The ISBGroup Blog

I have just jumped on the train from Linköping, Sweden, heading south, and this train ride marks the beginning of an intensive 4 week travelling period, entailing 4 conferences, 6 conference presentations, and numerous visits to groups all across Europe. If you want to catch and meet us along the way, read on below!

Figure 1: Just as in an earlier blog post, I am writing this blog post on the train. This time, I have an interrail ticket and some of my favorite cheeses in front of me!

My first journey heads down to London, where I will attend a workshop on September 14-15 I just very recently discovered: “Accelerating the acceptance of mathematical models as evidence in safety and efficacy decision making”. Apart from some individual exception, this will be a mostly new society of scientists I haven’t interacted with before, but the topic is one that lies close to my heart: how to incorporate mathematical models in drug development and certification. As some of you may know already, we work closely together with AstraZeneca, who also finance a position in my group, on exactly this topic. At the meeting, I am looking forward to hearing more about the Padova diabetes simulation engine (which we have used as a basis for our multilevel type 2 diabetes models), and about modelling for cardiac safety assessments. Both of these are examples where modelling as a replacement for test animals has gone a long way, and it will be nice to hear some updates, and to hear what else has happened in this field recently. This will be the only workshop where neither me nor somebody from my group presents with an oral presentation, and the reason for that is that I signed up only a few days ago, when the programme was already set.

Figure 2: This a picture from the event that in many ways can be seen as the inaugural event of my group: ICSB in Stanford 2009. Since then we have gone to almost all of the ICSB conferences.

My second journey continues on south, down to Barcelona and the International Conference of Systems Biology (ICSB), which is held September 16-20. ICSB (link) is the biggest annual conference in the field, and since it is the first time in a few years that the conference is held in Europe, it is important for us attend. The conference is arranged by the International Society for Systems Biology, headed by Hiroaki Kitano, who also was a guest professor in my group for a few years. We will go there quite a few of us from our group – me, William Lövfors, Elin Nyman, Sebastian Sten, Karin Lundengård, and Johanna Fridberger – and then there are anyway 3 people who intended to go but ended up not going (Maria Engström, Hao Li, and Rikard Johansson). At this conference, many people will be familiar faces, and we are looking forward to meeting both them and new scientists. At this conference we will also give two oral presentations:
1) Karin Lundengård with the presentation: “A mechanistic model for investigating the biological mechanisms behind fMRI“. This is based on our published model for describing the BOLD response in fMRI, and also goes into how it can be used to more correctly and precisely estimate neural activity. The presentation is held 12.15-12.35 on the Monday, in Hall 5.
2) William Lövfors with the presentation: “A phosphoproteome-wide mechanistic model of insulin signaling“. This is the updated version of the story already described in a previous blogpost, and it is held on Sunday 17.35-17.55 in the Auditorium.

Figure 3: The loggo of the Virtual Physiological Human conference.

The third conference is the Virtual Physiological Human (VPH) conference, held in Amsterdam September 26-28. This is a bi-annual conference devoted to multilevel modelling of biomedical, and often even biomechanical, systems. The VPH community is headed by the new director Adriano Henney, who also leads the Avicenna Alliance and is/was the Speaker of the german systems biology network “The Virtual Liver Network”. Before that, the VPH grew out of successful lobbying on the EU level to create a European version of the Physiome project, which e.g. pioneers the multilevel biomechanical and bioelectrical models for the heart. We will go to this conference for the second time, and our troup this time includes me, Rikard Johansson, Tilda Herrgårdh, Hao Li, and Tim Beishuizen. Originally, Elin Nyman also intended to go, but she will already have left for Boston by then. For this reason I will take her oral presentation, and thus give two lectures, along with a third presentation given by Rikard Johansson:
3) Markus Karlsson/Gunnar Cedersund “Meta-modelling combined with non-linear mixed-effects modeling for fast and robust estimation of biomarkers for diffuse liver disease”, Monday September 26, 14.20-14.40 in Emmazaal
4) Rikard Johansson “Model predictive glucose control in intensive care:
assessment in realistic clinical conditions”, Monday September 26, 15.40-16.00 in Emmazaal
5) Elin Nyman/Gunnar Cedersund, “The Virtual Adipocyte – from Big Data to
simulations of human disease”, Wednesday September 28, 09.40-10.00 in Emmazaal

Figure 4: My first slide, which I added just before holding my presentation at the last edition of ISGSB, in Durham, UK, 2014. Then I had noticed that the ISGSB has something that I really like: lots of social events, and informal activities, and a very relaxed and open athmosphere that really makes people get to know each other. The man down to the right is Stefan Schuster, who is the main arranger of this year’s edition. However, even though he was a part of the competition last year, I am not sure he has picked up on the idea for this year’s event. Nevertheless, an informal music session is on the programme, and they do have a grand piano there, which I plan to make use of!

The fourth and final conference planned to be a part of this conference is the International Study Group for Systems Biology (ISGSB), in Jena, October 4-7. There I (Gunnar) am an intricate part of the arrangements, since I am part of the ISGSB board, and since many decisions are taken jointly by this board. We are going also to this event (link) for the second time, and we will be a troup of 3 people: me, William Lövfors, and Sebastian Sten. Here Sebastian will give our final lecture for this tour:
6) Sebastian Sten, “Investigating hypotheses describing the negative brain responses in fMRI using a systems biology approach”, Friday October 7, 10.25-10.50.

Finally, and perhaps most importantly, I, Gunnar, will travel between all of these conferences by train, and will stay in Europe this entire period. In other words, I plan to visit quite a few research groups, and discuss projects and possibly also give some more lectures in local seminar series. If you are interested in meeting up with me either at one of the above events, or in between some of them, send me an email at gunnar.cedersund@liu.se . I will probably mostly be in France, England, and the Netherlands between September 20-28, and then in Germany and Austria between September 29 and October 7. But even that may be flexible to some degree!

I am looking much forward to this new travelling period, and I am looking forward to meeting many of you – colleagues and friends – at various places along the way!

Spara

Before this summer, Elin received a 2-year career support grant “International Postdoc” from the Swedish Research Council. This grant allows junior researchers to go abroad and work in world leading research environments to improve individual qualifications and extend their network of collaborators.

Elin applied for the grant together with Chris Sander at Harvard Medical School in Boston, MA, and Emek Demir at Oregon Science and Health University, OR, and will start this fall in the Sander lab. The research project is about using large-scale data handling to improve drug treatment in pancreatic cancer.

During this project, Elin expects to broaden her knowledge in large scale data handling, machine learning approaches, and cancer biology. And on top of that, being in an atmosphere like the one at Harvard Medical School, with famous researchers and the newest experimental techniques, will absolutely give her many new and exciting experiences.

Two new students are joining us this summer. Here is their introduction:

—————————————————————————————

Hello!

Our names
are Erik and Martin and we are working here at the ISB-group over the summer.
We thought that it might be appropriate to tell you about who we are, and what
we are working with!

We are both
students here at Linköping University, studying engineering in biotechnology. We
have both just finished our third year and completed our Bachelor’s project
together under the supervision of Gunnar.

During the
summer, we will continue with the bachelor’s project in cooperation with
AstraZeneca. The project revolves around creating and evaluating a mathematical
model over how the maturation of macrophages can be regulated, and throughout
this, be able to control the immune response in the immune system. If we were
able to control the immune response we could for example limit the symptoms of
auto immune diseases, in which there usually is a too high pro inflammatory
response.

A new travel period is just completed. The first part of this travel period can in many ways be described as the travel of 2: 2 continents were visited (North America and Europe), it took 2 weeks and 2 days (June 14-30), two research groups were visited (Chris Sander’s and Markus Covert’s), two companies were visited (Merrimack and AstraZeneca), two scientific conferences were attended (Systems biology of human disease in Boston and BioSynSys in Bordeaux), and two lectures were held (at BioSynSys and Merrimack). This totalled a distance of approximately 22 000km (Figure 1).

Figure 1: Outline of the first part of the travel.

The travelling in the US generally went to Harvard and MIT in Boston, and to the universities in California (Stanford, UCLA, etc). These visits mark a new phase in our groups development, which just has begun: one where we focus and aim more for high-impact publications, and one where we start to focus on making a difference in society.

Figure 2: The methods we have developed, first in the thesis of Cedersund (left), and then by their application in end-usage projects (right). The idea is to combine a mechanistically detailed grey-box model (the box), with a well-determined core, a combination we refer to as a core-box model, which also is our group logo.

In previous and now more-or-less completed phases in our group development, we have had a series of other focuses, which still exist, but now have been transcended. The first focus, in the Ph.D. thesis of the group leader Gunnar Cedersund, was to adopt the data-driven methods in the system identification community (pioneered by e.g. our local legend, Lennart Ljung), to work also for mechanistic modelling of biological systems. This involved the creation of an embryo to our currently used core-box modelling framework, which consists of detailed mechanistic models (the white box in Fig 2) with a well-determined core (the sphere in Fig 2), which pinpoints the uniquely identified predictions. The second phase in our development was to establish a strong and integrated link with one experimental group, to learn to do truly integrated work, where modelling really makes a difference, and answers real, interesting biological questions. This resulted in a series of papers devoted to insulin signalling, where we first learned to use hypothesis testing (Cedersund, 2010) to systematically unravel a small system consisting of only two proteins (Brännmark, 2010), then learned how to map a simple intracellular system with the whole-body level in multi-level hierarchical models (Nyman 2011), and finally learned how to unravel network malfunctions in diseases (Brännmark 2013) (Fig 3). This process is still ongoing: we are still using our most recent version of core-box modelling (Cedersund, 2012) to add pieces to network, such as Erk and Elk (Nyman, 2014), fatty acids (Sips, 2015), and FOXO1 (Rajan 2016), and are also preparing for new quantum leaps to yet more comprehensive modelling levels.

Figure 3: Our multi-level model for insulin signalling and the induction of insulin resistance (red T2D inhibition of the green feedback signal), which also propagates to the whole-body level.

However, since Cedersund recieved a start-up FoAss project grant from the Swedish Research Council in 2011, he has expended this recipe to a third focus: to apply these new tools to a more wide variety of biological problems. This focus has resulted in the joint recruitment of 5 new Ph.D. students, which are jointly employed with other researchers, who do experiments on other systems, but who cannot themselves do the modelling. The general recipe for all these types of collaborations are that the students sit a few days of the week in our group, and the other days of the week in the experimental group (Figure 4).

Figure 4: Our group structure, we are in the middle, and our collaboration partners, providing data and biological expertise have a shared environment with us, in terms of shared students, who sit partially with us, and partially in the experimental environment.

This phase is still ongoing, and we now have more than enough of experimental collaboration partners, and these projects are also starting to produce papers on e.g. modelling of the liver (Forsgren, 2014), the brain (Lundengård, 2016), who use mechanistic models as a means to interpret imaging data in order to produce a new level of understanding and also new biomarkers that can be used in diagnosis of liver and brain diseases (Figure 5). All of these developments mean that we now know how to both methodologically and socially interact with a wide variety of experimental groups to produce a steady flow of papers.

Figure 5: Examples of other application areas, where we combine magnetic resonance imaging data from the brain (A) or the liver (B), with mechanistic models (green below), to identify model properties which serve as new biomarkers. These biomarkers are combining the information in the data with the prior process understanding, and typically outperform existing biomarkers, in terms of providing a correct diagnosis and patient stratification.

The next phase and focus will therefore be to also establish some more high-profile collaborations, that allows us to move upwards in journals, and eventually publish somewhat regularly also in top journals such as Nature and Science. To do this, we need not only top-notch, integrated modelling, but also top-notch experimental data produced by groups who already have a track-record of publishing in high-impact journals. The highest density of such groups exist in Boston (MIT, Harvard) and California (Stanford, UCLA, Caltech, etc). Therefore, this year I have made two trips to these areas to start to get familiar with these geographical areas, and to gradually start to interact with new groups in these areas. Therefore, a 2 or 3-week trip to these two areas is planned to be an annual tradition. And therefore, we have started to write applications together with groups from these areas. One of these applications has now been approved – a two year paid exchange visit by our junior group leader Elin Nyman – but this is the topic of a separate blog post.

Figure 6: People walking around in the relaxed athmosphere that is Almedalen: on this streets you are equally likely to encounter a top politician as a top scientist, a business leader or an environmental activist or a journalist. They are all active, and all guests and participants in this exciting event.

Figure 7: A little bit further down the same street, I encountered one of the many many small little sessions. Most sessions feature 1-6 lecturers, and between approx 15-150 people in the audience. This allows for informal and many parallel sessions, where one can dive into in-depth and meaningful discussions. In total more than 3000 events are held during the 8 day event, and the events are spread out all across the biggest city of Gotland, called Visby.

The rest of this blog post, I instead want to devote to the final part of the just completed travel period: a visit to Almedalen. As is explained already in a previous blog post, Almedalen is Sweden’s, and potentially even the world’s, biggest political arena, featuring >3000 events in an 8 day festival. This is the first time I and we feature at this event, and also the first time we visit it. I am therefore happy to report that the event was every bit as exciting as I had hoped. There really are hundreds of fascinating talks and seminars and panel debates each day, the environment really is conducive for a relaxed, informal, and productive discussions, and the density of interesting and strategically important people is really so high that networking and chance encounters with strategically important people becomes almost automatic. In short, everybody is there: the most important political leaders, the most important media outlets, the most important organizations and companies, and – I learned now – also the most important scientists. I met and could easily engage with several key scientists that I have been wanting to meet for quite some time, and many of my favourite scientific topics (concerning replacement of test animals, eHealth, decision-support, automation and replacement of jobs, environmental solutions, etc) were brought up in numerous talks and debates, and it is really in the intersection of all of these sectors of society (science, politics, companies, etc) and all of these areas (environment, health care, jobs, etc) that I think that our society truly moves forward. I therefore for sure plan to make also this second half of my travel period, the Almedalen-visit, a regular tradition.

I will write a separate blog post about the particular panel debate in which I participated, and about the general topic on which it was held: the three Rs.

—

Functional Magnetic Resonance Imaging (fMRI) is a popular way of measuring brain activity in humans. However, this technique does not measure true neuronal activity but instead it measures changes in oxygen level in the blood, which are connected to the neuronal activity through the neurovascular coupling. In order to investigate the mechanisms of the neurovascular coupling, we have constructed and analysed a new mechanistic model. This model is based on current hypotheses of the mechanisms of the neurovascular coupling, and the model can both describe the estimation data and predict validation data. Unlike previous models of the fMRI signal, our model describes the biological system without predetermening the shape of the signal, and therefore opens up to a new way of analysing fMRI data.

Read the full article at PLOS computational biology

Reference:
Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI
Karin Lundengård, Gunnar Cedersund, Sebastian Sten, Felix Leong, Alexander Smedberg, Fredrik Elinder, Maria Engström
PLoS Comput Biol 12(6): e1004971. doi:10.1371/journal.pcbi.1004971

Two weeks
ago, the largest conference on biosensors in history was held in Gothenburg,
with over thousand delegates presenting work within commercialization of
biosensors, printable biosensors, single cell/molecule detection, lab-on-a-chip,
mobile diagnostics, nanonalytic systems etc. There was however room for mathematical
modelling as well. We presented with our poster a way of getting a requirement specification
for the development of glucose sensors.
Since the development and success of the finger prick, enzymatic glucose
sensor, several different glucose sensors has been developed. Despite the vast
amount of different glucose sensors out there, there is still an uncertainty
around which sensors to use when regulating glucose in the intensive care. The
regulation of glucose in the intensive care Is a bit more complex problem than
glucose regulation for diabetics, which is the market that most glucose sensors
aims at. A more complex problems requires a more complex analysis method, which
is why mathematical modeling has been used to predict glucose in the intensive
care. We have examined mathematical models developed for this purpose, to see
what abilities the glucose sensor needs to have to be able to be used for
glucose regulation in the intensive care when using a mathematical model. There
were several people who read the poster that said that they had been looking
for something just like this work, so there seems to be a need for the research
that we do!

We also had a lecture on the biosensors summer school on mobile diagnostics, titled “Biosensors and systems biology: from sensors to useful insights in biomedicine and clinical practice”. The lecture gave an introduction to how biosensors can play a key role together with systems biology when it comes to investigation of biological problems and in e.g. decision support, and regarding the research in the group it talked, among other things, about the developed multi-level diabetes model.

– Tilda

On Wednesday 18th of May, I had my final bachelor project presentation at ISB Group. I showed the results of my research on prediction of cardiovascular disease in type 2 diabetes patients, using Bayesian networks. Being a Dutch student, this concludes my time in Sweden, that started here: http://blog.isbgroup.eu/#post29 .

I can look back on a productive and instructive 4,5 months at ISB Group. The people in the group are awesome and I’m thankful for including me in all social events right from the start! The group proved to be a place that enables students to thrive at their own research projects and I can definitely recommend it to other international students.

– Gersom

Signaling to regulate FOXO1 may be the most important mechanism for
insulin to control transcription. In spite of this, little
is known about how insulin regulates FOXO1 and how
FOXO1 may contribute to insulin resistance in adipocytes, which is the
most critical cell type in the development of
insulin resistance. We report a detailed mechanistic analysis of insulin
control
of FOXO1 in human adipocytes obtained from
non-diabetic subjects and from patients with T2D.

Systems-wide
experimental and modeling analysis of insulin signaling through FOXO1 in human
adipocytes, normally and in type 2 diabetes.