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by Elise Wachspress with Peter Wang

Before COVID, before the Spanish flu, there was another highly infectious pulmonary disease that also changed entire countries and societies.

Tuberculosis, however, has been with us since antiquity. Like COVID, TB travels from person to person in droplets or aerosols. Caused by a mycobacterium, the disease was the most common cause of death in the nineteenth century. Populations who lived or worked in very close quarters—like migrants traveling in the holds of ships or poor people stacked in urban tenements—were the most vulnerable. But “consumption” was also somehow considered “romantic,” a wasting disease that also felled many writers and artists, the young John Keats famously among them. In fact, Edvard Munch’s “Sick Child,” above, documents his own sister dying of TB at age 15.

The advent of antibiotics made a big impact in curing the disease. But the mycobacteria that cause TB have evolved resistance, and poverty is still endemic around the world. The sad fact is that the disease still kills a million and a half people every year. That’s why the Bill and Melinda Gates Foundation is interested in TB research. One of the scientists whose work they support is UChicago’s Luis Barreiro, PhD.

Before antibiotics, French scientists Albert Calmette and Camille Guerin had already developed a vaccine against TB. In a way, it was similar to how the smallpox vaccine was developed from the much-less-virulent cowpox: Calmette and Guerin developed a vaccine for TB from a much less lethal bacterium also found in cows.

But BCG works unlike other vaccines. Most train the adaptive immune system, the specialized, “intelligent” commandoes that home in on very specific molecular targets. BCG also seems to affect the body’s innate immune system, a generalized assembly of cellular fighters once thought to be pretty untrainable. One clue is that BCG given in infancy or early childhood seems to reduce vulnerability to a whole range of diseases, not just TB.

And people now suspect that COVID-19 may be one of these.

Barreiro was working on TB and BCG long before the coronavirus reared its ugly head. He is developing the evidence that BCG ends up in the bone marrow, where it changes the epigenetics—the chemical “decorations” that hang off the basic structures of DNA and RNA—of the stem cells developing there. It creates something like a boot camp where newly emerging macrophages—the infantry grunts that rush to the front as part of the innate immune system—become better fighters against multiple diseases at once.

So the Gates Foundation is funding Barreiro’s research to understand whether this mechanism works in humans as it does in mouse models. In low-to-middle-income countries with high rates of TB and other infections, BCG is still given in infancy or early childhood and is known to reduce neonatal mortality for all causes. The Gates Foundation, focused on reducing TB in those countries, wants to understand how BCG works and if that knowledge can help scientists develop an even better vaccine.

One of Barreiro’s special talents in this quest is his abilities with “single-cell” technologies, because you can’t really characterize how different macrophages are working by looking at an “average” of their epigenetics and the “average” interactions they have with intruders. Barreiro uses automated processes that can look at individual cells—a lot of them, very quickly—to generate a fine-grained picture of how BCG vaccination fosters epigenetic variations in certain macrophages that allow these cells to fight many diseases.

Maybe even COVID.

As several recent journals have reported, there is growing evidence that countries with national BCG childhood vaccination programs have a much lower incidence of severe disease and death from COVID. So by developing an understanding of how BCG works, Barreiro and his team may generate important clues in protecting people from our latest scourge.

Science can’t, shouldn’t, won’t sit still and wait to address the next crisis. The work on TB (done centuries ago) and single-cell technologies (perfected over the past few years) may provide the answers to a crisis we didn’t even know we’d have to face.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office. Peter Wang is a second-year undergraduate student in The College.