How Matthew Might Is Using Computation to Fight Rare Diseases

<p>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.</p><p>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.</p><p>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.)</p><p>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 migh