The ISBGroup Blog

Here comes a few words from Linnea and David, two members of
the ISBgroup in Linkoping.

We are both currently living in Boston, USA,
experiencing systems biology in an industrial environment.

We are doing internships as modelers at Merrimack
Pharmaceuticals, a biopharmaceutical company focused on cancer drug development
using network biology. Linnea’s project involves mechanistic modeling of the
DNA damage response pathway, aiming at identifying possible synergistic drug
combinations. David’s project concerns PKPD-modeling of an in-house drug which
currently is in the end of its pre-clinical phase.

One month into our
internships, we have experienced long and intense work days, learned about the
company and its pipeline, lasted through a “monster blizzard”, and met a lot of
talented people from all over the world.

Linnea Bergenholm and David Janzen at Merrimack
Pharmaceuticals, Boston.

Right before christmas, Linnea Bergenholm presented her master thesis Modeling as a Tool to Support Self-Management of Type 1 Diabetes. This thesis work was done in our group, collaborating with the companies Linkura and Wolfram Mathcore, aiming to develop and investigate dosing tools for diabetics.

You can download the thesis here

Abstract:

Type
1 diabetes (T1D) is an auto-immune disease characterized by
insulin-deficiency. Insulin is a metabolic hormone that is involved in
lowering blood glucose (BG) levels in order to control BG level to a
tight range. In T1D this glycemic control is lost, causing chronic
hyperglycemia (excess glucose in blood stream). Chronic hyperglycemia
damages vital tissues. Therefore, glycemic control must be restored.

A
common therapy for restoring glycemic control is intensive insulin
therapy, where the missing insulin is replaced with regular insulin
injections. When dosing this compensatory insulin many factors that
affect glucose metabolism must be considered. Linkura is a company that
has developed tools for monitoring the most important factors, which are
meals and exercise. In the Linkura meal and exercise tools, the
nutrition content in meals and the calorie consumption during exercise
are estimated. Another tool designed to aid control of BG is the bolus
calculator. Bolus calculators use input of BG level, carbohydrate
intake, and insulin history to estimate insulin need. The accuracy of
these insulin bolus calculations suffer from two problems. First, errors
occur when users inaccurately estimate the carbohydrate content in
meals. Second, exercise is not included in bolus calculations. To reduce
these problems, it was suggested that the Linkura web tools could be
utilized in combination with a bolus calculator.

For this purpose,
a bolus calculator was developed. The bolus calculator was based on
existing models that utilize clinical parameters to relate changes in BG
levels to meals, insulin, and exercise stimulations. The bolus
calculator was evaluated using data collected from Linkura’s web tools.
The collected data showed some inconsistencies which cannot be explained
by any model. The performance of the bolus calculator in predicting BG
levels using general equations to derive the clinical parameters was
inadequate. Performance was increased by adopting an update-algorithm
where the clinical parameters were updated daily using previous data.
Still, better model performance is prefered for use in a bolus
calculator.

The results show potential in developing bolus
calculator tools combined with the Linkura tools. For such bolus
calculator, further evaluation on modeling long-term exercise and
additional safety features minimizing risk of hypoglycemia are required.

Better late than never! That’s unofficial motto of the
ISB-group. Last week we had a get-together to celebrate the new semester.
We said goodbye to some of our members leaving the group and a big welcome to
our new students. Everyone brought their own contribution to create a veritable
buffet of delicious food… and there was much rejoicing!

We are currently in the process of restructuring our home page (www.isbgroup.eu). Therefore expect some disturbances as we update the structure and content of the page. Hopefully a new edition will be completed within a couple of weeks or so. If you have any comments or suggestions on the home page, pls feel free to make your voice heard.

The ISB group.

Today Zaheer Ali, who has been working in our group since spring 2012, presented and defended his work.

The title was Mathematical Modeling of Electrophysiological Data of Facilitation in Layer 6 Pyramidal Cells (abstract below).

Abstract:

Facilitation is a distinctive activation pattern shown by pyramidal
cells in the layer 6 of the cerebral cortex upon rapid and repeated stimulations.
This behavior leads to the generation of tonic-clonic seizures which is a
defining feature of epilepsy. Patch-clamp recording techniques performed on
these cells show facilitation in different experiments. A mathematical modeling
approach is used in order to find the possible mechanism of facilitation
depending on different calcium domains in the presynaptic neurons. Four
different versions of the model have been constructed using ODEs. First version
of the model is a simple model of three compartments in the presynaptic neuron
with an influx of calcium at the triggering calcium compartment, the buffer
compartment and the stable internal domain of calcium can describe the data of
facilitation. Second version of the model has the calcium influx through a
micro-domain compartment near the cell membrane because of physical distance
between ion channel and the vesicle, in addition to the three compartments. The
third version of the model has a limited calcium buffer without micro-domain
calcium compartment which provides saturation to the buffer in this model and
the final version of the model is similar to third version of the model with
the addition of a micro-domain calcium influx. All models can describe the
experimental data sets of facilitation separately fitted to the model. In
addition, the third version of the model can describe all the experimental data
at the same time qualitatively.

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.

One of the major tasks this spring is to at last start forming a core-facility in systems biology and mathematical modelling.

This will happen as a natural out-growth from a process that has happened within the ISBgroup during the last 2 years or so. During this time we have started to co-supervise more and more students that are not within our main biological system (type 2 diabetes), but working with other biological systems (e.g., liver functionality, yeast transport, heart electrophysiology, heart adronereceptor signalling, etc), and where we have only supervised the modelling side. In other words, these students have had us (usually me, Gunnar, plus one of our Ph.D. students) as modelling supervisors, and another group and supervisor for the biological aspects. Since this is now starting to grow beyond our internal capacity, and also starting to make our group a little bit dis-proportionate, we feel that the time is now ripe to externalize these activities to a separate location.

The idea is that this location should be a modelling centre, where people from different biological groups sit one or several days with their modelling, to share and discuss modelling-oriented aspects, and then sit the rest of the time in their biological group, where they can discuss the biological aspects of their work.

We will start to form this external centre at IMT, i.e., the department of medical technology. This department is situated within the university hospital, and within less than a few minutes walk from almost all biological groups at the campus. Nevertheless, they are still part of the technical faculty, and have already built up a good computer infrastructure, which has turned out to be a challenge for us to build up within the medical faculty.

We will probably start this move now within the next 3-4 weeks, and it will most likely be an ongoing discussion during at least the rest of the spring how to implement this modelling centre in a good way in practice. We will, e.g., have one such discussion meeting now this Monday, February 28, 2011, at 16-17, to which you are welcome to attend if you want.

The clear intent is also to have this as a strategic first step towards applying for major funding – both from within the university and from elsewhere – where this core-facility is part of the functionality provided by the Linköping Centre for Systems Biology. I therefore also attach some thoughts that I once wrote down on how this could be structured.

All in all, this is another important step forward towards establishing not only our group, but Linköping in general as a leading centre for systems biology. To expand our ambition beyond our own group is vital also for our own success, since many applications are network-based, and since for instance students need a bigger market than one group for their future carreers, etc.

We are now in the middle of preparing for (hopefully) four workshops to take place here in Linköping in the period of June 17-23.

One of the reasons for these workshops is that we want to make use of our newly recruited guest professors Hiroaki Kitano and Jens Timmer, by having some of the most important international players come here and discuss some vital issues with us. Kitano is one of the world-leading players in model construction (e.g. by being the founder of CellDesigner, the most widely used software in the field), and he has also recently moved into hierarchical modelling, which is the topic of one of the workshops. Similarly, Jens Timmer heads one of the leading groups of sound data-analysis approaches to systems biology modelling, including the handling of uncertainty in data; this is the topic of another workshop. The third workshop comes from a network that we are forming on multi-level hierarchical modelling of type 2 diabetes, and the final workshop is meant for us in the Linköping Centre for Systems Biology.

More information on all these workshops can be found here

So, welcome to Linköping in June! 🙂