The ISBGroup Blog

2015 was the most expansive and important year so far, since we started, and there were many important things that happened.

The perhaps most important thing was that Gunnar Cedersund, the leader of the group, got a permanent position, a senior lecturer position (Swedish: Universitetslektor). This ensures that the group will live on for many years to come: Gunnar is bound to retire only in 2046, and the plan is to stay in Linköping and help lead this group at least until then! Apart from this, the new position also implied that Gunnar was elected into the board of our department.

During 2015, we also recruited 3 new Ph.D. students: Markus Karlsson, Sebastian Sten, and Natasha Morales Drissi (see picture above). Markus will continue our work on MRI-based modelling of the liver, together with Peter Lundberg (who will act as main supervisor) and the other guys at CMIV. Sebastian and Natasha will focus on fMRI and how this can be combined with EEG data using mathematical modelling. Both of them will do both modelling and data collection, but Sebastian will focus mostly on modelling, and Natasha mostly on experiments. The main supervisor of both Sebastian and Natasha is Maria Engström.

In May of 2015, Elin Nyman was awarded a prize: “the best pre-clinical Ph.D. thesis published during 2014“. This prize is awarded by the Swedish association for diabetes research, and it is especially encouraging to notice that they think that our work om multi-level modelling of diabetes now is mature enough to really make a difference in the diabetes field.

Picture of Gunnar Cedersund giving a lecture at the award ceremony for Nytänkaren (photo by Anette Persson)

In December 2015, Gunnar Cedersund was awarded another prize: “Nytänkaren”. This prize is awarded by the “Swedish Fund for Research Without Animal Experiments“, who made a study visit in our group earlier in the year. During this visit, they became so enthusiastic over our results, and the general results of the field, that they decided to create a brand new award. Nytänkaren is a Swedish word, which means “The Innovator”, or “The Thinker of New Ideas”. This prize has also been reported in several news outlets, including the daily newspaper ETC, and Swedish television (see video below for English translation).

We also attended several international conferences and workshops, and gave oral presentations at e.g. the International Conference of Systems Biology (Singapore, Elin Nyman), Modelling Metabolic Health (Cambridge, Gunnar Cedersund), The European Shock Society (Cologne, Gunnar Cedersund), Swedish Bioinformatics Workshop (Stockholm, Gunnar Cedersund, Rasmus Magnusson, Mattias Köpsén).

During the year, we also expanded and deepened our collaboration with AstraZeneca. This included the launching of several new projects, the publication of some first papers, and we also planned for the hiring of a new postdoc, to start in the Summer of 2016. Apart from this, Gunnar also gave a 3 day intensive course on systems biology.

In the summer of 2015, we had many internship students, and several of those have remained with us for the following year as well. A picture of our group during the summer is given below.

In the autumn of 2015, we spent 2 days in an internal workshop on the country side, to talk about joint decisions, ongoing work, and to create new visions for the coming years. Below you can see a few pictures from this event.

Finally, and perhaps most importantly, 2015 was also the year when we broke our own record in terms of number of publications: 4 published journal articles, 2 accepted journal articles, and 2 published book chapters. The full list is given below.

In summary, 2015 has been our most productive and expansive year: we have published the most number of publications, hired the most number of Ph.D. students, and received the most number of awards.

PUBLICATIONS (all were accepted during 2015):

Nyman E,
Lindgren I, Lövfors W, Lundengård K, Cervin I, Arbring Sjöström T, Altimiras J,
Cedersund G, Mathematical modeling
improves EC50 estimations from classical dose-response curves, FEBS J, 2015, 282(5):951-62.

Jullesson D, Johansson R, Rohini Rajan M,
Strålfors P, Cedersund G, Dominant
negative inhibition data should be analyzed using mathematical modeling:
re-interpreting data from insulin signaling, FEBS J, 2015, 282(4):788-802.

Karlsson M, Janzén DL, Durrieu L, Colman-Lerner
A, Kjellsson MC, Cedersund G, Nonlinear
mixed-effects modelling for single cell estimation: when, why, and how to use
it, BMC Syst Biol, 2015, 9:52.

Sips FL, Nyman E, Adiels M, Hilbers PA,
Strålfors P, van Riel NA, Cedersund G,
Model-Based Quantification of the Systemic Interplay between Glucose and Fatty
Acids in the Postprandial State, PLoS One, 2015,10(9):e0135665.

Schleicher J, Conrad T, Gustafsson M, Cedersund G, Guthke R, Linde J, Facing
the challenges of multiscale modelling of bacterial and fungal pathogen-host
interactions, Briefings in Functional Genomics 2016; doi: 10.1093/bfgp/elv064 (accepted during 2015)

Nyman
E, Rozendaal YJW, Helmlinger G, Hamrén B, Kjellsson MC, Strålfors P, van Riel
NAW, Gennemark P, Cedersund G, Requirements
for multi-level systems pharmacology models to reach end-usage: the case of
type 2 diabetes, J Royal Society Interface Focus, 2016, (accepted during 2015)

Cedersund G,
Prediction uncertainty: a comparison of recent method developments, in
Uncertainty in Biology, from Uncertainty in Biology, Edited by Gomez D and Tegnér
J, Springer-Verlag, 2016

Cedersund G, Samuelsson O, Ball G, Tegnér J, Gomez-Cabrero D, Optimization in
Biology: Parameter Estimation and the Associated Optimization Problem, from
Uncertainty in Biology, Edited by Gomez D and Tegnér J, Springer-Verlag, 2016

Spara

2013 continued on the new and higher level we had achieved in 2012, and continued to expand from there. We sent two people to Merrimack, we got a new Ph.D. student, we had even more people at ICSB, and we published our probably most important paper to date.

* In the spring of 2013, we did a new version of the annual course TSRT17: Systems biology modelling project. This involved around 35 students from the biomedical engineering programme (TB) and the industrial engineering biotechnology profile. As usual the projects dealt with real-life problems from different research groups, who gave the students real unanswered biological questions, which only can be answered via the usage of mathematical modelling. The students were divided into 6 projects, who worked with i) the understanding of heart desensitization, ii) insulin signalling and lipolysis in adipocytes, iii) facilitation in neurons, iv) myelin-measurements from MRI brain scans, v) estimation of liver fibrosis based on MRI time-series, vi) cell-to-cell differences in yeast cells. Group ii) did their work as a B.Sc. project. As previous years, we had a logotype-competition, and below you see a picture of the winners of their logotype.

* As usual, we recruited some of the most talented students from the course, to work in our group in various types of student projects, usually with associated scholarships. Some of these student include Philip Blomström, who worked with facilitation in neurons, and Mattias Köpsén, William Lövfors, and Fredrik Söderquist, who worked together with us, Mika Gustafsson and Mikael Benson to develop a method to estimate mechanistic ODE-models from omics data.

* We also had some older students around, and some of these were also on their way out towards their future careers. As illustrated in a previous blog entry, Linnea Bergenholm and David Janzén visited Merrimack Pharmaceuticals in Boston for a 6 month internship. This then led them to positions as Industrial Ph.D. students at AstraZeneca. This recruitment process illustrates the competitiveness of students who have been trained in our group: 2 of our students applied, both got the position. Apart from this, David Jullesson worked with the finishing of his paper, which then led him towards a Ph.D. position on Synthetic Biology with Jens Nielsen in Gothenburg. David also started up Linköping’s participation in iGEM, an international undergraduate synthetic biology competition. In this project modelling was used to some extent. Finally, Markus Karlsson worked during the entire spring semester with the application of the nonlinear mixed-effects modelling software Monolix to our liver model: this showed that our model-based approach outperforms all other image-analysis approaches, when it comes to generating biomarkers that can predict liver fibrosis.

* 2013 was also the year when a new Ph.D. student started: Mikael Forsgren (picture above). He had already been around for several years, working on modelling and experiments on the liver, and had just started a position at Wolfram MathCore, as a consultant in modelling. This Ph.D. position meant that we got him back as a 50% industrial Ph.D., and that we further strengthened our collaboration with MathCore.

* 2013 also saw the publication of our perhaps most important publication to date: our multi-level explanation to the origin of insulin resistance. In this paper, we had complemented our existing data for insulin signalling with new experiments, to get a first collection of systems-wide time-series and dose-responses for the main players in the insulin signalling network, both normally and in type 2 diabetes (examples in sub-figure A above). These unique data allowed us to, for the first time, test existing hypotheses regarding the origin of insulin resistance, i.e. the malfunction in the insulin signalling network seen in type 2 diabetes patients. We could then show that a specific feedback, from the protein mTORC1 to the protein IRS1, is a potential such explanation. If the network is perturbed in this feedback (red arrow, sub-figure B), the entire network switches from normal to diabetic signalling. This model has since its publication gained a lot of interest from pharmaceutical companies.

* Several of these showcases were presented at large international conferences, most notably the International Conference for Systems Biology (ICSB). ICSB was this year held in Copenhagen, and we went down with the largest group yet: around 15 people from at least 4 different research groups were present from Linköping. We were also well received, and Linköping had three oral presentations: Robert Palmér from the spin-off company MathCore presented our joint story on understanding the T2D drug Anakinra, Gunnar Cedersund and Markus Karlsson presented the above mentioned story on liver diagnosis, and Mikael Benson – not from our group, but also from Linköping – gave a keynote lecture on clinical end-usage of systems biology.

All in all, this year demonstrated that the previous successes of 2012 were not a one-time luck, but that we could sustain this level of activity and international visibility, and thereby bring high hopes for the coming year of 2014.

2012 was the year when the core facility started to take shape as a separate unit. This had been a long-time dream of mine, and when I (Gunnar Cedersund) in 2011 was awarded a VR FoAss, I could slowly start the process of building up such a joint modelling environment, working as a common knowledge and computer resource and as a physical meeting place for all groups and people wanting to do mathematical modelling of biological systems.

The part of the group that went down to SBMC in June 2012. Above, from left: Patrick Weber, Rikard Johansson, Karin Lundengård, Mikael Forsgren, Gunnar Cedersund, Linnea Bergenholm, David Janzén, Magdalena San Roman, Elin Nyman. Front, from left: Zaheer Ali, David Jullesson.

Here are some of the more specific highlights:

* During the spring and summer, we had two external visitors: Patrick Weber from Stuttgart, who came to experience work in applied research and to contribute with his knowledge about Bayesian methods for parameter estimation, and Magdalena San Roman from Montevideo, Uruguay, who came to learn our type of modelling, but also to share her knowledge about metabolic control systems. They are both depicted on pictures below, and they both entered into different ongoing projects here, including in a joint project on new improved methods for sensitivity analysis with uncertainty.

Patrick Weber, our visitor from Stuttgart, Germany

* During the spring, Eva-Maria Hansson, who had previously worked and done her M.Sc. thesis with us, went to visit Merrimack Pharmaceuticals in Boston, US. She was therefore the first student, who initiated a tradition and collaboration between SBCF and this company: we train really talented students in the wonderful art of systems biology, and when they are finished, we each year send some 1-3 of these students to work in internships for them. These internships are payed employements where you do modelling in pairs with an experimentalist at Merrimack, together with which you test out a new idea for a drug or a biological mechanism. If the project turns out to be promising, they will take it further, and – with some luck – the results will one day form the basis for a new drug or treatment.

* During the year, we also had some internal M.Sc. students who finished their projects for us. For instance, Linnea Bergenholm, who had already been working for a year with us prior to her thesis (mentioned here), and Zaheer Ali, who initiated the work on facilitation, that we presented in Liepzig (mentioned below). Another Ph.D. student was David Janzén, who worked on usage of mixed-effect modelling for estimation of noise and for analysis of cell-to-cell variation.

* In June, we attended the bi-annual conference Systems Biology of Mammalian Cells (SBMC), in Leipzig. SBMC is probably the second biggest conference on systems biology, and the focus fits our research very well. We went down 11 people in two big rented cars/vans, and spent 4 days in what I will probably for a long time consider as the defining trip – as the trip that defines the ultimate group trip. That was not only because we were a number of people who had started to grow together over the years (see the picture above), but also because we made such a big overall impression on the event: we had 3 oral presentations, and I was chair for one of the sessions. This probably made us the most well-represented group at the whole event! The three talks are available as videos, and were given by Elin Nyman (who spoke about her recent paper on insulin signalling in rodents), Karin Lundengård (who spoke about modelling to unravel the mechanisms behind facilitation in neurons), and Mikael Forsgren (who spoke about our clinically useful modelling on liver diagnosis).

Our guest Magdalena San Roman, who took a beer at SBMC together with Jan Hasenauer, who was a previous guest of ours, from a few years earlier.

* In August 2012, I also – at last – published a paper on the set of methods for core prediction analysis that I had presented on posters and presentations for several years (it was also an invitated paper, following my talk on ICSB the year before). This was the presumably most important paper of that year, and it forms the basis for many future systems biology papers, both on methods and on applications in various fields. However, some other papers worth mentioning are this paper on describing large-scale networks in a manner consistent with modelling (developed together with our guest professor, Hiroaki Kitano), this review on modelling of insulin signalling, and the insulin signalling paper Elin Nyman presented at SBMC (video link above).

* Following these developments done during the first half of the year, on Sept 24 2012, we were finally ready to declary ourselves as an independent group. This date is henceforth referred to as the SBCF day, the day our systems biology core facility was officially launched.

Picture of Karin Lundengård, our new Ph.D. student.

* 2012 was also the year when Karin Lundengård started her Ph.D. with us. In practice she had been around since her M.Sc. thesis about a year earlier, but now we had gone through all the steps of finding money, supervisors, and the formal process of announcing positions etc. Karin is having me as co-supervisor: her main supervisor is Maria Engström, and her other co-supervisor is Fredrik Elinder. Fredrik has experience of both modelling and experiments on neuronal cell-biology and electrophysiology, and Maria is an expert on fMRI, used to investigate brain activity. Karin will in her thesis combine these levels, and provide a more mechanistic understanding for the data that can be obtained from fMRI, and thereby get more information from the data, eventually leading to better usage of the technique, and to better understanding and treatment of diseases like narcolepsi.

In Dec of 2012, Cecilia Brännmark graduated from her Ph.D. studies. Here we see her during the ritual known as “spikning”, where she nails her thesis to the “thesis tree”, seen to the right.

* At the other end of the spectrum, 2012, was also the year when our first Ph.D. student graduated, i.e. finished her Ph.D. studies. The student, Cecilia Brännmark, was the first one I (Gunnar) supervised, and she started back in the days when I did all the modelling myself. Hence, Cecilia was an experimental Ph.D. student, and she has done the majority of the experiments in the early defining papers, that came out of my collaboration with prof Peter Strålfors, who was her main supervisor.

* In December we arranged a 10-day Ph.D. course on Multi-level modelling of gluocse homeostasis. During these 10 days we had invited the most relevant and world-leading experts on systems biology research on all the main organs: the liver, fat tissue, skeletal muscle, the brain, the pancreas, and the whole-body level. For all these organs we had invited experts on both the experimental research and on the modelling.

* As a separate event in the middle of this course, we also arranged a workshop on Systems Medicine. This was a co-arrangement with Mikael Benson, who arranged the first day devoted to omics and large-scale network approaches, and isbgroup/me, who arranged the second day devoted to modelling. In other words, we tried to bring together all the different sides that are relevant to systems medicine, and regarding the modelling this importantly included the neighbouring biomodelling fields, such as pharmacokinetic/pharmacodynamic modelling, image-based modelling of the liver, medical decision making with probabilistic graphical models, and even an overview of the neighbouring research in technical diagnosis. At the event there was also a strong presence from several leading drug development companies. The event was atteneded by some 60-80 people, and the combined 10-day event was the – by far – biggest arrangement we had arranged at that point.

2011 was an eventful year for us, when many things happened. Here are a few of the main highlights:

* In June, we arranged a series of three workshops on systems biology: on conclusions despite uncertainties, on multi-level modelling of type 2 diabetes, and an internal one regarding systems biology at Linköping University

* We had quite a few students who finished their Master Theses: Robert Palmér, Mikael Forsgren, Ulrike Munzner, Fianne Sips, Karin Lundengård, and Linnea Järvstråt. All of these are now working with systems biology at various places out in the world.

* The new full-time professor Mikael Benson has started. He is a professor in clinical systems biology.

* Our two guest-professors Jens Timmer and Hiroaki Kitano has started their employments

* We attended the ICSB (International Conference on Systems Biology, in Heidelberg) with a large attendence. We had some 10 posters, and equally many participants, from Linköping; Gunnar Cedersund gave a presentation; and Mikael Benson arranged a spin-off event.

* In Dec of 2011 we arranged a new workshop. This time with the themes: Hierarchical modelling, Decision-support in clinical practice, Type 2 diabetes, and Liver diseases.

* On multi-level modelling of type 2 diabetes, we also got published one of our most important papers yet: describing the linking between intracellular mechanisms and whole-body glucose homeostasis.

* I was awarded a VR-FoAss, which is a position financed by the Swedish Research Council. It is a relatively high-status position (<8% success rate), and it allows me to act a little bit more independently of my joint group with Peter Strålfors. I have therefore started the process of dividing away part of my time to IMT (currently 40%), the neighbouring department on biomedical engineering. IMT is situated a few meters away from my IKE group with Peter, i.e. still at the hospital campus (HU), but it is formally located within the technical faculty, and is mostly populated by engineers. From here, I can and plan to start building up a more independent modelling environment.

This year will be an important year for our group, when many things will mature in various ways.

This will be the year when we will have to transform some of the student affiliations into scholarship students, and some of the scholarship students into Ph.D. student affiliations, and in this make use of our various sources of internal and external funding, and make use of all our collaborations with other groups. An example of the latter is our important collaboration with Freiburg, where I (Gunnar) have an external fellowship, and where half of Rikard’s employement is financed.

This will also be a year when we will will transform many of our almost finished projects into publications. Last year we grew substantially in personell, and this has allowed us a quite new work capacity, which we must learn to make use of properly, and make visible in terms of an increased rate of publications. Several papers have also been submitted or re-submitted in the last weeks, and with some luck, this will soon start showing off as new interesting publications, showing some of our ongoing projects more visibly to the rest of the world.

In this early phase of the year, we are also running the second edition of TSRT17, which is our own systems biology course. It is our intention that this year’s edition will be a clear improvement compared to last year, and that we just like last year will be able to recruit some of the most talented students as scholarship or project students.

One example of how this process is continuing is Mikael Forsgren, who took the course last year, has been employed in the group of Peter Lundberg ever since, and is now doing a little project also in our group, where he helps us finalize an interesting project on core-box modeling and back-translation. Two other new people in the group are Lovisa Österlund who is doing a boolean approach to the study of mTOR and autophagy and their relation to insulin signaling, and Gustaf Ullman, who will become our new expert on stochastic and single-molecule modelling and simulations.

We have also continued our team building activities, through regular whole-day meetings where we present our work for each other (see up-coming and previous events), through the continued application of wave and other online communication tools, and through various joint social activities such as weekly game-nights, and a joint vacation weekend in Romme. We also plan to expand our weekly meetings to include seminar-series with internal and external lecturers; this will also be a part of the continued launching and starting up of the Linköping centre for systems biology, which hopefully will also be stimulated by our upcoming recruitment of two world-leading systems biology guest professors.

All in all, we are moving into a very exciting year, where many of the plans and projects that were started last year hopefully will mature and bear lots of scientific fruits.

Summing up 2009, it must be said that it without a doubt has been the most important and expansive year so far, at least with respect to the systems biology part of the group.

Going into the year, there were only me (Gunnar), Cecilia “Ia” Brännmark, and two new students: Elin Nyman and Rikard Johansson. Then interesting and ambitious students appeared one-by-one, e.g., Robert Palmér, Fredrik Bäcklund during the spring/summer, Eva-Maria Hansson and Oscar Samuelsson during the early autumn, and Amanda Jonsson during the late autumn. This means that the group has more than doubled in size in a short period of time, and we have been in a very nice feeling of growth and “anything is possible” during the entire year. During this time we have spent quite some time to get a nice group feeling, creating our own home page, logga, name, and has also started to improve our internal communications through the adoption of the new and powerful google wave online communication tool. We had also to establish new routines for our internal meetings: we initiated weekly Monday meetings, and changed our joint supervision time where all students were present to entire supervision-days, all because of the rapid growth of the group.

2009 was also the year when TSRT17, our own course was launched. This is a project course that is held for 3rd years students at the Technical Biology program, and it will be held anually from now on. The project was done as a collaboration with the system identification/control engineering group at ISY (led by Torkel Glad and Lennart Ljung), and the MR-group led by Peter Lundberg. This course will be important for us to train and inspire students to be future project, MSc, and Ph.D. students in our group.

Another important event this year was to start the process of forming a systems biology center at Linköping University. We had a first meeting with all 15 groups, and have also combined these networking efforts with the participation in the formation of a national Wallenberg Institute for Systems Biology, and in various European network formations on systems biology of diabetes, several of which have been coordinated by us.

This important year will probably in many ways be remembered as the defining year of our group, and it is with great enthusiasm and anticipation that we move into the new year and into the new decade.