The ISBGroup Blog

Late last year, we were featued in a news article in the local news paper: Östgöta correspondenten (often referred to simply as “Corren”). The news article can be seen in the picture below, and it deals with research developed to replace animal experiments, and argues that Linköping university probably is the leading university on this topic in Sweden: we e.g. have a clear 3R-policy, have strong researchers in the area, and both of the two most prestigeous prizes from the Stockholm-based “Swedish Fund for Research without Animal Testing” called “Nytänkaren” has gone to researchers who (at the time) were located in Linköping. The article then goes on to feature an interview with me, and on our type of research: how mathematical modelling can and is replacing animal experiments.

This is not the first time we are featured in media lately. In fact, there have probably been written some 10 news articles in different media on this aspect of our research following our award in late 2015, and they have all been very similar. Most often, the reactions have been very positive, and congratulory, showing appreciation and a new hope over these new possibilities. Similarly, many researchers who have heard my lectures have also been very enthusiastic, and a common reaction nowadays is something like “I had no idea about these recent breakthroughs; I now feel that I lag much behind in my methodology, since I don’t use modelling; what can I do about that?”. This time, however, was the first time these things were featured in Corren, and perhaps for this reason, many of my colleagues read it, and some of them (mostly researchers who themselves do a lot of animal testing) reacted negatively to what it says. I don’t know all that was said about it, but some of the reactions I heard indirectly said that “one shouldn’t write that replacements of animal experiments are possible, since this will lead to the public mandating that this happens generally”. One colleague wrote an email to me directly, stating some specific and somewhat similar concerns about the artice. To this colleague, I wrote a detailed reply, which then led to us writing some rather long exchanges back and forth. All in all, this has now resulted in about 20 pages of text back and forth, dealing with different aspects on this topic.

Since much of these concerns are concerns and thoughts that I have heard many times before, and which most often are based on mis-understandings of what (sound) modelling is about, or in an unawareness of what the most recent developments actually entail, our exchanges have resulted in a growing resolve on my side to do something about this unawareness. To give a little bit of perspective on that: in all previous appearances we have made in the public world, the initiative has always come from some other source; we got the initial award “Nytänkaren” without even applying for it, and in all following media appearances, we have just responded to invitations, to give presentations, to do interviews, etc. Now, however, because of these exchanges, I have realized that I do feel quite strongly about these things, and that I really am concerned about all the mis-conceptions that are floating around (perhaps especially in the biological research communities) concerning what modelling can and cannot do, not only but also in relationship to animal experiments, I am hereby opening a new category in our blog, called “3R and animal experiments”. In this category, I will feature my thoughts and news concerning this exciting topic, and it is intended for both colleagues and for the interested public. Then all exchanges will be public for all to see immediately.

In general, I also want to state that I think that these kind of debates is exactly what I think that science should be about: on topic, honest, and sincere discussions, where ideas can be compared, exchanged, improved, refined, and viewed for all to see.

To start this off, I am attaching the 20 pages of emails below (also including a powerpoint presentation with some figures). That text, however, is pretty long-winding, and in Swedish. Therefore, many of these points will be summarized and explained more simply/clearly in shorter following blog-posts and youtube-videos, which also most often (but not always) will be in English. So stay tuned for that!

Part 1, text from colleagues in italics

Part 2, my colleague’s response to my reply in italics (written then, as a continuous text, without specific replies to my points), upon which I replied in the same way as the first time, by breaking down the statements in small bits, and answering to them one-by-one.

Part 3, final part of the interchange (so far), same structure as above.

Part 4, powerpoint with the figures alluded to in the initial answer (Part 1, above).

A couple of days ago, Gunnar Cedersund held a presentation at the local event “Linköping vego”, which is a little festival on vegetarian-related topics, featuring around 300-500 attendees, 10-15 lecturers, and 10-15 exhibitioners. Gunnar’s lecture was in the “Blanche Lindgren” seminar series, which featured 4×40 min lectures on topics related to research without animal testing. The 4 lectures complemented each other: the first, by Karin Gabrielson Morton, featured an overview of the field as a whole, some historical examples of breakthroughs, and also an overview of the organizing body, the Swedish Fund for Research without Animal Experiments; the second presentation was the one by Gunnar (picture below), who talked about how we and others use mathematical models to reduce and replace animal testing; the third presentation was held by Anna Herland, who is the newest recipient of the same prize that we got the first edition of, “Nytänkaren”, and she works with organ-on-a-chip developments for the human brain; the final lecture was held by Kathrin Zeller who is a member of one of the flag-ship groups for the research fund, which involves an animal-free test for whether a new skin product is likely to lead to allergic reactions. Apart from spanning 4 interesting directions of biomedical research, there were also natural overlaps of interests between us: Anna’s organ-on-a-chip might allow us to test some of our hypotheses regarding how the brain’s fMRI signal is created on a cellular basis, and Kathrin’s omics-based tests for the immune system might complement our own exciting plans and projects on the same topic together with AstraZeneca.

Picture of me in the perhaps most central slide in the whole presentation. The slide illustrates with a simple thought example that a model does not have to be perfect to provide a valid replacement of test animals – it just has to be comparably good/bad as the corresponding animal test. Then, because computer simulations are so much faster and cheaper (among other things) than animal testing, the switch will happen automatically, especially in the industrial sector, which typically switches immediately, if there is money to save. There are already examples where this has happened.

At the event, we also made some initial plans for how to feature ourselves at this year’s edition of Almedalen, to which we this year might go jointly as a group. More on that to come! 🙂

On October 26, 2006 ~ 10 years ago! – Gunnar Cedersund defended his PhD thesis. This was the start of the process of creating the reseach group isbgroup.eu. To celebrate the 10-year mark, we have decided to arrange on January 14th 2017 a reunion party for anyone who has been involved so far!

Event: Reunion

Location: Linköping (Specifics tbd)

Date: 14th January 2017

If you’re interested in the current projects or how your past project has fared, you’ll get the chance to catch up during the evening. We are also very interested in the path you’ve chosen, so if you can, please do join us and tell us what you have been up to since we last saw you in the group. The day will consist of some lectures and general social interactions with the chance to see what has happened with everyone in the day, and a BIG party in the evening.

In case your invitation got lost in the Internet, please contact us at reunion@isbgroup.eu to reserve. We hope to see you in Linköping in January!

Regards,
The reunion committee

Gunnar Cedersund
Elin Nyman
Rikard Johansson
Karin Lundengård
Fredrik Eklund
Johanna Fridberger

PS. Below are some group pictures to help you reminisce.

Gunnar defending his thesis 2006.

ISB group 2010.

ISB group 2012.

ISB group 2015.

Earlier this month I attended the annual meeting of the European Society for Magnetic Resonance in Medicine and Biology. At the conference I had the opportunity to giva a presentation of a part of my thesis project. In this part of the project, we’re using mechanistic modelling of data from contrast enhanced magnetic resonance imaging in order to get biomarkers that can quantify liver function. The idea is that our biomarkers should be used by physicians, e.g. when planning liver surgery.

/Markus

Picture of me presenting.

The travel period is now just completed, and I am looking forward to writing a report and summary of some of the most important discoveries and news discovered at these meetings in a later blog. Our field – modelling of biological systems – is in a very intensive phase of expansion right now, with a wide variety of events and simultaneous developments going on. Apart from the 4 meetings I/we have attended in the last 3-4 weeks, there are several other important events that we will miss, that are happening now (FOSBE, Magdeburg, Oct 9-12, on Foundations of Systems biology in Engineering) and within the next few weeks (e.g. the first conf of the European Association of Systems Medicine, Berlin, Oct 26-28, Berlin, link).

Figure 1: Me giving a lecture, before recieving the award Nytänkaren from the Swedish Fund for Research without Animal Experiments.

For now, however, I just want to say that one of the developments that is especially interesting to me right now is that concerning modelling in drug and device certifications, and how modelling there can be used in a 3R context, i.e. to replace, reduce and refine usage of animal experiments. I have previously won the first edition of a newly instated prize on this topic – Nytänkaren, Fig 1 – and several of the workshops and conferences I have just attended have had important news on the topic. For instance, I learned that the Food and Drug Administration in the US just have finalized a new report on how to use modelling in device certifications (Fig 2). I also learned interesting details of a second report, due to be published in 2017, which together with the first report will consitute a first complete guide to how modelling should be used in biomedical device certifications. In practice, the same guide will be used as a proxy also for certifications of new drugs, since the principles behind a sound usage of modelling are quite general. In fact, these guides have drawn quite a lot from similar guides already developed and established by NASA, where simulations already are considered mainstream in the development and certification of new space products. In short, I am quite impressed by these guidelines, and think that they have identified more sound principles than are being used in much of today’s research. In other words, these are really important developments!Figure 2: The new report just issued by FDA. Note the date, it was published a few weeks ago!

As a follow-up to these developments, and to me recieving the 3R award Nytänkaren, I have been invited to give a keynote lecture at a workshop at Karolinska Institutet, which takes place today. This workshop is arranged by Swetox and has the overall title “Replace animal use and increase scientific impact”. My talk is entitled “When laying the puzzle instead of just generating new pieces, animal experiments become increasingly irrelevant”. In this talk, I will give a more detailed report on some of the developments above, of my own research on the topic, and about some of the most important showcases that already are existing in the field. If you cannot attend the meeting yourself, you can still check out much of the material: some slides on the FDA developments are available here and a recent overview of our own research including an already FDA-approved glucose simulation model is found here. Finally, a two-sentence summary of the main statement given in the title of my talk is as follows: “if you want to test hypotheses regarding human mechanisms on the systems level, and create a systems-level understanding for the human system, you need data from a single system: humans. Thus, when science switches its focus to this more important endeavor, instead of just generating new hypotheses and pieces of knowledge that never are forged together and tested in a systems-level context, then animal experiments will become increasingly irrelevant”.

Figure 3: First page of my keynote presentation today. It is one of the first times, perhaps even the first time, that I am giving a lecture denoted as keynote, so I am looking much forward to it!

During the autumn we have three new students in our group
Nicolas, Fredrik, and Johanna: The latest students to join our group.

Here’s their introduction

Nicolas

I’m
a student at Linköpings university, studying for a masters of science in
engineering biology, I have finished my third year but have decided to take a
break to work as an intern at the ISB group.

The
project I’m involved with at the moment revolves around studying the regulatory
mechanisms that control the antioxidant levels in the body. Antioxidants are
generally believed to be unregulated and simply accumulate upon continuous
intake and such an accumulation could help explain the many health benefits
observed when eating antioxidant rich foods. However this accumulation has
never been observed for more than a few hours after intake. The results of
previous studies show that there is reason to believe that the antioxidant
levels are regulated by homeostasis. The purpose of this project is to use
systems biology to investigate the regulatory mechanisms involved with
antioxidant metabolism and see if there is a homeostatic regulation of the
body’s antioxidant capacity. This project will continue and expand upon the
project I did for my bachelor thesis in the spring of 2016 where I investigated
the regulatory mechanisms that control the antioxidant capacity (AOC) in the
cytoplasm and used mathematical modelling and prediction analysis in order try
to predict how the AOC levels would change after a single dose of antioxidants
are given to a test subject. At my disposal i had access to data collected from
experimental studies conducted at Newcastle university. With the results from
my bachelors project I was able to provide the team in Newcastle with a decision
basis for how to design a new experimental study which they conducted in the
summer of 2016. I will use this data, collected from the latest study in
Newcastle to continue investigating how antioxidant capacity is regulated and
also investigate how different test subjects react differently using nonlinear
mixed-effect modelling.

Fredrik

My
name is Fredrik Eklund and my background lies in bioengineering, with a focus
on materials and biosensors. I’m currently working on my master’s degree thesis
in the field of systems biology, however. The project I’m involved in is a
continuation of previous students’ work on a statistical heart attack model. It
is a predictive model meant to be used as decision support by doctors. In its
core, a Bayesian network is trained to understand relationships between a large
number of parameters. The trained network is then used on a new patient’s
measurements for prediction. Based on the result, a medical practitioner can
then take the appropriate course of action.

Johanna
My name
is Johanna Fridberger and I am a new member of the ISB group. I will be staying
for one semester conducting a project on the model developed by Fianne Sips described
in the article ”Model-Based Quantification of the Systemic Interplay between
Glucose and Fatty Acids in the Postprandial State” in which I will exchange the current NEFA (Non-Esterified Fatty Acids)
part of the model to one that better describes physiological conditions. This
is possible thanks to new data on NEFA homeostasis. I am doing the project as
part of my education in medicine at Linköping University, now reaching the end
of the third year. I have really enjoyed working in this group so far, and I am
excited over the next couple of months here!

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.