How Matthew Might Is Using Computation to Fight Rare Diseases

Harry's guest this week is Matthew Might, director of the Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham. Might trained as a computer scientist, but a personal odyssey inspired him to make the switch into precision medicine. Now he uses computational tools such as knowledge graphs and natural language processing to find existing drug compounds that might help cure people with rare genetic disorders.

Might's odyssey began with the birth of his first child, Bertrand, in 2007. Bertrand seemed healthy at first, but soon developed a cluster of symptoms including developmental delay, lack of motor control, inability to produce tears, and epilepsy-like seizures. For more than four years, doctors were unable to diagnose Bertrand's condition. But eventually a technique called whole exome sequencing revealed that he had no functioning gene for NGLY1, an enzyme that normally removes sugars from misfolded proteins. Bertrand, it turned out, was the first person in the world to be diagnosed with NGLY1 deficiency—and as with so many other "N of 1" diseases, there was no known treatment.

After the diagnosis, Matthew and and his wife Cristina decided to used social media and the Internet to locate other patients with NGLY1 disorders around the world. Eventually the couple discovered 70 patients with the condition. Reasoning from first principles about the role of NGLY1, Might discovered that giving Bertrand a sugar called N-acetylglucosamine, a metabolite of NGLY1, helped restore his ability to form tears. (Around the same time Might, co-founded a startup that screened existing drugs to see whether they could treat ion-channel-driven epilepsy similar to what Bertrand experienced; the company was quickly sold to Q State Biosciences.)

Working with collaborators at the University of Utah, Might studied planarian worms that had been engineered to lack NGLY1, and found that those that also lacked a second gene had a higher survival rate. That meant one way to treat Bertrand might be to inhibit the analogous gene in humans, in this case a gene for an enzyme called ENGase. Might used computational screening to look for existing drugs that would be inverse in shape and charge to the catalytic domain on ENGase, and might therefore inhibit it.

He found more than a dozen drugs that were already FDA-approved. One was Prevacid, a proton-pump inhibitor sold as common over-the-counter medication for acid reflux. It turned out that as a previously unsuspected side effect, Prevacid is an ENGase inhibitor. Bertrand started taking the drug, and Might says it was one of the treatments that helped to extend and enrich his life.

Sadly, Bertrand died in 2020 at the age of 12. But by that point, his father’s work to apply computation to basic biology, and thereby speed up the treatment of rare disorders, had sparked a movement that will long outlive him. Years before, Bertrand's story had caught the attention of the Obama administration, which invited Matthew to the White House to work on a range of precision-medicine projects. One was an NIH program called the All of Us initiative, which is collecting the genomes and medical records of a million Americans to search for correlations between mutations and health impacts. Might also launched a smaller pilot program called the Patient Empowered Precision Medicine Alliance (PEPMA) with the goal of repeating what he and Cristina had done for NGLY1 deficiency—that is, quickly diagnose the problem and identify possible treatments.

Might resigned from his White House role about one year into the Trump administration, then got an offer from University of Alabama to come to Birmingham to set up an institute to scale up the PEPMA idea. One project there called mediKanren involves using logic programming to highlight what Might calls the "unknown knowns" in the medical literature and identify existing, approved drugs that might treat rare disorders.

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