Function Follows Form
Simulations on XSEDE Resource plus Lab Work on Frog Neuromuscular Junction Sheds Light on Human Diseases
Why It's Important:
How XSEDE and PSC Helped:
Testing the Footing
XSEDE Resources Help Univ. of Chicago Team Simulate Cell Movement, Upending Scientific Expectations
Aug. 31, 2018
The movement of white blood cells to fight infections and the spread of cancer cells both rely on the same natural process. The cell reaches out to a new surface with a lamellipodium—a kind of tiny foot that tests the surface like we'd test ice before stepping onto it. As part of a multi-institutional collaboration, a team from the University of Chicago simulated how the lamellipodium works, using XSEDE resources and online training tools in concert with laboratory experiments. Their virtual cells duplicated their lab findings perfectly, showing how integrin and fibronectin—two proteins scientists had previously not expected to play a role—tug on the surface before the cell commits to moving onto it. The discovery points to possible ways for doctors to encourage good cell movement and discourage bad cell movement.
Why It's Important:
The ability of the cells in our body to move around lies at the heart of vital life functions. It allows white blood cells to move into tissues to fight infections. It helps organs in developing embryos organize and grow. More ominously, it also enables cancer cells to move and spread. Fully understanding cell motion could help doctors better encourage the good cell movements and stop the bad ones.
The vital first step in cell motion is when the cell forms a lamellipodium—meaning "thin sheet foot." With its lamellipodium, the cell reaches out to test a surface, called a substrate, before the cell moves onto it. The amount of extension of the lamellipodium depends on the rigidity of the substrate. This motion is similar to how we'd gently step onto ice to make sure it's solid before we put our weight onto it. If the substrate is solid enough, the cell will move onto it. If not, the cell doesn't venture onto the "ice." By encouraging, or discouraging, that interaction, we could speed or stop motion of a cell into a given place or tissue.
"Sensing by the cell determines the first phase of cell adhesion to a substrate. Other things can then happen, but the very initial contact between a cell and a substrate is dependent on the lamellipodium."—Tamara Bidone, University of Chicago
Gregory Voth of the University of Chicago and his postdoc Tamara Bidone wanted to understand how a lamellipodium tests a substrate's rigidity, and to clear up some disagreements among scientists over how it works. With Patrick Oakes at the University of Rochester, NY, and colleagues at Chicago, they turned to a mix of laboratory measurements and computer simulations of lamellipodia. The latter employed the XSEDE system Bridges at the Pittsburgh Supercomputing Center (PSC).
How XSEDE and PSC Helped:
Oakes began by testing cells' ability to adhere to substrates of different rigidities in the lab. He found two interesting things—one new, another unexpected. First, the cells didn't just test the substrate and move. The interaction of the lamellipodium with the substrate was "biphasic"—the cell used the lamellipodium to tug in two steps. If the substrate gave way too much, nothing else happened. But if the substrate tugged back, the cell pulled harder, the first step in moving.
The team's other finding upended what many scientists had expected about how the lamellipodium worked. Most had thought that the cell would pull on the substrate using myosin, a protein that serves as a tiny motor within the cell. But Oakes found that when he added a drug that prevents myosin from using ATP, the cell's basic fuel, the two-step tugging process still happened. A motor other than myosin had to be at work. Further lab testing pointed to the interaction between integrin, a protein that sits in the membrane that surrounds the cell, and the substrate. Integrin serves as the anchor of the cell to the substrate. But it does not run on ATP like myosin does. Instead, the energy integrins use to tug comes from binding and unbinding the substrate.
The scientists wanted to understand how the cell could use integrin to sense surface stiffness. Bidone created a virtual lamellipodium in the XSEDE-allocated Bridges system at PSC. She then changed, in tiny increments, how the different components of the cell behaved. She needed to simulate about 300 seconds of lamellipodium behavior in three dimensions, under thousands of different assumptions for how the components worked. Each simulation took three to four hours to compute, with about a two-fold speedup over other available computers. Bidone's computation used about 2,000 of Bridges' computational "cores"—by comparison, most top-line laptops have 4 cores. Bidone got off to a great start in part because of the online tutorials on XSEDE.org, which helped her figure out how to set her calculations up successfully.
"A ‘catch bond' is a bond that strengthens as you pull on it. Depending on the applied force on the bond, it actually stiffens up and gets stronger, but above a certain threshold of force the bond disassembles. Tamara's simulations showed that, through this strengthening and weakening of the integrin binding, the substrate modulates its binding and unbinding, and very conclusively the simulations fit the experimental data. I think that's the key of where computation was valuable in this work. It showed the importance of the integrin catch-bond interaction with a substrate. Without computation, the interpretation of the experiments would be a lot more difficult."—Gregory Voth, University of Chicago
The cells' sensing of the surface rigidity, Bidone discovered, depended on a "catch-bond" mechanism. That means that the harder the surface tugged back, the longer the connections holding the integrin and fibronectin network together persisted. The virtual lamellipodia in her simulation recreated the real cells' behavior, duplicating the two-step process perfectly. It also reproduced the behavior of mutant cells with altered catch bonds. The team reported their results in the journal Proceeding of the National Academy of Sciences USA in March. Next, the scientists plan to study whether simple nudges by chemicals or other means might be used to direct whether cell movement happens or not. It's a first step toward drug therapies targeting cell movement in cancer and other disease processes.