Henry M. Colecraft
Growing up in Ghana in the 1970s, Henry M. Colecraft loved to read Sherlock Holmes mysteries; the intrigue, logic, outside-the-box thinking, and sense of discovery thrilled him. It wasn't until he was an undergraduate physiology student at King's College London that he realized science was full of mysteries just as enticing as those he'd read about as a child.
Those scientific mysteries have just taken a bit longer to solve.
Colecraft has spent the past decades-with Holmes-like creativity and tenacity-inventing new ways to manipulate molecules inside living cells, with the goal of treating conditions as wide-ranging as cystic fibrosis, chronic pain, and inherited heart disease. Now, his "Case of the Diseased Ion Channels" is nearly closed. In recent years, the inventions have succeeded in proof of principle studies, and Colecraft has co-founded two startup companies to further develop the approach and bring it toward clinical trials in patients.
"A lot of rare diseases don't get interest from big pharma because of economic considerations, but we think this provides academic labs like ours an opportunity to make a big impact on them," says Colecraft, who is the John C. Dalton Professor of Physiology & Cellular Biophysics and professor of pharmacology. "The ability to work toward these treatments really keeps me excited, but beyond that there's also the thrill of discovery."
The problem with ion channels
After graduate school, Colecraft was drawn to the mysteries surrounding the channels, pumps and transporters that move necessary materials across the cell membrane, into and out of the cell.
Ion channels, which allow charged molecules to cross the fatty lipid membrane, are particularly critical. The ions that pass through the channels enable heart, brain, and muscle cells the ability to conduct electrical signals needed to accomplish their jobs. "Science is such an incredibly exciting journey. You can be the first to observe something that has a real impact on society, but then there are always more questions to tackle and discoveries to be made."
"They're really beautiful molecular machines," says Colecraft, who started studying ion channels during a postdoctoral fellowship at Johns Hopkins University School of Medicine. "I was very interested at a fundamental level in understanding how an ion channel works and how their activities are regulated to change physiological states."
Ion channels also malfunction in so many diseases, including epilepsy, cystic fibrosis, and some cancers.
"On the surface, these are all very different diseases," he says, "but in many instances they have the same underlying biological problem: not enough functioning ion channels. What if there was a general way to solve that basic problem and apply it to many different conditions?"
That puzzle set the stage for Colecraft's research as he opened his own lab at Johns Hopkins and then, beginning in 2007, at Columbia.
Manipulating "The Queen of Biological Molecules"
A clue to solving the puzzle came to Colecraft when it dawned on him that many mutant ion channels are trapped inside the cell, unable to get to the surface where they function. These mutant channels are marked with a molecule flag, called ubiquitin, that also marks normal channels destined for removal or recycling. The fewer ubiquitins on an ion channel, the longer it sticks around and properly moves ions.
Colecraft and his students wondered whether stripping ubiquitin from mutant channels would rescue them and allow them to complete their journey to the cell surface to regain function."I call ubiquitin 'The Queen of Biological Molecules' because it really controls the life and death of every other protein."
"I call ubiquitin 'The Queen of Biological Molecules' because it really controls the life and death of every other protein," says Colecraft. "My lab realized that this gave ubiquitin an awesome power when it came to ion channels and all other proteins."
Removing ubiquitin from ion channels, he hypothesized, could boost the number of channels on a cell's surface, while adding ubiquitin could lower the number of ion channels. The challenge: Ubiquitin is aptly named for its ubiquity-it is found in cells throughout the entire body and controls expression of essentially every protein. Increasing or decreasing ubiquitin on many proteins at once could be disastrous.
Over the past five years, however, Colecraft and his team developed a method to remove ubiquitin from select ion channels. They connected a natural ubiquitin-removing protein to tiny antibodies (called nanobodies) that only recognize specific ion channels. That meant ubiquitin would only be erased from those channels, not all of the proteins in a cell.
They first tested the technique in heart cells impacted by an inherited disease called long QT syndrome, in which potassium ion channels don't work well. Their tool, enDUBs (for engineered deubiquitinases), restored the healthy function of the heart cells. Compared to the diseased cells, more functioning potassium channels were embedded in the membranes of the enDUB-treated cells. Since then, the lab has also used the approach to treat lung cells affected by cystic fibrosis and to change the number of ion channels in brain cells.
"The exciting thing is that this is an incredibly generalizable approach," says Colecraft. "You can take these enDUBs and use them to remove ubiquitin from other proteins that you want to stabilize."
Toward patients
When lab work slowed down during the COVID-19 pandemic, Colecraft took advantage of the lull to speed the translation of his work to patients: He founded two companies, Stablix Inc. and Flux Therapeutics, to commercialize targeted protein stabilization. Each company uses a different approach to alter ubiquitin inside living cells. With the help of Columbia Technology Ventures, Colecraft and one of his students began pitching both ideas to investors and raised tens of millions of dollars. That funding will support preclinical research on small molecules for targeted protein stabilization as well as enDUBS and, hopefully, clinical trials in the future.
While Colecraft is not involved in the day-to-day operations of Stablix or Flux, he remains a scientific advisor for both companies and continues-in his own lab-to work on studying how enDUBs can treat disease."The exciting thing is that this is an incredibly generalizable approach. You can take these enDUBs and use them to remove ubiquitin from other proteins that you want to stabilize."
Recently, a Columbia neurologist reached out about a patient who was born with a rare form of intellectual disability and epilepsy. Genetic sequencing revealed that the disease was caused by mutations in an ion channel. Now, Colecraft is collaborating with the neurologist to understand the consequences of the mutations on brain function and how enDUBS might be able to help treat the disease.
"The potential to apply what I'm doing to really make an impact in medicine and people's lives is exciting and an important part of what drives us forward," Colecraft says.
In December 2023, Colecraft was elected to the National Academy of Inventors in recognition of his development of enDUBS and related technologies. But like Sherlock Holmes uncovering a new mystery just as he finishes solving an old one, Colecraft's scientific inquiry is far from over.
"Science is such an incredibly exciting journey," he says. "You can be the first to observe something that hopefully has a real impact on society, but then there are always more questions to tackle and discoveries to be made."
