisae and H. sapiens (mutfunc). We have started to make use of cancer data as genetic resource to study human cell biology (preprint). We won't necessarily try to study cancer as a disease but I think that datasets for primary tumors and cancer cell lines are amazing resources to learn about how human cell biology and cell signaling work. The group will have its first big turnover of group members over the next 1 or 2 years which will be challenging professionally and personally. However this turnover will also allow for and shape future directions of the group which will also be exciting.

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State of lab, year 3 - the first group outcomes

Lab poster made by Omar for the EMBL lab day

This is the third blog post of what I hope will be a very long series. Even in just three years it is fun to go back and read the past yearly entries (year 1 and year 2). I am sure I will enjoy reading back over 5 and 10 of these yearly reports. This report marks the end of the third year of the lab. I have to stop thinking of how quickly a year goes by. We will have a review in March 2017 that will likely dictate our extension after the first 5 years and if extended the group has then an additional 4 years before having to leave the EMBL-EBI (after a maximum of 9 years).

During the third year we said goodbye to Juan A Cordero Varela (master student, linkedIn). Marta Strumillo, that was doing an internship, stayed on to do her PhD in the group. Towards the very end of last year we were joined by two additional postdoctoral fellows, Bede Busby and Cristina Vieitez. As I had mentioned last year they will be working at the Genome Biology unit in Heidelberg in a close partnership with Nassos Typas' lab. Bede and Cristina are setting up yeast genetics methods to study protein modifications. This year I also started a blog series on our group members and I will try to get everyone to participate.

Group size and grant applications

At least for one year I have let myself apply for fewer funding opportunities. The group has now 12 members with one additional person joining this March. I am not sure what is the best strategy to manage the size of a group. Most grants and fellowships have very low success rate (10% to 30%) and if the objective is to maintain a specific group size then one would have to be very lucky to get just enough funding to stay at steady-state. I suspect that many group leaders just keep applying to all available funding and let the group size increase and collapse according to the success of the applications. I would be curious to hear from others what their thoughts are on this. My current impression is that somewhere between 5-15 people is a manageable and efficient group size but does anyone limit growth to stabilize group size ?

To be, or not to be, an experimental group (revisited)

Cristina and Bede at the visitor
lab space in EMBL-EBI

As described in the first year report, we don't have lab space at the EMBL-EBI. To be able to have access to lab space my initial solution was to co-supervise group members with experimental groups. This has been useful, particularly in creating closer collaborations with some of the groups involved. Haruna and Brandon have worked with Jyoti Choudhary to have access to mass-spec instruments. Sheriff has been working in London in the lab of Silvia Santos where he has contributed to some microscopy experiments and Marco spent some time in Nassos Typas' lab learning how to do chemical genetic screens. In all of these projects the group members are spending >50% of the time analysing the data. Bede and Cristina will be the first group members that will be primarily dedicated to experimental work, although I am sure they will also have an opportunity to further develop their computational skills. So far, these arrangements have been working out scientifically. However, I am now sure that, when I move out of the EMBL-EBI, I will aim to have access to lab space.

Projects as science, stories and publishable units

As I had mentioned in the second year report, I am no longer working on a research project myself. I had two periods of time last year where I emptied my to-do list but it didn't stay down long enough to be able to pick up a project. I am more at ease with the management role in the sense that I have convinced myself that it is actual work. It took me a while not to feel guilty about just doing management tasks. It is actually great to be able to help guide the flow of the projects of all of the lab members. From the inception, through the initial stumbles, turns in direction, building up the promising results, up until there is enough progress to be worth communicating it. This also means deciding to quit an idea when the research direction is no longer promising. In this process of managing a large set of projects I have felt a very clear temptation to focus on the publishable units as the outcomes. Although science is nothing if not communicated there is a risk of losing track of the priority of moving science forward. Asking questions and gathering evidence happens always in a scientific context. This context or story is also important for properly communicating your results to others. The problem is when the focus shifts too much into thinking about what are the experiments that are needed to write a paper instead of what are the best experiments to answer the scientific question at hand. These two things are hopefully aligned but the publishable unit should not be the goal in itself.

The first group outcomes

In the past year I finally managed to publish the last papers still involving my postdoctoral lab. The two articles reflect the two strands of research in our group. One paper describes a set of phosphorylation sites collected for X. laevis and an analysis of its conservation and structural features. We found that the degree of conservation of phosphosites and putative kinase-protein interactions is predictive of functionally relevant sites and interactions. We also describe a potential way to identify PTM sites that may control protein conformations. The second article is a large effort to identify conditional genetic interactions in S. cerevisiae. The main message of that work was that there is a substantial amount of genetic interactions that are condition specific. These conditional genetic data allowed us to identify novel roles for yeast genes in the cell wall integrity pathway. Besides these studies we also published the first articles from work that was started within the group. I mentioned before Omar's method to predict kinase specificity from interaction networks. In addition to this we also published a news and views article highlighting recent work from Stelzl's lab and a review on the feasibility of using rational design strategies to create novel PTM regulatory sites in proteins of interest. I was anxious with the time it was taking to get the group to this point. Three years to have research outputs coming from the group feels slow but when talking with others it is apparently not unusual.

Preprints and open science

We have two additional manuscripts that are now making their way through journals. David's project on a map of human signalling states based on conditional phosphoproteomics data and Romain's phylogenetic based analysis of fungal phosphorylation sites. I am personally very much in favour of preprint servers. Although I think I have been ahead of others in suggesting the use of preprints in biology (blog post 2006) I have been slow to actually do it. My current policy in the lab lab is to first ask the authors in the group if they want to submit and then make sure all collaborators are ok with it. Unfortunately, so far, there was no consensus among the authors. I will start to push more strongly for future manuscripts to be submitted to preprint servers. When possible, we will also experiment with making a projects's data and initial analysis available online before the preprints. 

State of the lab, year 2 – reaching steady state

CC BY ,Jason Paul Smith

At the end of last year I wrote up a short description of what it was like to start a group at the EMBL-EBI. I though it would be interesting to try to make it an yearly event so here is the second installment. It is always scary how fast a year passes by and it is interesting to note how my perspective of managing a research group is changing.

During this year we said our first goodbyes as Vicky Kostiou (linkedin) finished her internship. We also welcomed several new members including Rahuman Sheriff (postodoc, linkedin) Haruna Imamura (postdoc, pubmed), Marta Strumillo (intern, linkedin) and Juan A Cordero Varela (master student, linkedin). Sheriff is working on a collaboration with Silvia Santos' group at the MRC-CSC in London to study cell-cycle regulation. Haruna came initially on a 1 postdoc fellowship in collaboration with Yasushi Ishihama's lab (Kyoto University, Japan) and she has recently been awarded an EIPOD postdoc fellowship to study post-translational regulation of Salmonella in collaboration with Nassos Typas and Jeroen Krijgsveld at the EMBL-Heidelberg. Marta is studying the functional role of PTMs in the context of protein structural information and Juan is participating in a project lead by Marco Galardini (postdoc, @mgalactus, webpage) to model and predict bacterial phenotypes from sequence. These new members join the group of people that I already mentioned last year: David Ochoa (postdoc, @d0choa, webpage), Romain Studer (postdoc, @RomainStuder, blog), Brandon Invergo (postdoc, webpage) and Omar Wagih (PhD student, @omarwagih).

Shaking off that postdoc feeling

In the first year my concerns were dominated by the stress of facing an empty room that I needed to fill. It was a mistake to take 6 months to find the first person since I felt like I was wasting time. This year I had to come to terms with the fact that I no longer have time to do my own research projects. After over 10 years of measuring my own productivity by the progress in my research projects it is strange to try to let it go. I am certainly doing work that I enjoy. The progress in the group has been fantastic this year but it took me time to accept that the management activities I am doing is something I should count internally as productive work.

Reaching steady-state

Any new group, specially one that starts in a place like EMBL with very generous core funding, will grow to occupy a space in research. Any movement from this position will then only happen with a slower turnover of projects and people. That seems to be one of the trade-offs from managing a research as group versus an individual. Changing directions for a whole group has to be slower than for an individual. However, as as group it is still possible to explore opportunities while maintaining a common theme of research underway. This year I think we have reached this steady-state. Although we got significant new funding starting next year I don't expect the group to grow much larger. I am curios to see how the research theme of the group will change with time.

The bad and the good of 2014

So I will start off by summarizing some of the aspects I wish had been different this year. Above all I had hoped to publish the first article(s) from the group in 2014. I am happy with the progress of the projects so far (see below) but I am still amazed on how long it takes to get a group up-and-running. Most of the group joined towards the end of last year so it has not been that much time objectively. The second aspect I think we could have done better was to communicate more online on what we have been up to. This has been one of the years with fewest blog posts since I started blogging about 11 years ago. We should do better than this, both because we are publicly funded and because the people (and projects) in the group deserve better exposure. So I will try to change this next year.

On a more positive note this has been great a great scientific year for me and the group even if not very visible to the outside. The two last papers that started still at UCSF are finally under revision and should come out next year. One is about studying the function and evolution of X. laevis phosphosites (biorxiv) and the second about conditional genetic interactions in S. cerevisiae. We also have 3 projects that are getting close to being finished from Omar, David and Romain that I hope we will submit early next year. If possible we will put them up on biorxiv as well before submission. It is obviously a great privilege to see this work take shape and I hope some of you will also be excited about it when we make it public.

Regarding funding, I had mentioned already that Haruna got an EIPOD fellowship. In addition we got a 5 year ERC starting grant awarded. I am very excited about the starting grant since this will allow us to start doing yeast genetics work to complement the proteomics and genome analysis we have been doing. This will feed in and complement almost every project in the group so I really have to thank the committee for this opportunity. For this purpose we will be hiring 2 positions (postdoc and/or technician) early next year. Since the EBI does not have lab space, the work will be done at the Genome Biology unit in Heildeberg. This means I will be traveling (even) more to Heidelberg next year. Those hired to these positions will have the opportunity.to interact with the Typas lab that conduct similar genetics studies in bacterial species. If you know anyone looking for jobs with PhD and/or postdoc experience in yeast genetics please do let them know about these positions. 

State of the lab, year 1 – setting up

I have used this blog in the past to keep track of my academic life where I can give a less formal perspective on papers I have published or ideas I am working on. Starting a group has made me think a bit about what I blog about. I have more responsibilities towards the people that have decided to work with me, towards the institution that has hired me (EMBL-EBI) and funding sources that support our work. At least for now I have decided to keep on sharing my personal view and in that context I though it could be interesting to write down my path as group leader in academia. This might become a yearly “thing”.

I started at the EMBL-EBI January 7 and in a blink of an eye one year has gone by. I have just arrived in Portugal for a conference and holidays and I said goodbye to four people that very courageously decided to work with a unknown newbie group leader. I could sum-up what happened in this first year by saying that the group-leader tittle now makes sense – I am coordinating an actual group. Most of this year was spent applying for funding, recruiting and trying to know more about the different groups working on campus.

From an empty room to a research group

EMBL-EBI is really a great place to start a group. For those that don't know the EMBL system, group leaders are given very generous core funding to work for 5 years, plus an additional 4 years after a review process. The chances of failing the review are small but there is essentially no tenure. Core funding and additional “internal” postdoc fellowships are sufficient to run a small group without external grants. We are encouraged to apply for funding but money is not the most immediate source of stress. So for me, since I started recruiting only after arriving in January, facing that empty room where a group should be working was the first thing on my mind. Recruiting postdocs for a unknown and empty group is particularly challenging. I tried to do some of the obvious things like emailing related groups that could have people about to finish the PhD and promoting the vacancies at conferences. It is hard to quantify but I do have the impression that my online presence has been an advantage in this. Once the first couple of people started and group meetings made sense the empty room stress went away. I know people starting experimental labs right now and I have to say that computational people have it way to easy. We can buy a few computers and the “lab” is set up. 

I spent a considerable amount of time applying for funding which is always somewhat frustrating. I don't mind writing grants but I am happier doing actual research. Around 6 months into the job I managed to re-start doing research and I have managed to keep working on fairly constant basis. I hope I will keep having/making time for research for as long as possible.

Meet the gang

This year we got an HFSP CDA and an ESPOD fellowship which together with the core funding allowed me to grow the group fairly quickly. The first to join was David Ochoa (postdoc, @d0choa, webpage) who will be working initially on PTM dynamics under different conditions. He also introduced me to the amazing BlackMirror series, the best fiction I have seen in a long time. Vicky Kostiou (intern) joined after and is doing a great job of improving the PTMfunc website which should be updated late January (stay tuned). The most recent arrivals were Romain Studer (postdoc, @RomainStuder, blog) and Brandon Invergo (postdoc, webpage). Romain will be using his phylogenetic and structural experience to study PTM evolution and Brandon was awarded the ESPOD fellowship to work with Jyoti Choudhary and malaria groups at Sanger on Plasmodium PTMs. Omar Wagih (@omar wagih) will be the fist PhD student joining in January. Finally, although we have still not signed a contract Marco Galardini (@mgalactus, webpage) will likely join in February to work on a collaborative project with Nassos Typas' group at the EMBL-Heidelberg. 

To be, or not to be, an experimental group

One of my concerns when I joined the EMBL-EBI was that, although the Sanger is just next door, EBI is a purely computational institute. Doing computational work is pretty amazing but progress can often be limited by lack of data. High-throughput research is removing somewhat this limitation since there are probably more observations made than we can all analyze. Still, if you are really interested in going in a specific direction then a experimental group simply has more power to make the right observations. My solution for this problem, for now, will be to co-supervise people with experimental groups including Brandon's EIPOD project, Marco's project with Nassos Typas and a future hire with Silvia Santos' lab in London. This is an experiment in itself and I guess in 2 to 3 years I be able to evaluate how practical this is. One alternative is to make use of research services such as the ones listed in Science Exchange. I have discussed with a couple of companies what would be the prices for some of the work I am interested in doing. These are fairly expensive but might be a good complement to the collaborations.

Summary

So overall, the group is off to a good start. It is funded for a few years at a reasonable level and we have collaborations with other groups that share some common interests. There were some things I wish could have gone better. I didn't get all the funding I applied to, which is expected. I also didn't manage to submit the two last manuscripts that still contain work from my postdoc. It would have been great to start the second year with that off my back. Still, I am happy with how things look for the next few years. It is a privilege to be able to coordinate this group of people and level of resources around topics that I find so interesting.