The ISBGroup Blog

What makes a modelling work Science? Its ability to describe data!Systems biology and science

Posted by Gunnar Cedersund Mon, March 04, 2019 00:51:15

In my work as a scientist, one of the possible tasks I can take upon myself is to be a reviewer. This is important, but almost completely non-valued; there is no pay, and no funding agency cares very much whether you do it or not. However, the review process is the most important place where scientific discussions are taking place, because currently - and unfortunately - this is virtually the only criteria for what constitutes a scientific finding today: has it been published in a peer-reviewed journal? I therefore do spend some time doing this. And I fight a lot of the time with papers and authors who want to publish mathematical modelling works without any comparison with experimental data. I strongly believe that such works are not science, and that they should not be published. Today, I just submitted such a response, and since the reply is written in a completely non-specific manner to the paper in question - it could have been written to any paper with the same problem - I also post it here. My principle for the the next decade of my life, which I just entered, is "going public, going deep", and this publishing of this here on the blog, is a part of me following that new principle.

Here is the review reply that I wrote:

"Thank you for your comments.

I do recognize the fact that you and others have published similar papers in the past, where models have been developed and presented with no comparison with data. There is nothing I can do about that. However, that fact does not transform such works into science. Modern science is, in my very firm opinion, the truth-seeking tool that was established by Galileo, many hundreds of years ago: it builds on i) the mathematical formalization of mechanistic hypotheses of the system that you study, and then ii) usage of *data* to distinguish between those hypotheses. The hypothesis that has the best ability at describing data - in the first round estimation data, and in the second round independent validation data, based on predictions and *then* experiments - is the superior hypothesis. It is this formula for truth-seeking that distinguished the science that started with Galileo, and the church-driven epistemology that ruled science before him (note that the prior Aristotelian science worldview also involved mathematics, and data, but not in the same hypothesis-testing manner). If Galileo’s formula is not followed, it is not science. That a paper has been published in a scientific journal does not make that work science. It does mean, however, that that work *should not* have been published. The only exception to that principle exists within the field of mathematics, which has other criteria for its judgements of a paper: e.g. that what is presented should be i) previously non-proven and ii) should hold true for a large family of equations/examples. Another type of paper in mathematics can be that of a new method, e.g. for optimization, that is proven to be superior to existing methods.

Unfortunately, this conception of what science is was lost in the field of modelling of biological systems during a large part of the 20th century. During this time, it was called mathematical biology, complexity theory, etc. This was, to a large extent, rectified, during the beginning of the 21st century, with the conception of systems biology. However, unfortunately, much old-school data-free modelling is still done. This has to stop! It is giving, and has been giving, the field of modelling in biology a bad reputation, with the impression that it has nothing to do with reality or biology – and rightly so, such modelling has nothing to do with reality! At least not in any way that has been demonstrated by science.

Two further clarifications and responses to your reply are in order:

i) You say that your model is based on data. That is true. The model structure is based on data. Your manuscript does therefore function as a review of existing biology. But that is something different than publishing an original research paper, with novel results. That is something that is fundamentally different than the kind of comparison between simulations of the *entire model structure* and data that I am referring to above. It is a bit like saying that the Ptolemaic worldview (with the sun in the middle) is based on data because it includes the sun, the planets, and the earth; which are observed in experiments. The question is not if they are present. The question is which way of connecting them in relationship to each other that is the correct one. To go beyond what can be said with biology alone – i.e. to do mathematical modelling – requires that one puts the structure together using competing hypotheses (e.g. one with the sun in the middle, and one with the earth in the middle), and then sees which of the two corresponding models that produces simulations that best agrees with data (existing data and future data). That is how science has functioned since Galileo, and that is how it should still function today.

ii) You say that a model component in your model – that has not been validated in any fashion whatsoever – produces a prediction that a specific component is important; you then also point to some papers that claim the same thing. That could, on the surface, seem like a comparison with data. However, with the model structure that you have put together – with the most well-known and most often considered main players in the beta cell ethiology – you could identify any component in your model as the most important one, and then find many papers that claim that that component is the most important one. That is, unfortunately, how biology is allowed to work today, with many co-existing hypotheses, that are allowed to continue to co-exist, where each lab focusing on one of the components is allowed to point to limited results as to why their particular component is the most important one, and without forcing anyone to challenge these claims with respect to each other; without finding out what the big picture looks like. That is where systems biology can and should come in and make a difference: by putting up alternative hypotheses regarding what is the most important component(s), and then letting data, systems-level data, judge which of the hypotheses that is the most compelling one. This is how systems biology has worked in many/most of the papers that are cited in the review paper that I gave you. That way requires a model that produces simulations (time-curves, typically), that agrees with estimation data, and with validation data.

In summary, for me to judge this or any paper as publishable, you need to produce (at least) these two things: i) at least one curve, e.g. a simulation of a variable as it progresses in time, that agrees with corresponding data; ii) a prediction that is validated by another dataset, not used for estimating the parameters in the model. In fact, apart from that you should also demonstrate that your model is superior to other models, i.e. that it can describe all data that one of the currently most important and realistic models can, and then more data apart from that.

In other words, there are many papers that are published for beta-cells, including for their ethiology. These models can describe a lot of data, in the above manner. Why not take one of those models, find a feature or dataset that they cannot explain (there are many), and then go ahead and improve the model to make it able to explain those data (while still retaining the ability to explain all old data). If you then also show that this is not due to overfitting w.r.t. all data, i.e. if you then show that your new model also can describe some validation data, not used for model fitting, then you will have contributed with an improvement that follows the tradition of science. Then, and only then, I will judge your – or any scientist’s – paper as publishable.











Ellen’s master thesis defenceEvents

Posted by ISB Group Wed, January 23, 2019 14:53:04

Today, Ellen Lesshammar defended her master thesis project: ‘Mathematical modelling of TLR4-activated macrophages in inflammation’. The project aimed to use a model-based approach to investigate the synthesis and release of cytokines from macrophages during inflammation and also when inflammatory response is suppressed by anti-inflammatory drugs. The models Ellen constructed have the potential of being further refined and extended to include other aspects of inflammation and might thus hold the possibility to contribute to the further understanding of inflammation and how it can be the root cause to several common diseases.

The work was done here in the ISB-group but also at the Linköping based company Wolfram MathCore. We would like to congratulate Ellen on a job well done, and we wish her luck with all future endeavours!





Nicolas’s master thesis defenceEvents

Posted by ISB Group Mon, December 03, 2018 14:56:21

Nicolas’s master thesis defence

Last week a member of our group held his master thesis defence. The member in question was Nicolas who has been doing in his master thesis in our group, as well as some work prior to that.

Nicolas hold a well-structured and informative presentation of his work and defended his thesis in a great way.

Nicolas project aimed to characterize the metabolic fluxes of carbon-13 labelled metabolites throughout parts of the metabolic system. The fluxes were determined from the structure of the metabolites in the end of the metabolic system. By knowing the reactions in the system and the number of intermediate products from the inserted labelled metabolites, one can determent the fluxes between the reactions. This method is called metabolic flux analysis. Although this is to hard math to do by hand, one can use mathematical modelling.

The second part of Nicolas project was to validate that his model could accurately predict the quantities of the metabolic fluxes. However, today, there is no established method for this kind of validation. Nicolas validated his model by the model’s ability to predict a validation dataset, data that the model have not seen before. By using this approach, one wish to see how the model react to new data and judge the model quality by how true the model’s prediction of this data is.

Additionally, the uncertainty of the predictions was analysed with a profile likelihood analysis. With such predictions, one can place more trust in fluxes determined by the model. Consequently, this allows for more challenging issues to be tackled in the development process of new treatments.

With this we want to congratulate Nicolas on his completed master thesis and wish good luck in the future.

Blog image





New PhD studentNews

Posted by ISB Group Wed, November 21, 2018 13:20:01

Hello!

My name is Tilda and I have been in the isb group before, but this November I started my phd here. I am financed by an EU project called precise4Q. The project aims at personalising treatment of stroke by developing model-based decision support systems. I will be working with combining mechanistic multi-level models and machine learning models.Blog image






3th national diabetes summit Events

Posted by ISB Group Wed, November 21, 2018 12:16:27

Blog image


On November 16th and 17th Gunnar, Elin, William, Tilda, Christian, Kajsa and Jonna attended the 3th national diabetes summit in Stockholm. During this conference the Karolinska institute was the scene of many interesting conversations, posters and presentations.

The program consisted of many interesting presentations covering various aspects of diabetes research. Our group was represented with, apart from a poster, a very nice talk by Elin. We have had many interesting conversations with other researchers that may lead to some very nice collaborations. For me personally the conference was a unique chance to see what kind of diabetes research is performed in Sweden.

Since the end of November is approaching rapidly my time in Sweden is almost coming to an end. I look back at a very nice time in Sweden were I’ve learned a lot about modeling and applications of modeling to the liver. And of course my new knowledge about things like Fika and warm meals during lunch ;)

Regards, Jonna





Ph.D defence of Belén CasasEvents

Posted by ISB Group Fri, November 16, 2018 13:19:11

Last week we attended the Ph.D defence of Belén Casas, who has worked with our group during her research.

It was a pleasure to listen to the great presentation of her work and her defence. A short description about her work follows below.

Belén’s work aimed at improving the current diagnostic tools in the field of heart diseases. By analysing data gathered from using 4D flow-MRI (a technique with 3D time resolution and phase contrast magnetic resonance imaging) with mathematical models, Belén has developed tools that can be of help to improve a subject specific assessment of a patient’s cardiovascular function.

After a successful defence, there was a celebratory afterwork in Belén’s honour. We want to take our time to congratulate Belén to her well-deserved Ph.D title and wish her good luck in her future work.

Links to published articles
Briding the gap between measurment and modelling: a cardiovascular functional avatar

Non-invasive Assessment of Systolic and Diastolic Cardiac Function During Rest and Stress Conditions Using an Integrated Image-Modelling Approach

Blog image









New money, from VR, SSF, H2020, and AstraZenecaNews

Posted by Gunnar Cedersund Sun, October 28, 2018 16:57:59

We have gotten money - and lot's of it!

While on a 6h train ride between Malmö and Stockholm, I at last have time to share some of the good news that have come to us, one after the other, but that I haven't had the time to share with you here until now. The good news is that we have had a series of successful grant applications, which mean that we now have reached a whole new level, in terms of money flows, and that our group will significantly grow in the next 2-3 months.

This new money flow actually started about a year ago, when I got money for a new 2 year postdoc position from AstraZeneca, i.e. approx 3 MSEK (300 000 USD). In this postdoc, we will create models for a new type of animal-free experiments, called organ-on-a-chip. In this technique, you build a system of realistic 3D organs made up of human cells, which are interconnected by an artificial blood flow. This is a supercool possibility, which is ideal for both modelling, for replacing animal experiments, and for understanding diseases.

This grant was then followed by a new EU project, called PRECISE4Q, which was approved in January this year. In this project, we will make use of our multi-level mathematical models for diabetes and cardiovascular disease, to create a new clinically useful tool. The basis of this tool will be quite general, and applicable to a wide range of diseases, but the focus will be on helping patients who have or who are at risk of suffering a stroke. The total budget of this project is 60 MSEK (approx 6 million USD), and of that approx 4 MSEK goes to my group (400 000 USD).

After that, during the spring, I used these already approved projects to write applications about other projects, which could build upon my already approved projects. And this too has now started to bear fruit.

First off was an application to SSF, the Swedish Foundation for Strategic Research. They have awarded me and a researcher from Karolinska Institutet in Stockholm (Roland Nilsson) a grant of 7.5 MSEK in total, out of which I will receive 3.5 MSEK (~350 000 USD). The topic of this project is to use my modelling to extract quantitative fluxes for all of the metabolic reactions in a cell; this is possible because of Roland's unique experimental skills, where he tags metabolites outside of the cell with C13 carbon molecules, and then uses mass spectrometry to measure where these tagged carbon molecules ends up in all in metabolites inside the cell. We will use these money to both transform this tool from a big potential to something that is useful in practice, and then also to apply the technique to understanding both metabolic diseases and cancer on a new level - useful for both research, drug development, and diagnosis.

The last major grant we got, and just a few days ago, this Thursday, was from VR, the Swedish Research Council. This high-prestige grant builds upon my previous collaboration with AstraZeneca, and will allow us to spend 4.2 MSEK (420 000 USD) to further strengthen our collaboration with AstraZeneca. More specifically, we will make use of the new and more complete models developed within the PRECISE4Q EU network (mentioned above) to understand how a brand new diabetes drug, dapagliflozin, works, and if, how, and when it can be used to also treat cardiovascular diseases like stroke, heart attack, and heart failure. This project will also allow us to understand more about which patients that should have which treatments, and more about the different mechanisms at play in the newly sub-divided grouping of diabetes into 5 sub-types.

One very good aspect of this new situation is that we are really well-prepared for it. This is due, in part, to some very useful grants we have gotten from the Swedish Foundation for Research without Animal Experiments. Using this money, we have been able to train talented undergraduate students in real research projects, which they have done in parallel to their M.Sc. studies, by awarding them scholarships (several of the recent blog posts have been devoted to presenting new such students). These new, and previous old, such quite unique students are now ready and eager to start as Ph.D. students, and they are much more well-trained than normal applicants would be, which we could find in normal open announcements. For this reason, we already now know that we will be able to fill all of the new positions with really great people, and are therefore looking much forward to working with for, at least, the next 4-5 years. However, all of the new positions will be announced in open competition, so if you are a great candidate, who wants to join our group, don't hesitate to apply, or to contact me for discussions on joint collaborations or positions.

All in all, it is also a very great feeling to suddenly have such much money now at our disposal. And also quite humbling. Now we need to really demonstrate to our funders that we can convert these great money into the equally great research we have described in our visionary applications. Into research that will be useful for both other researchers and for those who want to develop and use new and improved treatments - both treatments such as drugs, and treatments such as yoga and meditation. It will be great fun to enter this next step in our group's development!

Blog imageThis is a picture of our group during a recent group meeting. Not all were there, but most of them were. Some of the people in the picture are excellent M.Sc. students in the end of their studies, who we now can offer 2 Ph.D. positions. Apart from that, we will hire two new people, one new Ph.D. student, and one postdoc, but also those will probably be recruits building on previous collaborations and projects. To help as manage all of these new people, we are also very fortunate that Gunnar's second-in-command in the group, Associate Professor Elin Nyman, now is due to come back after an almost 2.5 year long leave in Harvard, Portland, and an almost 1 year maternity leave. For all of these reasons, made possible thanks to the new money described in the post above, our group will now take a step up to functioning on a new level - one with more senior people, more people financed fully by the group itself, and with long-term funding secured. Now we will be able to fully focus on all of the great research projects we are working on, without worrying if the money will ebb out in the middle of the project!



Retreat Liu Circ-MEvents

Posted by ISB Group Fri, October 12, 2018 14:59:02

At the time of writing some members of the ISB-group (Henrik, Kajsa and Gunnar) just returned from attending the retreat of the research network CircM. Here they took part of presentations born from the network, one of which Gunnar took part in. Discussions of how the network can move forward with new ideas and challanges were also a part of the agenda.

We enjoyed the retreat, which took place outside Norrköping, and we are glad that we could take part of the presentations and discussions during the retreat.

Down below we leave you a link if you want to check out CircM and get into contact with the network.
https://liu.se/forskning/liu-circm

Regarding the picture down below, the wheater was unaccounted for, and an idea of a picture with Bråviken as background, turned out to be one with a nice forrest background instead.
Blog image