Structural biology and collaboration are two strong points at the University of Wisconsin–Madison. In keeping with this tradition, a concerted cross-campus effort partly spearheaded by the Department of Biochemistry is working to bring a cryo-electron microscopy (cryo-EM) facility to campus.
Cryo-EM is a burgeoning tool that can help UW–Madison researchers make significant contributions to many areas of structural biology, including enzymology, virology, cell biology, and medicine. These discoveries can lead to a better understanding of many diseases and possible treatments.
“I think cryo-EM has emerged as an indispensable method for structural analysis in the biosciences,” says biochemistry professor Robert Landick, who is one of the leaders on the project. “It is not hyperbole to say that it is revolutionizing our understanding of large macromolecular machines. For UW–Madison to remain a powerhouse in bioscience research, it is crucial that modern cryo-EM capabilities be brought to campus.”
The facility will be housed in a 1,250-square-foot space in the Hector F. DeLuca Biochemistry Laboratories building but its users will be from across campus. Numerous colleges, research centers, departments, and researchers are coming together to secure the resources needed to establish the facility. Among those collaborating on projects and supporting the multi-million-dollar facility are the Morgridge Institute for Research, Materials Science Center, UW Carbone Cancer Center, Vice Chancellor for Research and Graduate Education, and School of Medicine and Public Health.
Along with ordering equipment in the form of a Titan Krios microscope, they are currently hiring a faculty member to specialize in cryo-EM and a Ph.D.-level scientist to help establish and coordinate the facility. Anyone with a Ph.D. in biochemistry or a related field with an outstanding record of teaching and research relevant to high-resolution cryo-electron microscopy of biomolecules or cellular function is invited to apply for the faculty position. Applications will be reviewed starting July 1 and continue until the position is filled.
The other position, the new UW–Madison cryo-EM scientist/facilitator, will provide guidance to the facility’s users, such as training them in sample preparation, imaging, and analysis — playing an integral role in the facility’s success. All individuals with an outstanding record of research relevant to high-resolution cryo-EM are invited to apply by June 10, 2017. The research team recently secured funds for this position through a UW2020: WARF Discovery Initiative Award.
“This level of staff support is essential to the operation of a modern cryo-EM research facility,” Landick says. “With this project underway, we are excited to bring this staff member on board to anchor our efforts to establish this facility.”
Cryo-EM is a technique that allows researchers to get an extremely detailed look at a molecular structure, often at atomic resolution. This allows them to uncover how a protein or other structure functions, and also how mutations that cause changes in those structures can lead to disease and possible treatments.
For experiments, samples must be frozen to extremely cold temperatures and electron beams are shot at the frozen molecules in the microscope to capture an image of its structure. When the electrons hit the sample, they scatter and their pattern passes through a lens to create an image. Scientists can discern the structure by computationally processing tens of thousands or more of such images.
“Cryo-EM allows the reconstruction of a 3D-image of a molecule at near atomic-resolution and has unique advantages over other structural methods,” says biochemistry professor Sam Butcher, who is part of the team working to establish the facility. “It allows researchers to ‘see’ molecules that have been quickly frozen in their native states, yielding molecular information that would otherwise be impossible to obtain by other methods such as X-ray crystallography or nuclear magnetic resonance spectroscopy (NMR). I think cryo-EM will have a huge impact on research at UW–Madison, particularly for the many researchers that are studying molecular machines, enzymes, cellular substructures, and viruses.”
The process can produce detailed structures to define the location, architecture, and dynamics of a wide array of biological process and molecules, such as cellular membranes, organelles, enzymes, and viruses. They can shed light on scientific issues in development, disease, drug treatment and discovery, infections, and protein function, spanning themes such as biotechnology and biomedical research.
At UW–Madison, faculty are exploring every corner of these areas — from biochemistry professor John Markely studying mechanistic origins of mitochondrial disease to bacteriology professor Katrina Forest wanting to investigate the structure of tiny microbes often abundant in fresh water.
In virology, biochemistry and Institute for Molecular Virology professor Ann Palmenberg recently solved the structure of a virus responsible for asthma in small children. She collaborated with Purdue University because they have the sufficient cryo-EM equipment, unlike UW–Madison currently. Also, oncology professor Paul Ahlquist aims to use the new facility to visualize the structure of how some viruses replicate, particularly those responsible for Zika, MERS, SARS, Dengue Fever, and Chikungunya.
Getting even further into the basic sciences, other researchers are interested in the structure of biological molecules involved in ion channels and transporters, DNA replication, RNA transcription, the spliceosome, communication between synapses in the nervous system, and more. All of these structures could shed light on aspects of human development and disease and will be made possible by the cyro-EM facility at UW–Madison.
The facility will also foster collaborations on and off campus, as well as have an impact on teaching. Many of the faculty coming together to establish the facility are working to design coursework to teach undergraduates and graduate students about this new technology.