Throughout history, observations of structure, from Robert Hooke’s cells to the beaks of Charles Darwin’s finches, have been fundamental to our ability to understand how life works.

This is particularly true in structural biology, a discipline dedicated to visualizing the molecular machines and components that underlie almost all of life’s processes. The efforts of structural biologists have spawned vast and diverse fields of research and, with the discovery of the structure of DNA, helped launch the modern era of biomedicine.

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A transformational tool has recently joined the arsenal of the structural biology community—cryo-electron microscopy (cryo-EM), which makes it possible for scientists to visualize, at the atomic level, complex proteins that were difficult or impossible to determine before.

“Knowledge of molecular structure is fundamental for developing new therapeutics and vaccines against cancer, neurodegeneration, emerging infections and many other diseases,” said Stephen Harrison, the Giovanni Armenise-Harvard Professor of Basic Biomedical Science at the Blavatnik Institute at Harvard Medical School.

“The best way to study those structures is now cryo-EM,” said Harrison, who also serves as the director of the Harvard Cryo-EM Center for Structural Biology.

In this video, scientists from across the Harvard community describe how they are using the power of cryo-EM to study the inner workings of molecular machines involved in everything from cancer to inflammation to circadian clocks.

Featured investigators include:

• Jonathan Abraham, HMS assistant professor of microbiology
• Alan Brown, HMS assistant professor of biological chemistry and molecular pharmacology
• Michael Eck, professor of biological chemistry and molecular pharmacology at HMS and the Dana-Farber Cancer Institute
• Maofu Liao, HMS associate professor of cell biology
• Sichen Susan Shao, HMS assistant professor of cell biology
• Charles Weitz, the Robert Henry Pfeiffer Professor of Neurobiology at HMS
• Hao Wu, the Asa and Patricia Springer Professor of Structural Biology and professor of biological chemistry and molecular pharmacology at HMS and Boston Children’s

Game changer

Researchers around the world have embraced cryo-EM for its enhanced power and for the myriad possibilities it offers to advance the rational design and evaluation of therapies.

In recognition of the importance of this technology to the future of biomedical research, a consortium formed by HMS, Harvard University’s Office of the Provost, Boston Children's Hospital, the Dana-Farber Cancer Institute and Massachusetts General Hospital established the Harvard Cryo-EM Center for Structural Biology, which makes access to cryo-EM broadly available to the Harvard research community.

The center currently operates three state-of-the-art cryo-EM microcopes, with a fourth soon to be online. Since April 2019, the facility has:

• Been utilized by 60 different users, representing 28 laboratories or businesses.
• Collected 882,972 images.
• Operated for 7,084 hours of screening/data collection time.
• Generated ~700 terabytes of data.
• Supported 101 currently approved projects.

“HMS structural biologists have used cryo-EM to understand the molecular anatomy of proteins that play critical roles in human health and disease,” said George Q. Daley, dean of HMS, in his recent State of the School Address. “The addition of cryo-EM to the structural biology toolbox has opened our eyes to a breathtaking new level of structural complexity.”