When people hear botulinum toxin, they often think of either the cosmetic that makes frown lines disappear or the deadly poison.
But the “miracle poison,” as it’s also known, has long been approved by the F.D.A. to treat a suite of maladies like chronic migraines, uncontrolled blinking, and certain muscle spasms. And now, a team of researchers from Harvard University and the Broad Institute have, for the first time, proved they can rapidly evolve the toxin to target a variety of different proteins, creating a suite of bespoke, super-selective proteases with the potential to aid in neuroregeneration, regulate growth hormones, calm rampant inflammation, or dampen the life-threatening immune response called cytokine storm.
“In theory, there is a really high ceiling for the number and type of conditions where you could intervene,” said Travis Blum, a postdoctoral researcher in the Department of Chemistry and Chemical Biology and first author on the study published in Science. The study was the culmination of a collaboration with Min Dong, an associate professor at Harvard Medical School, and David Liu, the Thomas Dudley Cabot Professor of the Natural Sciences, a Howard Hughes Medical Institute Investigator, and a core faculty member of the Broad.
Together, the team achieved two firsts: They successfully reprogrammed proteases — enzymes that cut proteins to either activate or deactivate them — to cut entirely new protein targets, even some with little or no similarity to the native targets of the starting proteases, and to simultaneously avoid engaging their original targets. They also started to address what Blum called a “classical challenge in biology”: designing treatments that can cross into a cell. Unlike most large proteins, botulinum toxin proteases can enter neurons in large numbers, giving them a wider reach that makes them all the more appealing as potential therapeutics.
Now, the team’s technology can evolve custom proteases with tailor-made instructions for which protein to cut. “Such a capability could make ‘editing the proteome’ feasible,” said Liu, “in ways that complement the recent development of technologies to edit the genome.”
Current gene-editing technologies often target chronic diseases like sickle cell anemia, caused by an underlying genetic error. Correct the error, and the symptoms fade. But some acute illnesses, like neurological damage following a stroke, aren’t caused by a genetic mistake. That’s where protease-based therapies come in: The proteins can help boost the body’s ability to heal something like nerve damage through a temporary or even one-time treatment.
Scientists have been eager to use proteases to treat disease for decades. Unlike antibodies, which can only attack specific alien substances in the body, proteases can find and attach to any number of proteins, and, once bound, can do more than just destroy their target. They could, for example, reactivate dormant proteins.