Alex Pollen, PhD

Prize Winner

Position

Associate Professor Neurology

Prize

MIND Prize

Cohort

2024

Program

MIND Prize

Institution

University of California, San Francisco

Website

www.pollenlab.org

Project

Dissecting Mechanisms of Human Neurodegeneration through an Evolutionary Lens

Vision

We envision that genetic, molecular, and cellular studies of the origin of human brain specializations will illuminate therapeutic targets and underlying mechanisms of neurological disorders that are enriched in humans compared to other primates. Such studies are now possible by combining stem cell models and interspecies brain organoids with genetic and pharmacological perturbations.

About

The Pollen lab combines advances in single cell genomics, genome engineering, and great ape cerebral organoids to study specialized features and vulnerabilities of the human brain. This research program builds on a longstanding interest in studying the evolution of brain structure and function. As an undergraduate at Harvard, Dr. Alex Pollen studied comparative neuroanatomy among cichlid fish in Lake Tanganyika with Hans Hofmann. Their fieldwork 10 miles from the chimpanzees at Gombe inspired Dr. Pollen to study the human brain from a comparative perspective. Dr. Pollen next trained in evolutionary genetics and neuroscience during his PhD studies with David Kingsley at Stanford University and in stem cell biology and cortical development during his postdoctoral studies with Arnold Kriegstein at UCSF. As a postdoctoral fellow, Dr. Pollen identified molecular specializations of outer radial glia that may contribute to the developmental and evolutionary expansion of the cerebral cortex. Recently his lab identified developmental mechanisms contributing to the evolution of novel cell types in the primate brain and established a CRISPR-based strategy for discovering human-specific vulnerabilities. Ultimately, the lab aims to illuminate molecular mechanisms contributing to human origins and to identify therapeutic targets in selectively vulnerable neurons. His research has been recognized by support from the NIH New Innovator Award, the Innovative Genomics Institute, the Schmidt Futures Foundation, the New York Stem Cell Foundation, and the Pershing Foundation.

The potential for innovation is greatest when new concepts are combined with new techniques.

Many neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease are enriched in humans compared with other primates. While current genetic and neuropathology approaches focus on variation among humans, we propose to interrogate human-specific changes that may confer vulnerabilities to all humans. We hypothesize that recent evolutionary tradeoffs created a mismatch between ancestral cellular functions and demands on vulnerable cell types in the human brain. We will test this hypothesis by developing cellular models of candidate “vulnerable joints” in the brain, focusing on neuronal populations whose projections and target regions have expanded disproportionately. By employing comparative genome engineering screens, we will further identify human-specific genetic vulnerabilities. Finally, we will test the hypothesis that compensatory adaptations evolved in human neurons that may buffer these evolutionary tradeoffs, representing candidate therapeutic targets.

The MIND Prize will allow us to systematically interrogate genes and compounds linked to neurodegenerative disorders enriched in humans using cellular models and genome engineering screens.