I’m a physicist by training so I started my PhD doing colloidal matter and soft matter physics and then moving gradually to single molecule biophysics. Then four years ago I moved from France where I have a CNRS position and then I moved to Singapore to embark on the Mechanobiology Institute adventure. So I moved more into cell biology and trying to look at the microenvironmental effects on cell behaviour. So I’m still a CNRS person technically and we are having now this joint group with France and Singapore at MBI that has now another four years to go before renewing. So it’s a nice thing.
As a physicist how do you feel working in cell biology?
It’s nice, somehow. Well, it depends where you are but definitely MBI is a very good place for that because the initial idea of the centre was really to bring together physicists, material scientists, chemists and biologists, of course, to look at this problem of force generation and measurement of forces at the level of cells or tissues. So clearly it’s a very interdisciplinary field so it’s very nice because the interactions are easy actually.
Multidisciplinary, and the good thing also is that we all work together in the same institute, not only collaboration from different places. So that really helps in developing common projects, not only collaborative projects. So that was a great help.
What is your research focused on?
What we do is we endeavour to find ways to control the microenvironment around cells and, as I’m a physicist, I’m trying to simplify things as much as possible, so typically around single cells or just a few cell aggregates. And to understand how this microenvironment that’s around the cell, which we make artificially just to make sure that we control the parameters, how this microenvironment controls the way cells interact. So we’re not so much into looking at how the cells directly interact with their microenvironment, in a sense, but really how that microenvironment around the cells influences cell-cell interactions. So we’ve developed a number of technologies because there weren’t things really established for looking at that sort of problem. Based on the fact that, say, for MBI we have this microfabrication facility we developed techniques to control the microenvironment around the cells by controlling in 3D how the different proteins that can be presented on different surfaces of the cell or the rheological properties that the cell is filling, and it can be differential properties on the lateral part of the cell or basal part of the cells, so we can control all that microenvironment around the cells. Eventually also the topography that the cell is feeling and different topographies.
So doing that we were also able to image the cell at the single cell or single molecule level. So the idea is really to look at cell-cell interactions at the single molecule level if possible. Or with the highest possible resolution in terms of microscopy in order to look at really how the molecular process occurs in cell-cell interactions in a controlled microenvironment.
Under which research conditions do you carry out your work?
It could be any kind of conditions. This is a complete microfluidic free approach so we can very easily change buffers and so you can do any conditions but still in vitro, it’s not in vivo. And you can stress, mechanically stress, your cells; you can stretch, you can apply external stimuli, mechanical stimuli, to the cells if you wish using micropipettes, using aspiration, using stretchable devices. So this is all compatible, not everything combinatorially, but most parameters can be addressed with the kind of approach we developed. So it works well. Yes, I really enjoyed it.
Are there therapeutic implications?
So it’s not directly related, I’d say. My research is not completely focussed on cancer or a specific type of cancer or something but what we expect, and we are now collaborating with a French company who want to sell this system and develop it in a more commercial manner, the hope is that this environmental control system we have can be translated into a platform. I would say it’s lots of expectation but the next generation, or at least one step towards the next generation, of cell culturing in vitro where you don’t only grow cells on the petri dish but you try to exploit them and make them grow on substrates which are close to in vivo situations or, if they’re not close to in vivo situations, at least have the cell behave as much as possible as the in vivo situation. So that’s the kind of hope we have. We’re trying to go in that direction and then see how these interactions, cell-cell interactions, are hindered or changed under drug treatments or under different kinds of gene mutations and stuff like this. So this goes along the lines of this trend of organ on a chip type of thing but it’s not really an organ, it’s really trying to go still at the single cell or multiple cell level but not really integrating. Organ on a chip usually is integrating all blood circulations, multiple cell interactions. So here we’re trying to stay at the level of cell culture as people have done in the past with microenvironmental control and also keeping the ability to do high resolution and super resolution imaging. That’s what really interests me.
Can you tell us more about the impact of microenvironment on cancer cell growth?
Yes, exactly. So that has been seen for years, starting with the work of Mina Bissells and so on where the microenvironment around the cells is determining, or contributes to the determination of, the fate of cells. There are really little ways where you can control the microenvironment in vitro in a combinatorial fashion. In other words, in some sense you can change, say, the rheological properties of the substrate by changing its softness or stiffness but usually when you do this you can’t really at the same time change the chemical properties or change the structure. So usually you have a compromise between structure, rheological properties or chemistry, that’s number one. Number two is usually you have hardly any control when you go out of 2D. So in 2D you know how to change the topography, you know how to change the rheology; in 3D there’s a lot of work looking on Matrigel or any kind of matrixes, artificial matrixes, where you can start controlling things. But it’s not really at the level of a single cell or a few cells; usually for the moment you dump your cells into a hydrogel kind of thing and the cell interacts with its environment and restructures it, which is somehow close to what’s going on in vivo. But when you do this it’s very hard to image the cells with high precision. So we came up with an intermediate state where we can still control the rheological and topographical properties of the cells by embedding them into small cavities which are microfabricated. These cavities have the right properties in 3D. So you can control this microenvironment but still now image the cells in relatively high precision, even super resolution in some sense.
What are the future prospects?
We all hope that it could be useful en masse or large scale. I don’t know; we’re working on that. We’re working on trying to find examples and systems where this sort of combinatorial fashion of looking at the environment can be useful. One way is about stem cell differentiations where it’s clearly that the micro-niche around the stem cell is very important into directing the lineage and there’s a very active area of research that goes into looking in the rheological properties of the substrates or the topographical properties of the substrates, how these properties influence the cell lineage differentiation. And it’s true also for cancer where you can start looking at how much of a phenotype comes out of a different mutation of an oncogene, or something, in these cells.
But still, changing this environment in a combinatorial fashion is not something extremely common and addressable, actually. So that’s the direction we want to take and if we have that then that’s what I would call the next generation of cell culture where you can now direct your cell lineage, you can direct the fate of cancer cells and looking how they behave, not only by soluble factors that you add to it but also by a lot more of the components. You can think of platforms where you would test for which is the best environment to grow your cells or actually to develop certain resistance to certain drugs or inhibit resistance to a certain drug. Then once you have looked at what is the best environment then now you can scale up this environment and grow a lot of cells. You have a test case and then you grow a lot of cells and then you can test your drugs and so on. You can even think that one potential, but that’s very speculative, but one potential treatment for some types of cancer is not so much on controlling what’s going on at the cell level but trying to change the microenvironment around the tumour or around the cells so you don’t directly affect the cancer cells but try to affect the environment around the cells. But for that you need to know first how to affect their environment and second what kind of environment you need for the cells to remain benign or to kill a tumour or something. But that’s a long prospect, not tomorrow.
Do you have shared projects between France and Singapore?
No, so that’s one model that some people have. I made another choice, I made the choice to move to Singapore completely. So four years ago I moved all my lab to Singapore entirely but I kept my position in France, this is one of the advantages of CNRS, that you can be abroad and keep your position. I developed more collaborations when I was in Singapore than any collaborations I developed when I was in Paris, so that’s the paradox when you’re a bit away then all of a sudden you get more people. Last year it turned into a real CNRS MBI lab, so with people coming and having a CNRS lab, they call it a joint unit, a joint lab if you wish. So now I’m bringing friends to Singapore.
