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Here you can read about everything that's happening in the ISB Group.

Double jackpot from Swedish Research Council – glowing 3R project reviews

Uncategorised Posted on Tue, November 07, 2023 02:25:35

This year, we got a double jackpot from the Swedish Research Council – who gave us glowing reviews for the 3R project, scaling from microphysiological in vitro systems to humans using scalable digital twins.

In Sweden, the Swedish Research Council (Swe: Vetenskapsrådet, VR), is the most central research grant, and it is often considered a key quality stamp of a top researcher to have at least one grant from VR. Therefore, competition is usually fierce (acceptance rate usually is 5-15%), and it is not at all guaranteed that you get money, even if you have a competitive application. Therefore, I am proud to say that this year, I got not only one grant, but two – and that the evaluation from the reviewers was unusually high and glowing.

The project I have gotten the review responses for so far is a special call on 3R, i.e. Replacement, Reduction and Refinement of animal experiments. This is a topic, I have been very active in ever since 2015, when I was awarded the first edition of the prize “Nytänkaren” (the thinker of new ideas), by the Swedish Fund for Research without Animal Experiments. The project extends on our experimental work, both within the group, doing cell biology cultures using 13C-labelled metabolites on liver and adipose tissue taken from surgery), and that in collaboration with AstraZeneca, centered around organs-on-a-chip, i.e. small microphysiological systems (MPS), with organoids and spheroids consisting of human cells (Fig A, recent paper). In the project, we will i) analyse these in vitro data using mechanistic modelling to get more information out of the data (e.g. metabolic fluxes), ii) plan new experiments, by first doing the experiments in the computer, and iii) translate the results to humans, by e.g. scaling the volumes of the spheroids to human sizes, and by adding the missing organs, which allows us to re-assemble the digital twin in the computer (Fig B-C, Step 1 and 2). The project will evaluate and quantify the benefits of this for e.g. drug development, and we will disseminate the results to pharma, scientists, and regulatory agencies (Fig C, Step 3).

In the evaluation, we only got 6s and 7s, which means that we were among the highest rated of all applicants, even among the few who got money (6 out of 56). The ranking is from 1-7, where a “normal, decent” scientist usually get a 3 (meaning “good”), and where you need at least a mixture of 5s and 6s to have any chance of getting money. If you get all 6s, you are usually getting the money for sure, and 7 is only very rarely given out (I was a reviewer for ~60 applicants two years ago, and then I think only one or possibly two got a 7 on any criterion). Therefore, I am very grateful that this year, I got only 6s and higher, and that two(!) categories got a 7: “merits of applicant” and “relevance for 3R” (Fig D). If the rating levels were the same as when I was a reviewer, I would – I think – have been number one of all applicants that year, and in any case, I must have been among the very top of all the 56 applicants also this year.

The life of a scientist is filled with many many rejected applications, so when you get a jackpot once in a while, it is important to stop a bit – and celebrate! Because tomorrow, it is time to get started working on the new exciting research projects! 🙂



Concluding keynote at Data-driven mechanistic modelling in life sciences

Uncategorised Posted on Mon, October 30, 2023 17:00:09

Last week, I had the honor of giving the concluding keynote lecture at the event “Data-driven mechanistic modelling in life sciences”. This follows a trend of being invited to give more and more keynote and plenary lectures at events, for which I am very grateful. Such longer lectures also give me the chance to expand a little bit more on my point-of-view. The focus of this particular workshop is also something I am very keen to promote, since I think that this particular overlap (mechanistic and data-driven modelling) is under-represented in many communities and conferences.

The centrality of this overlap is actually seen even in our group logo (Fig A). a) The fact that it has an open non-black box, represents the fact that we do mechanistic modelling. b) The data-driven aspect of our models is represent by the purple core in the middle, which represents the fact that we always look for core predictions. Core predictions are predictions that are well-determined from the current prior knowledge and data, even when taking all uncertainties in data and prior knowledge into account.

While I personally think that this is the way to work, and while we have a very well-established workflow for how to develop models in this fashion, mechanistic modelling and data-driven modelling are unfortunately often done in two disjoint communities, with too little overlap (Fig B). Mechanistic modelling often results in mere simulation-based results, which have not been validated using independent data, i.e. data that has not been used to train the model. This is often the case for e.g. PDE and agent-based models, but also common in e.g. theoretical ecology, theoretical biology, etc. It was therefore encouraging too see that one of the presentations at the workshop (by Joshua Bull) looked at spatial models, and on how to quantify the comparison between simulations and data also for spatial models. Data-driven modelling is too often interpreted to mean only machine-learning, narrow AI, and other black-box modelling techniques. While these are big and very hyped communities and approaches at the moment, they are not the only techniques that can be used to do data-driven modelling. In other words, while these black-box models include important techniques, which are useful if one has standardized large-scale data, they also have critical short-comings. Black-box models e.g. have big problems incorporating the type of data that is present in most biological papers, including the prior that is knowledge available. For these reasons, explainability and trustworthiness are challenges. I therefore think that hybrid modelling is the way forward (see e.g. this review, and this example). At the conference, there was also an excellent opening keynote of day 2, by Alvaro Köhn-Luque, which showed some additional and interesting examples of hybrid models.



Invited lecture (and possibly teaser-performance) in upcoming MBM workshop

Events, News Posted on Thu, September 10, 2020 00:57:45

There are quite a few public lectures planned for this autumn, and one of the ones I am looking forward to a little bit extra is the MBM workshop, in Gothenburg, on October 15-16, 2020. MBM stands for Modelling in Biology and Medicine, and this is the second edition of the workshop. The workshop started as an initiative by a couple of enthusiastic Ph.D. students at the Math Department at Chalmers/Gothenburg University. But since it turned out so successful, they easily got both the support by the more senior leadership at the department, and enough positive feedback to decide to do a second edition. I really liked attending it last year, both since it was a Swedish workshop on systems biology, which means that it helps foster and grow the Swedish systems biology community, and since they managed to create a nice and cosy athmosphere. Partially because of this, the post-conference informal conversations last year led to me mentioning some of the bigger plans I am working on, which are going to become more public this year.

My dual life: scientist by day, pianist by night. Now they are starting to come together at last!

Those plans involve me combining my science and create careers into one, by doing joint lecture-performances, mixing piano, dancing, and digital twin-based stories. The original plan for this year’s workshop was to do some version of such a lecture-performance at the physical workshop. But since the physical edition had to be cancelled – due to the pandemic – the lecture will be held online. Nevertheless, in the presentation text of me at the home page, my CV covers – for the first time in a scientific event! – both my science and creative careers are mentioned side by side, and as two parts of the same thing. Already this feels really cool! And during the lecture, I plan to say, and probably also show, something short about those new and border-crossing plans in action. The workshop is held completely online, so you will be able to see it, also if you are not living in Sweden. And, later in the autumn, a more proper trailer for the first such lecture-performance will be released. The first proper such lecture-performance is planned be held during the autumn of 2021.

An exciting autumn awaits! And, the workshop is still open for abstract submissions!

 



New grant: 2 MSEK from ELLIIT “Usable digital twins in healthcare”

News Posted on Tue, September 08, 2020 00:28:07

We have gotten a new grant! The money this time comes from ELLIIT, which is a joint technology programme for Linköping, Lund, Halmstad University, and Blekinge Institute of Technology. The project we applied for is called “Usable digital twins in healthcare“, and it will focus on solving the many different practical challenges involved in bringing our digital twins into actual clinical practice: involving e.g. legal, technical, and ethical issues. A summary of the project and its main steps is given in the figure below. The funding is 2 MSEK, i.e. 200 kEUR/kUSD over a two-year period.



Upcoming lecture in new European webinar series on 3R, Sept 22-24

3R and animal experiments, Events, News Posted on Sun, September 06, 2020 22:56:51

A new international webinar series on 3R – replacement, reduction, and refinement of animal experiments – is about to start! And we are present with a lecture!

From our group, Gunnar Cedersund and Elin Nyman are members of the National Committee on 3Rs, which also serves as the steering committee for the Swedish 3R center (S3RC). Our S3RC has now joined forces with a few other corresponding national centres, and this has led to the launch of a new webinar series. The first edition of this will take place on Sept 22-24, lunch times i.e. 12.30-13.30 CET. Gunnar will present a lecture on digital twins on the last day, i.e. Sept 24.

This is a great initiative, and I hope it will be the start of more collaborations between the centres!

More info, and sign-up here.



Upcoming Ph.D. defense, Sebastian Sten, “Mathematical modelling of neurovascular coupling”

Events, News Posted on Sat, September 05, 2020 01:59:22

On Friday, this coming week, September 11, 2020, at 9AM CET, our Ph.D. student Sebastian Sten will defend his Ph.D. thesis, entitled “Mathematical modelling of neurovascular coupling”.

Sebastian has been co-supervised between Gunnar Cedersund (who leads this group), Fredrik Elinder (BKV and electrophysiological expert), and Maria Engström (who was the main supervisor, and who is an expert on fMRI). In the thesis, Sebastian presents four papers which incrementally unravels more and more mechanistic details of how the main signal in fMRI – the BOLD signal – is generated. In Paper 1, he demonstrates that the main part of the BOLD signal response can not be caused by a negative feedback, as was first believed, but by a combination of a fast positive and a slow negative feedforward arm. In Paper 2, the model from paper 1 is extended with GABA, which makes it able to describe the negative BOLD response. In Paper 3, he unravels more mechanistic details of the two arms, and finds out that there are in fact at least three arms: the fastest positive is the NO-arm from interneurons, the slightly slower positive arm is the PGE2 arm from pyramidal cells, and the slowest negative arm is caused by NPY interneurons. In the final paper 4 (still in ms), these mechanistic details for the signalling and the control of the arteriolar diameter is embedded in a larger model, which also contains the biomechanical flow to capillariies and venules, and the creation of the actual BOLD signal. The final model is – to the best of our knowledge – the most complete and comprehensive model for the BOLD signal, and it simultaneously describes data and extracts information from informative optogenetic stimulation experiments in mice, from unique BOLD and Local Field Potential (LFP) experiments in monkeys, and from advanced MRI measurements of BOLD, volumes and flows, in humans.

Front page of the thesis, illustration done by our other group member Christian Simonsson, who wanted to capture not only the brain, but that experiments, analysis, and mathematical modelling has come together.

Overview of the main processes studied in the thesis.

After the defense, Sebastian will work for two more weeks, wrapping up the final paper. Thereafter, other people in the group will continue to work on these models, e.g. by connecting them to more detailed models for metabolism, electrophysiology, and – eventually – to clinical practice, e.g. by allowing for more measurements to come together into a more comprehensive and complete analysis of fMRI data. However, Sebastian himself will thereafter start a position at AstraZeneca, in the group we have the most contact with there: their metabolic and cardiovascular preclinical modelling group.

A link to the Ph.D. thesis is found here, and a link to the youtube event where the defense is broadcasted is found here.

Sebastian about to do the final formal step before the actual defense: nailing his thesis to the “thesis tree” of the medical faculty.



Presentations at the VPH Virtual Physiological Human conference

3R and animal experiments, Events, News Posted on Sun, August 30, 2020 01:43:23

As usual, we have attended the Virtual Physiological Human conference, which this year was given as an eConference. This year, our group was represented with two oral presentations, and three poster presentations. The first oral presentation was held by Gunnar Cedersund, with the title: “Multi-organ and multi-level digital twin models enters the clinic”, and it was similar to the presentation already held at numerous earlier occasions, e.g. at Almedalen, in the Swedish Parliament, at NIH, etc.

Screen short from Peter Gennemark’s presentation at the VPH conference

The second presentation was of a new project: Belén Casas’ postdoc project on modelling of microphysiological systems. This project is financed by AstraZeneca, who are the ones who do the experiments, in collaboration with the company TissUse. This modelling has allowed us to both understand the available system better, and to create a first translation up to humans. This brings us one step closer to finding a workable replacement for animal experiments regarding research on type 2 diabetes and Nonalcoholic SteatoHepatitis (NASH) in the liver. The postdoc project has been supervised by Gunnar Cedersund and Peter Gennemark (AstraZeneca, but also adjoint associate professor in our group). Since Belen is now away on parental leave, Peter gave the presentation. The three final poster presentations were on digital twins and multi-level modelling (Tilda Herrgårdh), on modelling of fatty acid fluxes in the fat tissue (Kajsa Tunedal), and on a new model for exercise (Antonia Klingsäter). Apart from our own presentations, it was interesting to see that the new ASME V&V40 guidelines from FDA, on usage of modelling in certification, are getting more and more traction. Another interesting presentation was the keynote held by Tarique Hussain, who talked about how he has been using advanced modelling of the heart, to help guide treatment planning of complicated cases in child cardiology.

Screen short from the presentation by Tarique Hussain


New postdoc position in the new 12 MEuro X-HiDE project

Uncategorised Posted on Sun, August 30, 2020 01:17:35

There is a now a first postdoc position open in the new X-HiDE project, of which we are a central part. X-HiDE is a new major systems biology center that is about to launch in Sweden, which recently got a major grant of 12 MEuro, over an 8 year period. The topic will be systems biology of immunology. The over-arching goal is to build up a comprehensive and re-usable model, to be useful as a module in other models for a wide variety of diseases associated with dysfunctional inflammation: cardiovascular disease, auto-immune diseases, NASH, COPD, diabetes, cancer, etc. There are more than 10 experimental and clinical partners on board, which all will contribute with data and biological/medical expertise. Apart from this, a number of large and small companies are on board as co-funders, including e.g. AstraZeneca, and Wolfram MathCore. This particular postdoc is focused on modelling, and the main expertise sought after is data-driven mechanistic modelling (typically done using ODEs).

Because of the existence of the long-term substantial funding, there will be more similar modelling positions opened up later, including a soon to be announced more senior tenure-track position. These early positions will be excellent opportunities for junior researchers, who want to be a part of building up a new systems biology center.

NOTE: Deadline for this first postdoc position is midnight September 1 CEST!

/Gunnar Cedersund, leader of X-HiDE’s workpackage on modelling



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