The precise shapes of proteins at work inside our cells offer essential clues about the processes that drive health and disease. Structural biologists determine the forms of molecular machines, in atomic detail, to better understand how they function or what happens when they malfunction.
Now, with the Arnold and Mabel Beckman Foundation Sample Preparation for Cellular Cryo-ET Award, University of Michigan researchers will open new windows into the cell, transforming how biologists can see and learn from these atomic-level structures.
The $1.5 million award supports the expansion of a cutting-edge structural biology technique called cryo-electron tomography — or cryo-ET — at U-M.
Rather than looking at cellular components that have been purified and isolated out of cells, as other structural biology approaches do, cryo-ET examines complex molecular machines within the context of their cellular environment.
The process involves flash-freezing cells in a thin layer of vitreous ice, etching thin windows into the cells, and then using electrons to determine the shapes of the molecules preserved in these thin sections. It requires not only expertise in a quickly evolving field, but also access to highly advanced microscopes and other technologies to capture the 3D structures. The award from the Arnold and Mabel Beckman Foundation offers funding for both.
“This award will allow us to support our early-career faculty with the most state-of-the-art technology, which is essential for their career development,” said the program’s principal investigator, Melanie Ohi, the Rowena G. Matthews Collegiate Professor in the Life Sciences and research professor in the Life Sciences Institute, and professor of cell and developmental biology in the Medical School.
“But a big part of this work will also be broadening access across the university, to build a vibrant community of researchers in various fields who can use this technique to answer important biological questions.”
In addition to Ohi, the research team for this program includes faculty members Michael Cianfrocco, Shyamal Mosalaganti and Janet Smith of LSI and the Medical School, and Min Su, LSI cryo-EM resource director.
Cianfrocco is an assistant professor of biological chemistry, Mosalaganti is an assistant professor of cell and developmental biology and Smith is the Margaret J. Hunter Collegiate Professor in the Life Sciences, Martha L. Ludwig Distinguished University Professor of Biological Chemistry, professor of biological chemistry in the Medical School, and professor of biophysics in LSA.
This latest award will enable the cryo-electron microscopy — or cryo-EM — facility at LSI to build on previous investments from President Mark Schlissel’s Biosciences Initiative.
With a grant from the U-M initiative, LSI invested in new equipment to make single particle cryo-EM more available across campus and in establishing a sample-to-structure pipeline to train a new generation of users.
These established strategies will now be replicated for the new cryo-ET program. The Biosciences Initiative funding also enabled the recruitment of cryo-ET expert Shyamal Mosalaganti, assistant professor of cell and developmental biology. These investments were essential to U-M’s successful application for this latest award, Ohi said.
“Support from the Biosciences Initiative enabled us to clearly show that this university is willing to invest in and advance the latest approaches to innovative scientific research, and that we have the experience to expand access to these highly specialized techniques,” she said.
Because the Biosciences Initiative funded the previous purchase of some equipment required for cryo-ET, as well, Ohi and her colleagues can use more of this new award for training and educational programming to increase the number of researchers who can benefit from the technology.
“The goal of the Biosciences Initiative was to advance U-M to the cutting edge of science in the United States by investing in expert faculty and the technology and resources that support true innovation,” Schlissel said. “This award from the Arnold and Mabel Beckman Foundation shows the value of that investment, recognizing U-M as one of the top cryo-EM centers in the country.”