I don’t have many distinct memories from childhood. Certainly not of global events. But given the sweltering weather, the recent Canada 150 celebration, and a cool new paper published in Cell Chemical Biology, my mind wandered back to the ’96 summer Olympics (Atlanta), when Donovan Bailey raced through the finish line with his arms in the air to win Canada gold.
Now while he was an extremely agile athlete, the event I’m thinking of was the 4x100m men’s relay. This run required a team effort. In fact, if any of the sprinters missed the hand-off or ran too slowly, the success of the whole team would be compromised.
So how does this relate to a science publication?
Well, the “relay” is how I think about the therapeutic strategy for targeting immune cells described in this publication out of the University of Toronto.
The authors noted that there were several disease states, such as atherosclerosis and cancer, where immune cells secrete damaging pro-inflammatory cytokines like TNF-a. Furthermore, these cells reside in dense masses (i.e. the atherosclerotic plaque or tumor), which have a pH much lower than the rest of the body.
Rather than give patients anti-inflammatory drugs, which circulate systemically and can have many unwanted side effects, the authors designed a targeted cell therapy based on the above observations. And like our relay team, it has four important players (proteins) that act in sequence.
Player 1, The Detector: A “detector” cell line is first engineered to have a chimeric TNF-a receptor (TNFR1chi). This receptor is special because it links binding of TNF-a to the creation of an intracellular calcium signal (not the typical response the receptor generates).
Player 2, The Motor: Next, a second engineered protein called calcium-activated RhoA (CaRQ), causes non-apoptotic “blebbing” of the detector cell in response to the calcium signal. Curiously, this blebbing creates cellular movement. While the cell moves in a random direction, the blebbing decreases if the cell moves away from the source of TNF-a (motion stops), and it increases if the cell moves toward the TNF-a signal. Over time, this means that the detector cell migrates toward pro-inflammatory cells that secrete TNF-a.
Player 3, The Unifier: If the detector cell approaches a TNF-a source cell in a dense mass where there is a low pH (i.e. plaque or tumor), a third protein called vesicular stomatitis virus glycoprotein G (VSVG) will cause fusion between the detector cell and the source cell.
Player 4: The Trojan Horse: Finally, the detector cell has a fourth protein called thymidine kinase (TK; originally a herpes simplex virus protein), which is now shared with the TNF-a source cell due to the fusion event. TK makes cells susceptible to death from a drug called ganciclovir.
To summarize, a therapeutic detector cell senses TNF-a (P1), migrates towards the TNF-a source cell (P2), fuses with the source cell (P3), and then makes it selectively vulnerable to death when the drug ganciclovir is given (P4).
Alas, at the end of the relay, the TNF-a source cell can be finished off!
Admittedly, the data in the publication is all in vitro, and there would be many challenges to directly translating it to an in vivo setting. For example, the authors point out that some of the viral proteins incorporated may elicit an immune response in humans. They also acknowledge that other protein-receptor interactions can naturally generate a calcium signal, which could lead to off-target detector cell migration. However, the authors believe the calcium signal would be milder in the non-engineered system, and the detector cell still only fuses to cells in a low pH environment (fail-safe).
My own question is: how do the detector cells behave in circulation vs. in a tissue? For example, atherosclerotic plaques are found in blood vessels, and there are many larger forces than blebbing at play when dealing with circulating cells.
Nevertheless, this paper is a nice proof-of-concept for how modern genetic/protein engineering can be used to create targeted therapies based on a “team” of cells/proteins. It is a little strange to think about a therapeutic relay team, and yet this approach describes most successful life ventures.
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