David Sinclair: Computational Screening Narrowed One Trillion Molecules to 200 Candidates for Cell Testing

David Sinclair: Computational Screening Narrowed One Trillion Molecules to 200 Candidates for Cell Testing

On August 7, aging researcher David Sinclair described his search for a single compound to replace a cellular cocktail on the Joe Rogan Experience podcast. Computational screening narrowed the field to 200 candidates, which his team planned to test in human cells.

The search for a single molecule grew out of work on OSK, a combination of three proteins that alter gene activity. In a 2020 paper, Sinclair's group activated OSK in mouse retinal cells and tested whether the cells regained younger characteristics, damaged neuronal projections regrew, and vision improved in a glaucoma model. This combination became the starting point for finding a single molecule that could perform several of the same functions in a cell.

In his conversation with Joe Rogan, Sinclair defined the goal more precisely: a single molecule would need to perform three or four of the cocktail's functions in a cell. A computer first narrows the vast number of possibilities to a list that can be tested in the laboratory.

To do this, the team used computational methods to match potential molecules with enzymes, which are proteins involved in cellular chemical reactions. Sinclair estimated that the work took several months and would have required about 160 years without computational screening. The analysis left 200 compounds for the next experiment.

“This funnel is filled with a trillion molecules, and we need to get down to one,” Sinclair says.

The team planned to test these 200 compounds in human cells. This experiment was intended to show whether any candidate could perform several of the cocktail's functions in a cell.