Conference Presentation, Lecture
Matt Might: The Algorithm for Precision Medicine
- Matt Mite is the director of the Hugh Call Precision Medicine Institute at the University of Alabama (UAB), holding endowed chairs in Personalized Medicine and Professorships in Internal Medicine and Computer Science, despite lacking formal medical training.
- Mite asserts that data is the "greatest drug of the 21st century" and defines precision medicine as a computational optimization process using big data to deliver the right treatment to the right patient at the right time.
- The speaker claims that for precision medicine recommendations to be actionable, they must be accompanied by a logical proof explaining the mechanism, a requirement driven by physician legal liability and skepticism of "black box" AI.
- Mite's work began with his son Bertrand, who suffered from undiagnosed NGLY1 deficiency characterized by seizures, developmental delay, and an inability to produce tears, leading to corneal damage.
- Exome sequencing (analyzing the 2% of the genome encoding proteins) identified two syntax-error-like mutations in the NGLY1 gene: a stop codon insertion and a frameshift deletion, causing a loss of the enzyme responsible for de-glycosylating misfolded proteins.
- To treat the resulting deficiency, Mite administered N-acetylglucosamine (a sugar supplement) to Bertrand, which resulted in the patient producing tears for the first time at age 4; subsequent trials on genetically modified flies showed an 80-90% survival rate improvement with the sugar.
- Mite co-founded a company for ion channel-driven epilepsies, acquired by Q-State Biosciences, and identified the existing drug Prevacid (pantoprazole) as an inhibitor of the ENGASE gene, a compensatory target found via computational docking of 200,000 compounds against 14 FDA-approved drugs.
- Bertrand has shown significant gains in development and communication while on Prevacid, and the UAB Institute now uses this drug repurposing strategy for other patients.
- Mite collaborated with the White House on the Precision Medicine Initiative, leading to the "All of Us" program, which aims to correlate a million genomes with medical records to build a "Rosetta Stone" of the human genome.
- The UAB Institute employs a "Research Consultation Service" where undergraduates act as a scalable workforce to analyze patient data, utilizing a knowledge graph called "Medicanon" built from 30 million medical abstracts via Natural Language Processing (NLP).
- The institute's algorithm follows a logic chain: identify the core mutation, determine if a mechanism is overactive (inhibit), underactive (activate), absent (compensate), or toxic (eliminate).
- Successes of this undergraduate-led service include:
- Recommending carnitine supplements for a patient with a TMLHE mutation, reducing seizures from frequent to none.
- Identifying Celecoxib as a treatment for a RhoBTB2 gain-of-function mutation, leading to improved alertness in a patient in Brazil.
- Prescribing high-dose Vitamin A to a patient with a MAPK8IP3 mutation, enabling a non-walking child to stand and walk.
- The system successfully diagnosed and treated intractable cyclic vomiting in a 19-year-old woman (weight 78 lbs) by ranking obscure literature to identify inhaled isopropyl alcohol, resulting in weight gain to 125 lbs and remission after years of daily vomiting.
- Medicanon recently generated a logic proof recommending sulforaphane (found in broccoli) for Bertrand to upregulate the NRF2 pathway as compensation for inactive NRF1 in NGLY1 deficiency.
- During a life-threatening septic shock episode with negative cultures, Mite used Medicanon to rank potential diseases by symptom constellation and applied metagenomics to blood and lung samples.
- Metagenomic analysis revealed a specific overrepresentation of Pseudomonas in lung tissue (rising from 2% to 13% after cell lysis) and E. coli, prompting treatment with the antibiotic Meropenem.
- Bertrand survived the septic shock, was discharged from the ICU, and is scheduled to enter a clinical trial for NGLY1 deficiency at the Mayo Clinic starting in two weeks.
- Mite emphasizes that "nothing is non-actionable," asserting that even when no drug exists, the scientific process of running experiments and generating data is always the path forward.