The Inaugural Symposium for the Harvard Cryo-Electron Microscopy Center for Structural Biology hosted some of the world's leading structural biologists. Top row (from left to right): Axel Brunger, Nikolaus Grigorieff, Thomas Walz, Bridget Garragher. Bottom row (left to right): Roderick MacKinnon, John Kuriyan, Richard Henderson, Stephen Harrison, Jue Chen, Sir John Skehel. Image: Steve Lipofsky.
“It is very easy to answer many … fundamental biological questions; you just look at the thing!” – Richard Feynman, in a lecture to the American Physical Society, December 29, 1959.
It’s often said that in biology, structure is the key to understanding function. For this reason, advances in revealing the molecular structures of biological molecules have been among the most celebrated in all of science.
From ribosomes and hemoglobin to ion channels and, perhaps most famously, DNA, discoveries of important structures or of new methods to identify them have earned a number of Nobel Prizes over the past century.
The work of the world’s structural biology community has spawned vast and diverse fields of biomedical research and led to the development of a wealth of life-altering therapeutics. Most of these structural insights were achieved through a relatively small set of highly productive tools, primarily X-ray crystallography and NMR spectroscopy.
In recent years, a new tool has joined this arsenal and it is rapidly transforming the field. Driven by advances in imaging technology, computational power, algorithms and innovative methodologies, cryo-electron microscopy (cryo-EM) is allowing scientists to visualize, at near-atomic resolution, structures of molecules that were difficult or impossible to determine previously.
Biological scientists around the world have embraced cryo-EM for its enhanced power in making discoveries about the molecular structures that underlie life, and for the myriad possibilities it offers to advance the rational design and evaluation of therapeutics.
In recognition of the importance of this technology to the future of biomedical research, a consortium formed by Harvard Medical School, Harvard University’s Office of the Provost, Boston Children’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital has established a new facility to make cryo-EM more broadly available to the Harvard research community.
To celebrate the new Harvard Cryo-EM Center for Structural Biology, which, when it opens later this year, will mark a new era of structural biology research and discovery at Harvard, HMS hosted the Inaugural Symposium for the Harvard Cryo-Electron Microscopy Center for Structural Biology on May 30.
The day-long event featured some of the world’s most esteemed structural biologists, including two Nobel laureates. Reflecting Harvard’s distinguished history of leadership in the field, the speakers all shared deep connections to the university, either as students, postdoctoral fellows, former faculty or longtime collaborators.
“This special occasion marks a historic commitment to leadership in structural biology, a field central to so much of modern biomedicine, by Harvard and our clinical partners,” said HMS Dean George Q. Daley in his welcoming remarks at the symposium, held in the Joseph B. Martin Conference Center on the HMS campus.
“This extraordinary partnership emphasizes the joint commitment that we have to collaborative research, and to supporting truly important projects that may be too large or costly for any one research group to achieve alone,” Daley said. “I have no doubt that this center will have an enormous impact on our ability to advance fundamental science and the development of therapeutics.”
Located on the HMS Quad, and headed by renowned structural biologist Stephen Harrison, the HMS Giovanni Armenise-Harvard Professor of Basic Biomedical Science, the Harvard Cryo-EM Center will house four state-of-the-art microscopes, along with sample preparation areas and tools to support their use. The facility will be operated by full-time staff who will provide training, supervision and user support.
The Center will greatly expand access to cryo-EM for researchers working to answer important basic and clinical science questions, and the potential impact of this resource will travel well beyond the university.
“Harvard will be giving science a new pair of eyes,” said Rick McCullough, Professor of Materials Science and Engineering and Vice Provost for Research at Harvard University. “Cryo-EM is a revolutionary tool that is allowing scientists to see, for the first time, the structures of very large bio-molecules. This could help us understand the causes of some diseases and support the development of new drugs that benefit human health.”
“This is a perfect example of how we can leverage the scale of our combined facilities to advance science and medicine for the benefit of society,” McCullough added.
The Harvard Cryo-EM Center installs its first microscope.
Legacy of Leadership
At the inaugural symposium, hundreds of attendees from across HMS, Harvard, HMS-affiliated hospitals and other institutions packed the conference center for presentations about the past, present and future of cryo-EM. The collaborative spirit of the Harvard Cryo-EM Center was reflected by symposium attendees, who intermingled and discussed projects and research.
The event also represented an opportunity to acknowledge the rich history of structural biology at Harvard, a legacy that the university’s structural biology community gladly carries forward.
“This occasion is a celebration not only for the opening of the new center, but also in some sense the 60th anniversary of structural biology at Harvard, when Don Caspar and Carolyn Cohen established the Laboratory for Structural Molecular Biology in the Children’s Cancer Research Foundation at Boston Children’s Hospital, which was the precursor of the Dana-Farber Cancer Institute,” Harrison said in his opening remarks.
“Caspar and Cohen recruited students who also were initiators of the tradition of leadership in structural biology at Harvard, including Don Wiley and myself. It is fitting that Boston Children’s and the Dana-Farber Cancer Institute have played such an instrumental role in initiating this center,” Harrison said. “It was our goal to make Harvard a leader in the nascent field we were part of, and it is exciting to help it going long into the future.”
Guest speakers at the symposium included:
Richard Henderson, recipient of the 2017 Nobel Prize in Chemistry for his contributions to the development of cryo-electron microscopy. Henderson was the first to successfully use cryo-EM to produce a 3-D image of a biological molecule at atomic resolution and has for decades focused his research on overcoming technical and conceptual limitations in cryo-EM technology. A group leader and emeritus scientist at the Laboratory of Molecular Biology at the University of Cambridge, Henderson presented his work on the theoretical and mathematical underpinnings of cryo-EM, and the technical limitations that still need to be addressed before theory can truly be reflected in practice. Henderson is a longtime collaborator with Harvard structural biologists, including Stephen Harrison.
Roderick MacKinnon, recipient of the 2003 Nobel Prize in Chemistry for his work on the structure and operation of ion channels. The John D. Rockefeller Jr. Professor and head of the Laboratory of Molecular Neurobiology and Biophysics at Rockefeller University, MacKinnon studies the principles of electricity production in living cells through analysis of ion channel structure and function.He presented his work on how structure yields clues on the functional mechanisms of Piezo proteins, which are mechanically activated ion channels that are important in touch sensation, vasculature development and many other functions. MacKinnon was faculty at HMS from 1989 to 1995. He also completed an internship and residency in internal medicine at Beth Israel Deaconess.
Jue Chen, William E. Ford Professor and head of the Laboratory of Membrane Biology and Biophysics at the Rockefeller University, who presented her work on the structure of ABC transporters, a class of membrane transporters that use energy to transport necessary nutrients as well as unwanted toxins across cell membranes. Her lab resolved the structure of a long sought-after ABC transporter, the cystic fibrosis transmembrane conductance regulator, which plays a major role in cystic fibrosis, shedding light on its function and mechanisms of action. Chen was a graduate student in the laboratory of Don Wiley at Harvard from 1994 to 1998 and continued as a postdoctoral fellow in the Wiley lab until 1999.
John Kuriyan, Chancellor’s Professor at the University of California, Berkeley in the departments of Molecular and Cell Biology and Chemistry, who presented his work on mutations that affect the structure of the Ras protein, a key molecule in many forms of cancer. Ras has largely been considered an undruggable target, but structural studies may shed light on ways to modulate its function. His lab studies the mechanisms, evolution and structures of the molecular switches that carry out cellular signal transduction. Kurian was a postdoctoral fellow at Harvard from 1986 to 1987.
Bridget Carragher, Co-Director of the Simons Electron Microscopy Center at the New York Structural Biology Center, who presented her work investigating sample preparation issues that can limit cryo-EM results and potential paths toward overcoming these obstacles. She is director of the National Resource for Automated Molecular Microscopy, which aims to develop automated imaging techniques for solving structures using cryo-EM. Her research focuses on developing new methods to improve the process of cryo-EM, from sample preparation to the generation of a final 3-D map. Carragher is a longtime collaborator with Harvard structural biologists and is a scientific advisor to the Harvard Cryo-EM Center.
Axel Brunger, Professor of Molecular and Cellular Physiology at Stanford University, who presented his work on the molecular mechanisms of neurotransmitter release. Among the focuses of his research are SNARE proteins, which are found in the membranes of both nerve cells and the vesicles used to transport neurotransmitters at synaptic junctions. His lab uses structural and biophysical tools to shed light on the functional and dynamic aspects of this system. Brunger was a postdoctoral fellow and research associate at Harvard from 1982 to 1983, and 1985 to 1987.
Thomas Walz, Professor and head of the Laboratory of Molecular Electron Microscopy at Rockefeller University, who presented his work on the molecular architecture of the BBSome, a protein complex involved in trafficking molecular cargos to cilia. Mutations to BBSome proteins cause Bardet-Biedl syndrome, a genetic disorder that affects a wide range of body systems. His lab uses structural methods to study the function and mechanisms that underlie the BBSome to shed light on how it causes the disease and potential treatment interventions. Walz was a member of the HMS faculty from 1999 to 2015.
Nikolaus Grigorieff, group leader at Howard Hughes Medical Institute’s Janelia Research Campus, who presented a historical overview of two decades of cryo-EM research at HMS. He traced cryo-EM technology from when it was referred to as “blobology” due to the low-resolution, blob-like structures it produced around the turn of the millennium, to the “resolution revolution” of the past few years when cryo-EM could be used to visualize structures at near-atomic resolution. Grigorieff has made major contributions to the advancement of techniques that improve the resolution and power of cryo-EM, and has long-standing collaborations with Harvard structural biologists.
Sir John Skehel, Emeritus scientist at the Francis Crick Institute in London and former director of the National Institute of Medical Research, who presented his work on cryo-EM structural visualization of haemagglutinin, a protein found on the surface of influenza viruses. The protein is responsible for binding the virus to cells and plays a major role in the virulence of the influenza virus. His research on haemagglutinin and the mechanisms of its binding, fusion and antibody recognition was done with Don Wiley, and continues with former Harvard structural biologists Steve Gamblin and Peter Rosenthal.
