Expanding the Frontiers of Imaging

New RFA Supports Technology Development for Understanding Life at the Cellular Level

The microscope was invented in the 16th century, but it took another 200 years for scientists to appreciate its role in medicine. The invention of the X-ray machine in 1895 was another breakthrough that solidified the important role of imaging in human health diagnostics. Further advances in imaging technology — such as magnetic resonance imaging (MRI), computerized tomography (CT) scans, and ultrasound — have allowed us to explore the inner workings of the human body to amazing extents. CT scans have been used to diagnose cases of coronavirus by revealing white spots on the lung, while MRI scans allow clinicians to diagnose tumors and certain sports injuries like a torn ACL. Yet to cure, prevent, or manage all diseases by the end of the century, we need a much deeper mechanistic understanding of biological systems.

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Current tools provide a limited view of biological systems and tend to focus on a specific biological scale (such as proteins, cells, or tissues) in an often artificial context, like isolated proteins or extracted cells. To advance the field of imaging, we need to push the boundaries of what biological processes we can visualize and measure. This means imaging across biological scales and in the necessary context, such as viewing protein interactions inside a cell or cell signaling in the living system — tasks that are mostly beyond current capabilities.

Overcoming existing barriers to visualization and measurement will require significant technical and computational advances. New, high-resolution imaging technology could allow researchers to watch cell division or growth, such as tumor growth, deep within the human body in real time and in a minimally invasive way. Such advances would open up new insights for understanding cellular processes, and for developing treatments and cures for many diseases.

Discussing the State of the Science

To understand how to help advance the imaging field, we spoke with dozens of experts, attended conferences, and hosted two workshops in November 2019 and January 2020. These workshops brought together imaging scientists, engineers, physicists, mathematicians, computer scientists, and biologists from all over the world.

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Participants of the Electron Microscopy Workshop in November 2019.

Workshop participants identified four major facets of imaging technology that must be supported today in order to enable breakthroughs in our understanding of complex biological systems:

  • A universal method to enable cellular or even sub-cellular resolution for imaging deep in tissues;
  • The ability to observe proteins in cells and monitor changes in their structure, quantity, distribution, and interactions;
  • Well-defined computational standards and infrastructure and commonly shared open source workflows to process tremendous amounts of imaging data; and
  • Ensuring that new technologies and analysis workflows are available, accessible, and affordable to broad groups of biomedical researchers.

This community engagement formed the basis of CZI’s new Frontiers of Imaging effort, part of CZI’s broader Imaging program.

Visualizing Cells in Deep Tissue

While fluorescence microscopy has reached a high level of resolution, performing microscopy on multicellular animals is restricted to small, clear creatures because images with visible light are impossibly distorted by just a millimeter of tissue. Microscopy cannot be done through human skin or bone, which fundamentally limits what biological questions scientists can address today. In contrast to light microscopy, ultrasound penetrates skin and MRI penetrates both skin and bone, such as the skull, but these deep tissue imaging methods have low resolution and often lack molecular contrast.

To be able to “see” through the skin or skull at cellular resolution would allow researchers to watch the building blocks of life in unprecedented detail, such as observing how drugs alter the behavior of cancer cells and invade immune cells. Exciting advances in bioacoustic, biomagnetic, and biochemical probes; imaging hardware and acquisition methods (e.g. adaptive optics); and computational techniques may make such frontiers possible.

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In this illustration, T lymphocytes (orange), a type of white blood cell, attack a cancer cell (blue).

In response to the needs identified by imaging experts, CZI is launching a new Request for Applications (RFA) to advance the field of deep tissue imaging. The Deep Tissue Imaging RFA supports the development of technologies that will allow researchers to view information at cellular resolution, in complex tissue and through skin and bone, in living organisms. Pilot projects could include hardware and biological probes needed to visualize and label important cellular processes, as well as new computational techniques and algorithms for deep tissue analysis, that we hope will be transformative in driving breakthroughs to better understand health and disease. Awards are for $1 million total in costs over 2.5 years for each pilot project, and successful pilots will be eligible to apply for up to $10 million in additional funding.

Visualizing Proteins in Cells

The ability to view protein molecules in cells and monitor changes in their structure, quantity, distribution, and interactions is key to understanding what causes diseases and finding treatments and cures. Scientists can now use electron microscopy to obtain the structure of proteins at high resolution by averaging the images of thousands of individual, purified protein molecules. A number of super-resolution light microscopy techniques enable subcellular localization of proteins in cell cultures and thin tissue sections, but still pose various challenges for exploring dynamic processes in live cells. In addition, some very large proteins have been detected inside frozen cells. Using electron microscopy to resolve the structure of smaller proteins and using optical imaging to see their locations and interactions in real time in live cells will further our understanding of how cells function in normal states versus diseased states.

Reaching this level of insight requires better contrast, better electron detector sensitivity, improved sample preparations, and substantial computational and analytical advances, all of which were discussed at our November Electron Microscopy Workshop. CZI is continuing discussions with leaders in electron microscopy and visual proteomics to determine how we can help accelerate advances in this area.

Creating Universal Standards for Quantitative Imaging

Imaging at high molecular or even cellular resolution generates gigantic volumes of data. For example, acquiring images at molecular resolution with an electron microscope from just a cubic millimeter volume can produce a petabyte of data. Moreover, to be informative, these volumes of data have to be quantified, and the extraction of quantifiable features from biomedical images remains a significant bottleneck. Problems exist at each stage of the data lifecycle, from acquisition, storage, and image processing on large data sets, to the sharing of analysis pipelines.

To meet the demands of modern and future quantitative imaging, we need standards and infrastructure, including:

  • Universal, standard quality control metrics;
  • A solid code base when hardware is developed and a desire to build computation into the microscope itself, making it possible to do analysis as an experiment is underway;
  • Easy visualization and analysis of imaging data, particularly data that is 3-dimensional, time lapsed, super resolution, multi-channel, multi-field of view, or multimodal;
  • Efficient workflows that can be shared, reproduced, and scaled; and
  • A clear, open-source framework for easy development, long-term maintenance and support of analysis software.

CZI has supported Imaging Software Fellows and numerous imaging essential open source software packages, and is co-developing napari, a fast, interactive, multi-dimensional image viewer for Python. Our imaging team will continue to explore how we can help address the significant challenges posed by quantitative imaging.

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A video of the napari visualization interface, browsing and segmenting cells infected with SARS-CoV-2 virus from a high-throughput screen. Data from Recursion Pharmaceuticals.

Democratizing Technology

Access to new technologies and training in advanced imaging methods is critical to enabling and advancing scientific research. Participants in CZI workshops outlined problems limiting the spread of new technologies and possible solutions:

  • A major blocker is a lack of funding for technology maturation. Open source hardware efforts often struggle with support, and operational inefficiencies and can distract from scientific investigation.
  • Companies are a critical component of the imaging ecosystem and can build robust systems with appropriate support networks; however, their incentives can be misaligned with the nonprofit science research space. For example, companies tend to create their own data structures, which can act as a bottleneck.
  • Using imaging core facilities as centralized hubs of access to and training for advanced imaging methods could be a potential solution, yet they are often plagued by insufficient and unstable funding.

To help support these crucial core facilities, CZI previously funded 17 Imaging Scientists in the United States and is currently accepting applications for a second round of its Imaging Scientists RFA, open to applicants worldwide. We also support Global BioImaging, an international network of open access infrastructures for cutting-edge imaging technologies in the life sciences.

We want to enable researchers everywhere to visualize, measure, and analyze the biological processes underlying health and disease. By supporting transformative technology and increased collaboration, we hope to accelerate imaging science to reach new frontiers of understanding health and disease. We are excited to continue to learn as we support the imaging field.

More Information

Deep Tissue Imaging Request for Applications and selected grantees
Imaging Scientists Request for Applications and selected grantees
Visual Proteomics Request For Applications
CZI Imaging Program
WIRED Frontiers of Imaging video

Stephani Otte, Science Program Manager for Imaging, Chan Zuckerberg Initiative

Stephani Otte leads the Imaging program at CZI and is focused on the creation, dissemination, optimization, and standardization of transformative imaging technologies. Prior to CZI, Stephani was Director of Science at a neurotechnology/microscopy company, Inscopix. She received her PhD in neuroscience at the University of California, San Diego, and did postdoctoral fellowships in systems neuroscience at the Salk Institute and University of California, Berkeley.

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Supporting the science and technology that will make it possible to cure, prevent, or manage all diseases by the end of the century.

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