by Elise Wachspress
All systems depend on moving information. Whether you are running a household, a company, or a country, relaying knowledge is critical.
As institutions grow in size and complexity, new forms of communications become ever more essential. Drums, yodeling, and semaphores have given way to cell towers and the Internet to relay information around our big, curved planet. Complicated systems need network nodes and signaling that transmit knowledge quickly, reliably, and accurately.
Our own bodies also depend on information transfer as well, and thanks to evolution, our biological systems are remarkably well-honed. Millennia of natural selection have left us with internal signaling tuned precisely to deliver the intel our cells need to keep us healthy and functioning.
But, in every system, some new problem always comes along.
This year, it’s COVID. It invades our bodies, commandeers cellular machinery, causes tissue damage, and, most dangerously, hijacks our internal signaling system, invoking a storm of immune agents that fails to kill the virus and instead kills the host—us.
The most straightforward intervention strategy is just to neutralize the interloper: develop a vaccine or a drug that kills off the coronavirus and go back to our normal lives. And many labs around the word, including some at UChicago, are working on that.
But in a situation as potentially cataclysmic as this pandemic, it behooves us to work in tandem on multiple strategies. What if we took a host-centric approach and figured out how to regain control of our internal signaling system so the virus loses the power to cause serious damage?
A huge group of UChicago scientists and clinicians, in areas from cancer to chemistry to pulmonology and more, are already working together on this, and investigators from Northwestern and the University of Illinois at Chicago have now joined them. They are using their vast collective knowledge of cell signaling pathways—the movement of information from one internal “cell tower” to another—and molecular therapies to figure out how to keep the immune system on track after coronavirus infection.
The team’s is a three-step approach. First, survey compounds known to be active at various points in cell signaling, identify those with antiviral potency, and test them on lung cancer cells. This will help them identify “nodes” where the hijacking is happening so they can shore up these weak links in the signaling pathway. This is possible thanks to some fairly new technological approaches known collectively as “omics”: transcriptomics, proteomics, metabolomics. Together, these can show how the cell is responding to environmental stresses: which parts of the cell’s genome are activated, what proteins it’s making (important because viruses need LOTS of proteins to replicate), and what other byproducts are formed.
The next step is to see how these “omics” compare with those in cells actually infected with the coronavirus. To do so, researchers will take cells from healthy patients into the lab and inject them with the virus. The differences and similarities they see between the “omics” of the cancer cells and the COVID cells will tell them a lot about how to proceed. These infected cells will also serve as a substrate for testing the compounds identified earlier, thus sussing out the most promising candidates for drug development.
These first two projects are only possible because the team has access to UChicago’s Howard T. Ricketts Laboratory, one of 13 regional biocontainment facilities in the US, located at Argonne National Laboratory, also managed by UChicago. (As you might imagine, the demand for services at Ricketts has multiplied exponentially over the past few months.)
Once the team has identified compounds active in calming relevant parts of the signaling pathways, they will start testing various drug cocktails in live organisms, at first mouse models. The team will see which can tamp down the “cytokine storm,” the signature, out-of-control immune response to COVID-19 that damages the lungs, and, we are learning, often cardiac and brain tissue as well.
The team started the research with a seed grant from the University’s Big Ideas Generator program, set up specifically for the kind of promising, “out-of-the-box” ideas rarely funded by the government. Now most of the team are borrowing resources from other projects in their individual laboratories to continue the momentum. The landscape is full of researchers desperate for support to see if their approaches can help stop this pandemic, and even once grants are won, getting the money rolled out is slow. So Marsha Rosner, PhD, the leader of this strike force, is hoping for early help from a philanthropic “angel.”
What is unusual about this team—its size, coherent integration, access to unusual laboratory resources, and the infrastructure to make eventual clinical testing possible—suggests they have a better shot at success than most.
The payoffs may be large. Because they are looking closely at the host—our own cells—rather than this specific virus, what this team learns may eventually help protect us from other respiratory viruses. So when the next new problem comes along, we’ll have a better understanding of our immune system and be much better prepared to keep the deaths from mounting.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office.
