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C. Shan Xu, PhD

Harvey and Kate Cushing Professor of Cellular & Molecular Physiology
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Contact Info

Cellular & Molecular Physiology

PO Box 208026, 333 Cedar Street

New Haven, CT 06520-8026

United States

About

Titles

Harvey and Kate Cushing Professor of Cellular & Molecular Physiology

Biography

C. Shan Xu graduated from the University of Science and Technology of China and obtained his Ph.D. in physical chemistry from the University of California, Berkeley in 1997. Xu went on to serve as a technical director at Lam Research Corporation, where he oversaw research, development, and dissemination of cutting-edge semiconductor technologies. In 2009, he joined the Janelia Research Campus of Howard Hughes Medical Institute to develop enhanced focused ion beam-scanning electron microscopy (eFIB-SEM). In 2022, Xu joined Yale School of Medicine as a Harvey and Kate Cushing Professor in the Department of Cellular and Molecular Physiology.

In addition to his contributions to technology development, highlighted by more than twenty patents, Xu is known for his innovation and leadership in transforming conventional FIB-SEM from a lab tool that is unreliable for more than a few days to a robust imaging platform with 100% effective reliability: capable of years of continuous imaging without defects in the final image stack. The enhanced FIB-SEM technology has enabled significant discoveries in tissue biology, cell biology, and neuroscience where nano-scale resolution coupled with meso and even macro scale volumes is critical. It enabled the largest and most detailed Drosophila brain connectome in 2020, and created the first open-access, 3D atlas of whole cells and tissues at the finest isotropic resolution of 4-nm voxels in 2021.

Xu lab focuses on pushing the boundaries of volume electron microscopy. A primary goal is to break through the existing SEM resolution limit, a critical milestone that will connect two seemingly disparate fields: structural biology and cell biology. This pioneering effort aims to enable researchers to explore and understand architectural intricacies across multiple scales, from the molecular level, through organelles, up to entire cells, all within their native tissue environments.

Appointments

Education & Training

PhD
University of California at Berkeley, Chemistry (1997)
BS
University of Science and Technology of China, Physical Chemistry (1992)

Research

Overview

Google Scholar: Profile

Conventional FIB-SEM

Focused ion beam scanning electron microscopy (FIB-SEM) has been used in materials science and the semiconductor industry for decades, with applications in biological imaging emerging since 2006. The conventional systems, however, offer slower imaging speeds and lack of long-term system stability, limiting their acquisition volume to less than 103 µm3.

Enhanced FIB-SEM (eFIB-SEM)

We redesigned the system architecture and transformed FIB-SEM from a conventional system lacking long term reliability to a robust imaging platform with 100% effective reliability. This enhanced FIB-SEM (eFIB-SEM) technology expands the maximum imageable volume by more than five orders of magnitude and achieves the finest isotropic voxel resolution at 4 nm (Xu et al., eLife 2017; US patent 10,600,615; Xu et al., Nature 2021). By combining with super-resolution fluorescence imaging, the CLEM applications unleash the full potential of intracellular organelle identification with labeling insights.

Using the eFIB-SEM platform, we generated the largest and most detailed connectome in 2020, highlighted in Nature & The New York Times. Additionally, we established the first open access, 3D reference library of whole cells and tissues at the finest isotropic resolution, featured in Nature & TheScientist.

By coupling nanoscale isotropic resolution with meso- and macro-scale volumes, the enhanced FIB-SEM pipeline (Pang & Xu, 2023) ushers in a new era of high-resolution large volume electron microscopy to reveal the structure-function relationships in biology. This is demonstrated by over 40 publications since the technology's debut ( Xu et al., 2017), including Nature (Xu et al., 2021; Heinrich et al., 2021; Parlakgül et al., 2022; Obara et al., 2024), Science (Nixon-Abell et al., 2016; Gao et al., 2019; Hoffman et al., 2020; Ritter et al., 2022), and Cell (Ioannou et al., 2019; Weigel et al., 2021; Sheu et al., 2022), and Neuron (Handler et al., 2023), etc., contributing more than 5,000 citations over the past five years.

Beyond enhanced FIB-SEM

Despite how much the enhanced FIB-SEM technology has contributed, the 4-nm isotropic resolution falls short of robust visualization of 3D ultrastructure of sub-10 nm features. My lab aims to transcend the SEM resolution limit that has persisted for 80 years. Such a technology does not currently exist. With success, it will bridge the fields that are currently not connected: structural biology and cell biology, in the context of probing architecture across scales from protein to organelle to cell, within its native tissue environments.

In addition, we contemplate a 3D cryo-FIB-SEM technology that can reliably image a block of vitreously frozen cells or tissues with good contrast and without the need of heavy metal staining, dehydration, and plastic embedding. This streamlined approach will offer the potential to bypass tedious EM sample preparation needed to be individually optimized for large variety of tissues from different species. Most importantly, it allows the volume EM to unveil the fine details of cells and tissues in their native states.

Medical Research Interests

Biophysics; Engineering; Imaging, Three-Dimensional; Microscopy, Electron; Neurosciences; Physiology

Research at a Glance

Publications Timeline

A big-picture view of C. Shan Xu's research output by year.
49Publications
5,783Citations

Publications

Featured Publications

Get In Touch

Contacts

Academic Office Number
Mailing Address

Cellular & Molecular Physiology

PO Box 208026, 333 Cedar Street

New Haven, CT 06520-8026

United States

Locations

  • Sterling Hall of Medicine, B-Wing

    Academic Office

    333 Cedar Street, Ste BE36A

    New Haven, CT 06510