For decades, scientists described biology as a chemical conversation. Cells made decisions by following a manual written in their genes, executed through chemical signals. If a cell became a neuron, muscle cell, or red blood cell, it was because certain molecules instructed it to turn some genes on and others off. Finnish researcher Sara Wickström, 50, has helped show that at least one crucial piece was missing from that story: cells also sense their environment.
Cells do not just obey chemical and genetic instructions; they also interpret the mechanical properties of the world they inhabit. Not exactly as we do, but they can detect whether the tissue around them is under pressure, being stretched, or has become stiffer than normal.
Wickström, director of the Max Planck Institute for Molecular Biomedicine in Münster, showed that this physical information can reach the cell nucleus, where DNA is stored, and alter gene behavior. For work such as this, she was awarded the Körber Prize, one of Europe’s most prestigious scientific honors (eight previous recipients have gone on to win the Nobel Prize), which comes with a €1 million ($1.16 million) award.
One way to understand the mechanism uncovered by the Finnish researcher is to compare eyelid skin with the skin on the soles of the feet. Both structures are made essentially of the same cell types, yet one is thin and flexible while the other is thick and tough. How do those cells know which structure to build? Part of the answer lies in the physical forces to which they are exposed.
Her most influential finding came when she observed that applying mechanical forces to skin stem cells did not simply activate a few isolated genes. Instead, it triggered a large-scale reorganization of how DNA is packaged within the nucleus. That discovery was decisive in creating a new field at the intersection of physics and biology: mechanobiology.
Question. If you met your student-self today, how would you explain your discoveries?
Answer. My main discovery was showing that those forces influence, in a fairly direct way, which genes are expressed and which are not. This is critical to understanding our cells, because every cell in our body has the exact same DNA yet performs completely different functions. That happens because each cell decides which set of genes it will express.
Traditionally, regulation was thought to be purely biochemical. What we have shown is that mechanical forces also play a role. Those forces, naturally, must first be converted into biochemical signals, and those signals regulate chromatin — DNA plus the proteins that organize the DNA and regulate gene expression.
Q. When you talk about mechanical forces, do you mean something like the forces we experience, or is it something completely different at the cellular scale?
A. Essentially it is the same. Of course you must account for differences in scale. We know that this pressure causes the skin cells on the sole of the foot, even though they are the same cell type as those on the face, to develop a different structure precisely because they are exposed to a different mechanical environment. It is also clear in the cardiovascular system. Shear stress inside blood vessels [exerted by flowing blood on the vessel’s inner surface] or muscle stretching are important to maintaining the functional specialization of these cells. That is why, for example, when a person suffers a heart attack and the tissue scars, the mechanical properties of the heart change and that ultimately alters its function as well.
Q. People tend to think cells work like computers: they read instructions in genes and respond to chemical signals to execute those instructions. What is missing from that picture?
A. Our research brings in the context in which cells operate. Studying aging, we have seen that the function of the skin’s stem cells — which keep the turnover of the tissue, protect the skin and promote hair growth — declines as we age. But we have discovered that this does not happen because the stem cells themselves become defective; rather, the mechanical properties of their microenvironment change, and that change negatively impacts their function.
The medical implication is important. Instead of trying only to transplant or rejuvenate the cells themselves, the surrounding connective tissue would also need to be rejuvenated. That is much harder, because that tissue is secreted by the cells themselves and, once formed, has a bit of a life on its own outside of the cells.
Q. Are you already working on those kinds of applications?
A. We are working along two major lines. The first is cancer. In tumors, mechanical properties change significantly for two reasons. First, as the tumor grows, it generates pressure on the cells it contains. We believe that pressure contributes to reprogramming tumor cells and may encourage them to become more aggressive. The second reason is that the tumor alters the microenvironment around it, making it stiffer and more fibrotic.
We are also working on diagnostics. We want to use these mechanical changes as biomarkers to predict, for example, how aggressive a given cancer will be based on its mechanical responses. We have already made substantial progress in this area. We have even created a spin-off company that is specifically working to translate these biomarkers into clinical practice.
Q. Would treatments based on these mechanical changes resemble those we use today, or would they involve physically intervening in the tissue?
A. It is still very early days, so I don’t want to paint too concrete a picture. I think there are two possibilities. The first would be to develop small molecules, conventional drugs, that modify how mechanical forces reprogram the cell and revert it to a healthy state. The second possibility would be to directly alter how cells respond to mechanical forces. That second type of treatment is much further away.
Q. What is the evolutionary origin of this cellular behavior?
A. It is clear that multicellularity made it necessary for cells to communicate with one another, and I believe mechanical forces are one of the essential ways to communicate and perceive the outer environment. I also find another major evolutionary transition very interesting: the move from aquatic to terrestrial life. Moving from water to land meant facing completely different mechanical demands, which drove the need to develop tissues capable of withstanding mechanical forces. That means cells had to be able to detect how much mechanical resistance a tissue truly needed.
Essentially, that is also what happens in fibrosis: cells become overly sensitive and believe they still need to mechanically reinforce the tissue when, in fact, they don’t. That is why it is interesting to note that, for example, fish do not develop fibrosis. When a fish is injured, a scar does not form, whereas in terrestrial mammals it does. There seems to be an evolutionary trade-off between the two strategies.
Q. Could you give a concrete example of how those physical forces modify chromatin, change gene expression and eventually influence a health-related outcome?
A. I think a very important discovery — not made by us but by other researchers and recognized with a Nobel Prize — was that ion channels are mechanosensitive. What we have observed is that changes in ion flow are very likely one of the fundamental mechanisms by which global gene expression programs are altered. Our main discovery, which is now well established, is that changes in chromatin will really change the cell state.
Q. Do you think we may still be overlooking many important aspects of how biology works?
A. Undoubtedly. I think there is still a lot to discover, and precisely for that reason this is a very exciting time for biology. We are living through an era of enormous interdisciplinarity. And there is a second decisive factor: technology. Advances in optics and computation are driving a big revolution. Until relatively recently, we relied mainly on biochemistry, which is actually a very indirect way to study cells and tissues because it requires destroying or lysing cells to analyze their DNA. Now, by contrast, we can directly visualize many of those processes.
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