In October’s blog post, we feature an interview with Dr. Roeland Merks, Professor of Mathematical Biology, Leiden University. Dr. Merks was one of the plenary speakers at ECMTB 2022 just a few weeks ago!
When did you first become interested in mathematics and biology?
Since my childhood I have been interested in biology, electronics and computers. I used to keep fish and rats, and from about 14 I kept frogs, salamanders and lizards and lots of plants in my bedroom. I was the youngest of five. My three sisters and older brother had quite different interests than me, so I lived a bit in my own world. Around 1985 the first computer entered our home, a Commodore 16. I got hooked. My passion was programming, to the extent that I had to take care that my ‘zoo’ would not suffer too much. I got completely inundated in big projects, such as an extension of the BASIC programming language that I kept on extending and extending. It never got finished or released.
Somehow this always kept on nagging me a bit. During the first months of the pandemic, I found out that there’s still lots of enthusiasts for these old computers. I dusted off the good old Commodore and managed to recover my project TED BASIC from some old, big floppy disks, fixed the worst bugs, and put it up online at a big retro-software database for the Commodore 16 and the related Plus/4 computers… This sounds perhaps a bit crazy, but it felt good to have finally released it and it was a real fun lockdown-project. At highschool I was also a member of a club in my hometown Nijmegen in the Netherlands, called “The Young Investigators”, where I moved between electronics, computer and biology ‘departments’.
By the end of high school my interest in computers had waned a little bit, and I spent most of my free time in taking care of my ‘zoo’, and in writing prose and poetry for a literary magazine that I ran with two school friends. By that time I decided I wanted to become a veterinarian, and more specifically a veterinarian specialized in reptiles and amphibians and other ‘special animals’. In the Netherlands there was a lottery for a limited number of places at Utrecht University, the only place where veterinary medicine is taught in the Netherlands, and I was lucky enough to get in. I enjoyed the study tremendously – at the time the study was quite hands-on, so I got to study biochemistry, histology and cell biology quite thoroughly, doing lots of enzyme kinetics and microscopy for example, and I learned mammalian anatomy by dissecting a dog in a team of four over the course of a full year.
I also discovered at the beginning of my second year that veterinary medicine was oriented on practice and showed you how things in biology are, and how one can fix them. I wanted to know why and how they had come to be so: my interest and motivation were mainly scientific. I started reading quite old books on comparative zoology and paleontology that I found in a herpetology section of the library of veterinary medicine and realized more and more that I was in the wrong place. What did not help either was that veterinary medicine was not the safest place for the openly gay student that I was at the time. My social life was for the most part separated from my student life, and I had to go through some nasty and quite impactful events in the veterinary students’ house that I lived in.
Halfway through the academic year, in January 1993, I had found a better place to live and I switched to biology, also in Utrecht. Here I quickly found out that there were courses titled “Theoretical Biology”, “Bioinformatics”, and “Non-linear Dynamical Systems” taught by Paulien Hogeweg, Rob de Boer and Sasha Panfilov. These course titles alone already elicited enormous fascination, and they reignited my interest in computers and programming. I learned Pascal and C, and really inundated myself into these courses and got good grades.
Was the decision to do a Ph.D. an obvious and easy choice?
Doing a Ph.D. felt like a huge thing to me, a thing that was only meant for the very best-of-the-best, certainly not me. I am a semi-first-generation university student – my father got a Bachelor’s in pedagogy in his thirties and one of my sisters has a Bachelor’s degree in chemistry. I had no close examples of people doing a Ph.D., except for the people in Paulien Hogeweg’s research group where I was a Master’s student and teaching assistant, but what they did seemed unreachable to me. I could be shy at times and was not blessed with the biggest self-esteem. I really, really wanted to stay in science and continue for a Ph.D., but going to my professor to discuss possibilities for Ph.D. opportunities in Utrecht or elsewhere, this seemed like the most immodest and rude thing that one could possibly do. So apart from some awkward attempts I did not really manage to express myself.
What was fortunately easier for me is to see an explicit advertisement or call and apply for it. At that time there were two national grant programs for new Master’s students that allowed them to study abroad for one year. After a failed attempt to go and work in Paris, Paulien Hogeweg kindly brought me in touch with Prof. Kunihiko Kaneko of Tokyo University, where I could join a project on a dynamical systems approach to cell differentiation. I applied to both programs and they both came through, although I could of course keep only one. So in 1998, I spent nine months in the middle of Tokyo, a truly life-changing experience – it was my 2nd time on a plane and my first trip out of Europe, and the team of Prof. Kaneko was truly exceptional. I am still in touch with many of the students in Kaneko’s group at that time. In Tokyo, I came across an advertisement for a Ph.D. position on coral growth modeling in Amsterdam. It was close enough to my interest in morphogenesis, and going back to the Netherlands was the only option for me, as I had met my later husband Bart in 1995 with whom I am still together. In 1999, I was accepted to join the Section Computational Science of the University of Amsterdam where I worked with Jaap Kaandorp, Alfons Hoekstra and Peter Sloot, and with the usual ups and downs I graduated on my thesis “Branching growth in stony corals: a modelling approach” in 2003.
How did you come to run your own group?
My first postdoc was at Indiana University, Bloomington, where I worked with James Glazier, one of the developers of the Cellular Potts model, whom I had met during my time in Tokyo. With him, I developed the first Cellular Potts models of vasculogenesis and angiogenesis. I stayed only for a year and for a second short stay in the second year, because Bart and I did not want to live apart from each other for too long. Shortly after I got my Ph.D., he had become the foreign correspondent of Belgium for the Dutch national newspaper de Volkskrant in Brussels, and we hoped to experience this special five-year period together for a few years.
I got in touch with Gerrit Beemster, a plant researcher at the VIB Department for Plant Systems Biology in Ghent, Belgium, which was a reasonable commuting distance from Brussels. They were interested in having a mathematical modeler on board. That is how I got interested in plant modeling; I felt I could apply the cell-based (or cell-centered, as we called it then) modeling philosophy to plants as well. I could get a one-year postdoc position while waiting for the results of a Marie-Curie Fellowship application that I had submitted, and it was successful! I developed a cell-based modeling framework called VirtualLeaf, somewhat halfway between the Cellular Potts model and vertex-based techniques, overlayed with systems of ODEs for modeling signaling networks and polar auxin transport, which I applied to problems in leaf venation patterning. Towards the end of this fellowship in 2007, VIB opened a new program for ‘Young Leaders’, and I was encouraged to apply so I could set up my own group. So I did, and again this was successful! I could hire one Ph.D. student and also an ongoing Ph.D. student, Krzysztof Wabnik, started working with me and Jiri Friml to continue on the problem of leaf venation patterning. It was a great period, but at the same time Bart’s upcoming return back to the Netherlands was lingering on the horizon. It meant we had to move for a third time into a long-distance relationship, which we were not looking forward to.
So when I received an email calling my attention to an advertisement for a role as “head of the core modeling” group within a new national research program called Netherlands Consortium for Systems Biology (NCSB), of course I gave it a try. The successful application for this position would be responsible for a budget of 1.5 M€ for a period of five years to set up a biological modeling group at CWI, the Dutch national research center for mathematics and computer science. This ‘core modeling group’ of the consortium would collaborate with many other NCSB-funded experimental teams and ‘embedded modellers’ all over the country. Working with so many people on different topics to me sounded like a wonderful ‘playground’, much like the role I had taken up in Ghent where I was collaborating with several experimental groups. However, I also felt this position was not meant at all for the early career stage I was in. I was convinced I would not stand a chance, but well, since I was specifically made aware of the position, I thought it would not hurt to give it a try.
I studied the groups participating in the research program, and picked out a number of projects where I thought I could contribute something, wrote up my plans on how to do so and explained how these ideas connected to my current research. I submitted my plans, motivation letter and cv and did not think much about it anymore. We concentrated on our current situation, considered for a while to settle both in Antwerp (which would have led to the most horrible commute for both of us), and finally settled on a sort of weekend relation that we both did not quite look forward to. We bought a house in The Hague, where Bart would become political correspondent and I rented a small, but cute apartment in Ghent for my weekdays.
Well… the rest is history, as we were painting our house in The Hague and I had just brought a mattress and a camping refrigerator to the apartment in Ghent, the news came in that I was invited for an interview in Amsterdam! The interview was of course a nerve-wracking experience, but somehow I must have managed to leave a good impression, because they gave me the job. In the end, I worked for 10 years at CWI in Amsterdam. I continued work on plant modeling and angiogenesis, and took on new projects on tumor plasticity, on metabolic modeling and on multiscale modeling of the gut microbiota.
It was a great experience as well as a great challenge to start and run a group consisting of two Ph.D. students, two postdocs and a technician, and at the same time to try and make their efforts relevant for the other consortium partners, to tie the bonds between my group and the other modelers employed elsewhere in the consortium, and to perform managerial tasks for the whole consortium. Later on I applied for a career grant called the ‘Vidi’ in the Netherlands to focus more on angiogenesis again, and I could start this project in 2011. In 2017, I applied for the next tier in this Dutch system of career grants, the ‘Vici’. This helped me move to Leiden University, where I took up a full-time professor position in 2018 and even could start a small experimental lab focusing on angiogenesis, so that we can develop our models in direct interaction with experiments. I had dreamt about making this step for a long time.
My research group in October 2022 at lunch in "Landgoed Noorderheide", an amazing estate at De Veluwe, a forest and heath area in the Netherlands. My group and I got invited to stay there for three days as an award for a public lecture that I gave for the Koninklijke maatschappij voor Natuurkunde Diligentia ("Royal Society for the Natural Sciences Diligentia") in January 2021. View the lecture at https://www.youtube.com/watch?v=dV3DblXkxqg (in Dutch).
What are your main research questions and why are they interesting?
My main research questions revolve around morphogenesis: How can a collection of genetically identical cells self-organize into patterned tissues? The last few years I have focused on modeling the role of biomechanical interactions between cells and the extracellular matrix in morphogenesis, in particular in angiogenesis and vasculogenesis. This required us also to focus in more detail on the biomechanics of single cells, in which we modeled, for example, how cell shape can be regulated by the effect of mechanosensitive focal adhesions and the stiffness of the extracellular matrix. More recently we are incorporating more detailed models of the extracellular matrix in our model and we have also started to test some of our model predictions in the wetlab. These research questions are interesting, first of all because it is really fascinating to get more insight into how biological shapes are encoded into the interactions between individual cells and their responses to changes in the microenvironment. I am still mesmerized by seeing how relatively simple model assumptions on the cellular and subcellular level, usually with a pinch of stochasticity, translate to amazingly realistic predictions of the patterns at tissue scale.
Secondly, analyzing the details of how cells communicate during the formation of blood vessels can help identify new ways to interfere in cases where angiogenesis goes awry. For example, tumors can secrete growth factors to attract blood vessels, giving cancer cells access to oxygen and nutrients and a route for spreading further in the body. The old idea was that we should find ways to stop blood vessel growth, but more recently it has become clear that at least in some cases it may be wiser to help blood vessels to grow as normally as possible. In this way hypoxic regions are prevented, which may favor more aggressive cells that rely on anaerobic metabolism, and the route for delivering chemotherapies is maintained. Whichever turns out to be the best strategy, in any case we need to understand exactly the strategies by which we can nudge the collective behavior of cells in the right direction. Mathematical biology of collective cell behavior is a great help in this.
The big luxury of being a mathematical biologist – and perhaps also one of the big pitfalls – is that alongside this central topic of angiogenesis and cell mechanobiology, I can stick my nose into all kinds of other interesting problems through collaborations. I enjoy this a lot and actually I think it is mostly a good thing. It allows us to translate insights from one field to the other. Alongside our work on angiogenesis, my lab has recently started a new collaboration on natural pacemakers. Here we are combining our cell-based models with electrophysiological models to model cell cultures of pacemaker cells and cardiomyocytes. Also through various collaborations and student projects I am keeping alive the research line on plant modeling, which I started during my time in Ghent. During my time at CWI in Amsterdam, I also started a line of research on microbial ecology of the gut microbiota, which I am very excited about. In this topic, we apply multiscale principles very similar to the ones that my lab applies to problems in developmental biology. We start with a description of the metabolism of individual bacteria, using detailed genome-scale metabolic network models, and put those into the context of a gut-like ecosystem. Through cross-feeding and competition for space, cooperative and competitive interactions emerge, which again change the available metabolites and the bacterial species that can grow. In this way, the models allow us to see how changes to the environment, e.g., nutritional intervention, can nudge the microbiota in one direction or the other. The multiple scales that are at work in this system often lead to highly counterintuitive effects.
For this microbiota research, we are now financed by a large international food company and collaborate closely with their research scientists. As a scientist who is really focused on basic research, I hesitated a bit when this opportunity first crossed my path. Now I am really happy that we jumped into this. It is really exciting that large companies see that mathematical biology might be of value for their business, and that they gave us the opportunity to demonstrate to them what this approach can do for them. And it does bring us to really fundamental questions that are both interesting scientifically as well as societally relevant.
What makes you passionate about your work?
It’s the whole thing, really. It’s really fascinating that a bunch of cells can self-organize into a plant, animal or, in the case of our gut microbiome, a small chemical factory. I really like to read and write about science. I never get bored watching time-lapse videos of vascular networks and all kinds of simulations over and over again, seeing new things every time. I like to program. I like teaching mathematical biology. And of course I like to discuss science and life as a scientist with my students, Ph.D. students and postdocs. Helping and advising them in navigating the sometimes tortuous trajectory towards a Bachelor’s, Master’s, Ph.D. degree, or the next career step after a postdoc, is quite a special and rewarding experience. And, if it does not get too much out of hand, I like organizing things, although I have found out that I like that best when it does not drift too far away from the scientific content.
What is a typical work day/week like?
Of course I have a lot of meetings, but most of them are nice meetings. My week usually starts on Monday with a few ‘free’ hours – answering e-mails, writing, reading manuscripts – or a monthly meeting with collaborators. Then I have a series of weekly, one-hour meetings with Ph.D. students and postdocs, where we discuss research updates, open issues in their research, progress on papers, and so forth. In the late afternoon I have a group meeting of the animal science group of the Institute of Biology, which I occasionally skip – I am also part of the Mathematical Institute, so I have double the amount of institute meetings if I would attend all of them! Tuesday also starts with weekly meetings with Ph.D. students, but I also have a lot of time to get some work done and to have occasional discussions.
In the autumn semester, I teach my course Multiscale Mathematical Biology to 3rd year Bachelor’s and Master’s students in the biology and mathematics programs. In this interdisciplinary course, I teach mostly on modeling multicellular problems, for example Turing patterns, cellular automata, cell-based models, including (of course) the Cellular Potts model, vertex-based models and Vicsek-type models. I discuss these systems using applications ranging from mathematical oncology and angiogenesis, to plant morphogenesis and branching morphogenesis. On Wednesday, I teach in the morning and then with my assistants in the early afternoon there is a practical course where students learn to work with these models by themselves. I can rely on amazing teaching assistants, so that gives me some time to prepare my next lectures or to work on papers or grants, or prepare talks.
Usually on Wednesday afternoons we also have our group meeting. One of the Ph.D. students or postdocs presents an informal progress update, usually with lively discussions. Then we have a round of really quick updates of what everybody is doing, or to ask help with something, such as programming issues. Thursday and Friday is again a bit more open, and gives me time to read drafts, do editing work, and have discussions. But these days often also fall victim to committee meetings, collaborative grant discussions, and so forth. I also teach on Friday mornings in the autumn semester, and once in a while these days give me some time to do some research myself or work a bit on software like our package for plant modeling software VirtualLeaf, although sadly this happens not so frequently.
Do you have any advice for someone considering a career in mathematical biology?
Make sure that you really, really like the daily routine of scientific work. If you like math or coding, if you like watching cells, plants, proteins, or whatever you are studying, if you like watching simulations over and over again, if you like discussing the nitty-gritty details of scientific work with your supervisor and students, if you like reading, writing, teaching, giving talks and listening to talks, if you like organizing things, then it becomes much easier to keep going when things don’t work out as well as you hoped… Paper and grants will get rejected, you’ll find crucial bugs in your code (or not for many hours or weeks), your theories will be falsified, it will be difficult to find a next job, and so forth. These things are difficult, but much, much more difficult if you don’t really like your days, if your key motivation is to work towards some secondary, ‘greater goal’, such as ‘having a Ph.D.’, ‘curing cancer’, ‘getting a Nature paper’. Realize that these things don’t really matter in the end.
Also make sure that you work in a place where you feel well and are welcomed. You can’t always change your environment. Sometimes it’s just much better to move on, as I’ve done when switching to biology, and actually, also quite recently when moving from Amsterdam to Leiden.
What do you like to do in your spare time outside of work?
Together with my husband, I collect contemporary art. It all started about 10 years ago, when we got interested in buying a painting. It took a while before we found our way around the galleries in the Netherlands, and came across a work that we really liked. The whole process was very exciting and interesting. It was fun to meet the artists and gallerists, and you look at art in a different way if you consider buying it. So we kept on visiting other galleries, and fell for the next painting, which again led to the next… It took a while before we realized that, whoops, we have become collectors, but I guess that’s the reality now.
Starting about two years ago, we use a room on the ground floor as a “street gallery”, as we have called it. It has two big windows facing the walkway, so people passing by can look inside at what are mostly site-specific installations. The first exposition was an installation by The Hague artist Catinka Kersten consisting of three stuffed life-size Indian elephants lying on the floor, titled Come to me when thou hast seen the elephants dance, a citation from The Jungle Book by Rudyard Kipling, meaning “please don’t come back”. We’ve changed the exposition every three months, and are now at the sixth exposition by Peter Bes, entitled From Where. He has filled the space with life size people made out of painted cardboard. The artist sees them as actors. They interact and tell a story, the viewer’s story. You can get a glimpse of these exhibitions on http://www.despelonk.nl and on our Instagram account @de_spelonk_den_haag.
My research group in front of the installation Membrane by Pim Palsgraaf in "street gallery" De Spelonk, which we run at the ground floor of our house in The Hague (http://www.despelonk.nl).
Besides collecting art, there are of course many other things I like to do in my spare time. I like reading, cooking, I keep a lot of plants and have an aquarium, we have two cats, and we both like hiking and visiting museums and galleries. When there’s still time left, I collect and program old computers from the early eighties and nineties, mostly Commodores – sometimes trying to fix them – and I like to practice my Japanese (I recently passed the JLPT N4 exam). Way too much to do, and of course some of these things I rarely get to…
Any final comments or advice?
It’s quite easy to get lost in our work. Work is never finished, there are always unanswered emails, unwritten papers or grants, reports to write, people waiting for us to do really important stuff… Then the moment that the work that you really liked to do is suddenly not so much fun anymore, is always lurking around the corner, and you may just slow down and get depressed or bored. So it’s very important to have other things to do. For me, it’s collecting art and reading books, playing with the cats, all these things speak to different parts of me than my scientific work and these important activities energize me for the other important activity that is work. So whatever part of you gets neglected, find a fun way to attend to it.