Tim Grant Tim Grant

CZI project to enable high-resolution mapping of molecules within cells

Powerhouse new tools such as cryo-electron microscopy (cryo-EM) give scientists a way to define the structures of molecules at high resolution. But identifying exactly where these molecules reside within an ocean of structures inside a cell — and exactly how they interact with their neighbors — remains unknown.

Morgridge Institute for Research Investigator Tim Grant is part of a new project supported by the Chan Zuckerberg Initiative (CZI) that hopes to create a three-dimensional map that aligns these molecules in their proper neighborhoods within a cell. This knowledge can be essential in understanding how different protein molecules work together and illustrate pathways that are used both in normal biological function and in disease.

Grant, also an assistant professor of biochemistry at the University of Wisconsin–Madison, is partnering on the $1.3 million project with scientists Nikolaus Grigorieff, a professor of RNA therapeutics at the University of Massachusetts Medical School; and Bronwyn Ayla Lucas, a postdoctoral fellow in the Grigorieff Lab.

“The ultimate goal of this project is to make a precise atomic-level map of a cell,” Grant says. “That’s something that scientists basically don’t have at the moment. We know what these structures look like, but we often don’t know how they are positioned in relation to one another and how they are interacting.”

“This should give us an idea of how systems actually function within living cells.

Tim Grant

Currently, the most used method for localizing molecules within cells is to tag them with a fluorescent molecule that can be detected by a specialized microscope — a process that can be very challenging and can only be applied to one or few molecules at a time. This group is using an innovation called high-resolution template matching, a computational approach that takes existing known structures of molecules and finds their most likely matches within cryo-EM images of a cell.

“What’s really useful is you can see things that are commonly located next to each other, and so likely interacting,” Grant says. “They could be part of a pathway, for example. This should give us an idea of how systems actually function within living cells.”

The grant is part of CZI’s visual proteomics focus area. Being able to view protein molecules within cells opens a new frontier in medicine that can help determine the origins of cellular diseases and what treatments might be most effective.

In June 2020, CZI awarded more than $28 million to 14 visual proteomics projects all aimed at better understanding the intricate inner workings of cells. CZI was founded in 2015 to help solve some of society’s toughest challenges — including eradicating disease, improving education and aggressing the needs of local communities.

Grant is the third Morgridge investigator to receive funding support from CZI, along with medical engineering investigators Kevin Eliceiri and Jan Huisken.