Longzhi Tan, PhD

Prize Winner

Position

Assistant Professor Neurobiology

Prize

MIND Prize

Cohort

2024

Program

MIND Prize

Institution

Stanford University

Website

3dgeno.me

Project

How Does 3D Genome Architecture Shape the Aging and Degeneration of the Brain?

Vision

How do cells in our brain develop highly specialized functions, and how do they degenerate as we age? Genome architecture—the 3D folding of 2 meters of DNA into a 10-μm nucleus to control the activity of genes—plays a critical role in aging and neurodegeneration. To measure this intricate structure, I built an optics-free “microscope” that uses DNA sequencing to measure pairwise distances between molecules, solving the first 3D structure of our genome and discovering highly specialized genome architecture across the body and across the life span. Taking this technology to the next level, I aim to uncover the fundamental principles of how DNA folds and controls brain functions, filling in the mysterious link between genome architecture and neurodegeneration. Beyond the brain, my discoveries and technologies will be widely applicable to many areas of biomedicine such as cancer and immunology, enabling deeper understanding and better engineering of the human genome and paving the way for “precision 3D genome medicine.”

About

Originally from Wuhan, China, Tan received his S.B. in Physics (minor: Biology) from MIT in 2012, studying microbial and human evolution with Jeff Gore and Pardis Sabeti. He earned his Ph.D. in Systems Biology from Harvard in 2018, developing high-precision methods for single-cell genomics with Sunney Xie. He uncovered the 3D structure of the human genome in a single cell, revealed unique chromosome organization in the mouse eye and nose, and measured the true mutation spectrum of single neurons in the normal human brain. Tan also attended the Neurobiology course at MBL in 2014 and worked with Ibrahim Cisse at MIT in 2019. As a postdoc in Karl Deisseroth’s lab at Stanford Bioengineering (co-mentor: Howard Chang), Tan discovered major 3D genome transformation in the mouse brain after birth. Tan started his own lab at Stanford Neurobiology in Dec 2022, and discovered evolutionarily conserved 3D genome restructuring over the life spans of both humans and mice. Tan’s awards include PSF MIND (2024), Sanofi iAward (2024), HHMI FHS Finalist (2023), Baxter (2023), BWF CASI (2021), ISFS (2021), Berry (2020), Science & SciLifeLab Grand Prize (2019), HHMI ISRF (2015), and IPhO Gold Medal (2008). Outside the lab, he enjoys designing holiday cards, t-shirts, and music videos, and is a scientific illustrator.

My innovation comes from combining high-precision technologies across the fields of single-cell genomics, neuroscience, computational biology, and evolutionary biology to solve a fundamental physical mechanism of aging and degeneration.

We seek to learn the rules that govern how 6 billion base pairs of DNA folds into the tiny nucleus of each brain cell to dictate gene expression patterns across life. By developing a lens-less "microscope" that uses DNA sequencing to measure distances between molecules, my lab discovered that each type of cells folds their genome in a signature way that changes progressively over 100 years.

"The MIND Prize will allow me to pursue high-risk, cross-discipline research at the forefront of genomics and neuroscience: building the next generation of “biochemical microscopes” to precisely measure and manipulate the 3D genome architecture of individual cells in a living brain."

By learning the fundamental principles of genome organization, my project may pave the way for precisely rewiring DNA in 3D to revert Alzheimer's progression and slow aging.