Friday, January 13, 2017

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.