How 8 Scientists Are #ImagingTheFuture with Cutting-Edge Tech

Learn how CZI grantees are developing technology to revolutionize the field of imaging

Cutting-edge imaging tools can help scientists around the world visualize cells, organs, and entire systems within the human body — which can lead to breakthroughs in our understanding of health and disease. That’s why CZI’s Imaging program is focused on supporting and building new technologies — both hardware and open source software — capable of observing biological processes in action across spatial scales.

This #ImagingTheFuture Week, we’re highlighting some of our incredible imaging grantees, who are building tools to help advance biomedicine and scientific research. Read on to learn about 8 projects that are #ImagingTheFuture to reveal the inner world of our cells.

Cost-Effective, High Resolution Correlative Light and Electron Microscopy

This image shows the same area imaged by two methods, electron microscopy (the greyscale image) and light microscopy (the colorful insert). This demonstrates how correlative light and electron microscopy (CLEM) visualizes the structures of cells, whilst also revealing the location of specific proteins that may be involved in disease states. Courtesy of Lucy Collinson.

Correlative light and electron microscopy (CLEM) is a highly-specialized microscopy technique that preserves the structure of cells whilst also revealing the location of proteins, which can give clues as to their function in health and disease. Because of the complexity of the technique, it has traditionally relied on expert analysis and expensive equipment. VP-CLEM-KIT, developed by Lucy Collinson and team, is democratizing the field by developing a cost-effective pipeline for high-resolution CLEM that can be implemented in any light microscopy facility. VP-CLEM-KIT will not only enable CLEM research at smaller institutions, but will also have field applications — bringing advanced electron microscopy to more biologists and researchers across the globe.

Building a Microscope to View All Information in the Electron Beam

A laser-phase contrast electron microscope showing (from left to right) control system, laser rack, laser input optics, microscope column, laser output optics. Courtesy of Holger Müller.

Laser phase plate (LPP) technology provides the unique ability to extract the maximum amount of information that is physically present in an electron microscope’s beam for most biological specimens, which are so-called weak phase objects. This makes it a critical focal point for cutting-edge research. Current applications of this technology, however, are limited. Holger Müller and the team at the University of California, Berkeley, originally realized this technology and are now working to integrate the LPP into a state-of-the-art electron microscope, which would enable high-throughput data acquisition and optimize the existing design to account for flaws in already captured images. The microscope will improve the signal-to-noise ratio, allowing researchers to obtain 3D, high-contrast images of proteins in a cell or tissue to visualize in atomic resolution how these molecules work together.

Arboretum Plugin to Track How Our Cells Are Related

Arboretum, a plugin for napari that shows cell lineages, in action. Courtesy of Alan Lowe.

napari is a community-built, Python-based, open-source tool designed for browsing, annotating, and analyzing large multi-dimensional images. CZI both funds and helps build napari and the napari hub database of napari plugins, including Arboretum, which helps scientists better understand the interconnectedness of systems at the cellular level. Developed by Alan Lowe and team at University College London, Arboretum shows a “family tree” for a given sample of cells, indicating which are alike, and to what degree. The applications for this program go far beyond the cellular level — they can help scientists understand how disease states, samples, or even how entire biological systems are related.

Chip-Scale Light Sheet for High Spatiotemporal Resolution Imaging

A color-coded 3D projection of computationally separated cells from the eye of a developing zebrafish embryo as imaged using a lattice light-sheet microscope with adaptive optics. Courtesy of Gokul Upadhyayula.

Aseema Mohanty and Gokul Upadhyayula are pushing the field of microscopy by developing a rapidly reconfigurable nanophotonic chip to generate optical lattices for ultra-thin, light sheet-based volumetric imaging of subcellular processes. Their Chip-based Lattice Light sheet Microscope (ChiLL Microscope, currently under development, will enable flexible, simplified, compact and low-cost implementation of high-resolution microscopy. The ChiLL Microscope’s nanophotonic chip also allows for customization to a researcher’s unique imaging needs. This will expand access to advanced imaging techniques, enabling more researchers to view biology in action at high resolution.

HiP-CT Technology Images with Near Cellular Resolution Larger Samples Than Ever Before

HiP-CT technology shows damage to a COVID-19 victim’s lung, shedding new light on Long COVID. Image courtesy of Paul Tafforeau, data from UCL led ESRF beamtime 1252.

High-resolution x-ray tomography provides useful images of microstructure, but only over a very small field of view — often only for millimeter-sized tissue samples. Peter Lee and team are changing this. They’ve co-developed with ESRF Hierarchical Phase-Contrast Tomography (HiP-CT) technology that images larger specimen sizes with the same resolution as small x-ray tomography samples. This allows us to image intact human organs at near cellular resolution, providing us with the ability to link microscopic features to macroscopic consequences. This technology has already been used to visualize the impact of COVID-19 on lung health ex vivo, indicating areas of health and damage on a larger and more detailed scale than previously possible and providing clues to what causes Long COVID.

Using Deep Learning to Augment Scientists’ Expertise

An image showing the annotation interface via napari for napari-annotatorj. Courtesy of Réka Hollandi.

Sorting, categorizing, and labeling 2D images can be difficult and time-consuming for researchers working at the microscopic level. Réka Hollandi developed the napari-annotatorj plugin as an easy and quick way to add annotations to any 2D image. The technology uses deep learning-based contour suggestions to assist with annotations, with an interface that doesn’t require expertise in computer science. Not only does Réka’s plugin help researchers better understand biology at the cellular level, it has the potential to annotate and classify images for a wide variety of fields, from vehicle dash-cam footage to industrial pipeline monitoring.

High-Speed Photoacoustic Imaging in Glassfrogs

Photoacoustic imaging of circulating red blood cells within a glassfrog. The anesthetized frog (right) indicates the normal distribution of blood in the frog, and the sleeping frog (left) indicates how glassfrogs store blood in their liver while sleeping to become translucent and avoid predators. Courtesy of Junjie Yao at Duke University.

Photoacoustic imaging can provide high-resolution imaging at centimeter depth noninvasively, but has been limited by acoustic diffraction, which has led to an inability to take images at a cellular level. Grantees Junjie Yao and Vladislav Verkhusha have developed a comprehensive toolbox to enhance photoacoustic imaging, breaking the previous resolution limit and enabling never-before-seen depth and clarity of images. Their technology was recently applied to better understand how the glassfrog turns itself nearly invisible when sleeping to avoid predators. Using Yao and Verkhusha’s photoacoustic imaging technology, researchers found that glassfrogs store their blood in their liver while sleeping, draining it from areas of the body where it might be visible to predators. Yao and Verkhusha’s advanced imaging technology has enabled discoveries that have exciting potential human applications.

Enabling a New Type of Microscopy for Ultradeep Imaging

By measuring the nonlinear distortion matrix, scientists can image deep within tissue at a higher spatial resolution. Courtesy of Randy Bartels.

Imaging at high spatial resolution can be difficult, as it requires the coherent addition of a wide range of spatial frequencies. Randy Bartels and team are pushing the bounds of imaging tissues to depths by enabling a new type of microscopy. By measuring a nonlinear distortion operator, they can suppress multiply scattered light that degrades image quality. This, in turn, allows high-resolution imaging at significantly greater depths, enabling scientists to see fine details that they have never been able to visualize before.

By advancing imaging hardware and software, we’ll unlock new understanding about how our cells interact with one another in real time within our bodies — ultimately making it possible to cure, prevent or manage all diseases. Learn more about our imaging work.