# A Genetically Encoded Phosphorescent, Electron Dense Probe for Correlative Light and Electron Microscopy

> **NIH NIH R41** · PHOTON BIOSCIENCES, LLC · 2022 · $299,225

## Abstract

Abstract
The overall goal of this project is to engineer a genetically encoded phosphorescent, electron dense
probe for Correlative Light and Electron Microscopy, or CLEM, that allows a single genetically encoded
tag to be imaged under both modalities, cryogenic light and electron microscopy. This would greatly aid
in modeling cellular structures at sub-nanometer, pseudo-atomic resolution, leading to biomedical innovations
dependent upon understanding 3-dimensional cellular structures at the atomic level. The last decade has
witnessed a “Resolution Revolution” in cryo-electron microscopy (cryo-EM) due to preceding decades of
technical advancement in microscope design, direct electron detecting cameras, sample preparation techniques
and software development1. Combined, these advances have indeed revolutionized the field of structural biology.
However, the revolution is incomplete. The ultimate goal of structural studies is to understand the function,
mechanism and dynamics of macromolecules in vivo. While in vitro studies of isolated complexes represents a
critical progress towards this goal, ideally they should be visualized at high resolution within the context of their
native cellular environments. To this end, cryo-electron tomography allows three-dimensional visualization of
cellular structures, albeit at lower resolution than single particle analysis2. In this technique a tilt series of the cell,
or a slice through the cell, is taken under low dose conditions. The Fourier transforms of the individual images
are then taken to give the back projected image in reciprocal space, where the series of two-dimensional
transforms are then assembled into a single three-dimensional transform of the cellular structure. The three-
dimensional reciprocal space transform of the cell is then re-projected back into real space to give a three-
dimensional view of the cellular structure at low nanometer resolution. To enable proteins to be visualized at
super-resolution within the context of other cellular proteins and organelles, we are developing a genetically
expressible probe that works for both light microscopy and cryogenic electron tomography. This novel and
innovative probe will enable cellular structures to be modeled sub-nanometer resolution, leading to biomedical
innovations dependent upon understanding 3-dimensional cellular structures at the atomic level.

## Key facts

- **NIH application ID:** 10547694
- **Project number:** 1R41GM148117-01
- **Recipient organization:** PHOTON BIOSCIENCES, LLC
- **Principal Investigator:** CHARLES MARTIN LAWRENCE
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,225
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547694

## Citation

> US National Institutes of Health, RePORTER application 10547694, A Genetically Encoded Phosphorescent, Electron Dense Probe for Correlative Light and Electron Microscopy (1R41GM148117-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10547694. Licensed CC0.

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