Thomas Südhof

Avram Goldstein Professor of Neurosurgery and Professor of Molecular & Cellular Physiology at Stanford. Nobel Prize in Physiology or Medicine, 2013 (with James Rothman and Randy Schekman) — for the synaptic side of vesicle traffic: how neurons release neurotransmitters with millisecond precision. Panelist at Session IV and Session XII.

Current Research

• Pivoted from how a synapse releases neurotransmitter to how connections form — and what goes wrong in schizophrenia and Alzheimer’s
• Frontier: drugs that promote synaptic connectivity rather than just modulating receptors
• Excited about Montara (Kevan Shokat’s brain-only delivery platform, including brain-only LRRK2 inhibitor)

The A-beta Paradox (Session XII)

• Lecanemab made brains essentially plaque-free, yet cognitive decline only slowed by 27%
• iPSC-derived neurons with APP Swedish mutation showed increased synapse density and synaptic events, not loss
• A-beta 40 was never toxic and consistently increased synapse formation; A-beta 42 became toxic only at higher concentrations correlating with aggregation
• The pre-synaptic compartment selectively shrinks before neuron death

Advice to Young Scientists

• “Pursue with enthusiasm, stop with discipline” — his mistakes were all driven by enthusiasm, which he doesn’t regret
• Don’t romanticize the executive role — co-found companies if you must, but only take the CEO seat if you’d genuinely enjoy it

“A-beta is not simply toxic. There’s more going on here than first would be thought when you look at AD pathology.”