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The current issue of Current Biology has a special section on Cell Form and Physics that starts with a nice editorial by Florian Maderspacher. I wrote a review with my PhD advisor, Dennis Discher, for the issue that you can find here (or here [pdf] if that doesn’t work). Best of all, the articles seem to be freely available, at least for now.
The main point of our review is that for all the work identifying molecules that are associated with stiffness and force sensing, there has been relatively little progress towards understanding the actual force sensitive steps. That is, although it’s known that many proteins are recruited to focal adhesions when cells are stretched, and that others are phosphorylated and play a role in various signaling cascades, these processes themselves are not directly regulated by force—they are secondary players in mechanotransduction.
Recently there have been some interesting results showing that forced protein unfolding in several different contexts could be critical. We review some of this work and related work that points towards unfolding even in cases where it hasn’t been definitively demonstrated. Ultimately, it looks like there will not be a single cellular “mechanosensor” but instead a whole host of different mechanosensitive processes that contribute in different ways. There’s lots of room here for more work by physicists and I hope people continue to get interested.
Having defended my thesis, I set off to England about a month ago to start a postdoc at the Medical Research Council Laboratory of Molecular Biology in Cambridge. I’m going to be working in Bill Schafer’s lab studying neuroscience using C. elegans as a model system. This is a pretty big switch for me, but it’s exciting to try to orient myself in a new field and identify some interesting and tractable problems. 
It can also be frustrating when you can’t follow a lot of what people discuss in talks, but I’m trying to take advantage of my naivety to start something a bit original. It’s great to be a scientist.
Cambridge itself has been beautiful so far. It’s certainly colder than Philly, but it hasn’t rained much at all, despite everyone’s warnings. We’ve even tried some punting (that’s me trying to steer).
If you cut yourself, a blood clot can save your life: platelets aggregate and fibrin fibers form a mesh that catches red cells and prevents you from bleeding out. If you have heart problems, a clot can also take your life: heart attacks are often the result of clots in the coronary artery. Just such a clot is shown below. This is a colorized electron microscope image of a thrombus that was removed from a heart attack patient. You can see the mesh of straight fibrin fibers in brown, activated platelets in gray, red cells in red, and a leukocyte in green.
To do their job effectively, blood clots must have an open structure so that enzymes can diffuse in to break the clot down when it is no longer needed. This can be achieved with a stiff scaffold with lots of spaces between the structural elements. A scaffold of stiff structural elements would normally be stiff itself and probably also quite brittle, but one of the first things you’ll notice if you take a blood clot in your fingers is that it’s squishy and stretchy, something like a water-logged rubber (or hydrogel). The thing is, rubber is made of highly flexible, thermally oscillating chains that provide extensibility but they have very small pores that wouldn’t allow enzymes to diffuse through effectively. So how does fibrin balance the large pore sizes with high extensibility?
We argue in our paper in Science that protein unfolding gives fibrin’s stiff fibers an intrinsic extensibility. In other words, it is the unravelling of compact protein structures, possibly fibrin’s coiled-coils, that allow blood clots to stretch so far. We hypothesized that this would be the case when we published our single molecule study of fibrinogen mechanics a couple of years ago, but to nail it down, we had to look at several structural levels from the macroscopic (centimeter level), through the microscopic network structure, to the nanometer molecular level.
It seems then that fibrin has evolved a molecular structure that enables it to play its amazing role. It self-assembles in clots into an open network that stops blood flow but can also be broken down and avoids being brittle by having structural elements that unfold under force. It’s an amazing material, and you make it and break it all the time.
Biocurious is written by Andre Brown and Philip Johnson, since 2005. Content of the weblog is licensed under a Creative Commons Attribution-Share Alike 3.0 License.
