Matthew Miller, Ph.D., an assistant professor of biochemistry at University of Utah Health, was named as a 2022 Pew Scholar for his exploration of the cellular machines that help accurately divide and separate chromosomes during cell division. This work is critical as even the smallest errors in this process can have harmful consequences, including birth defects, miscarriages, and cancer.
Miller is one of 22 scientists nationwide to receive the honor from the Pew Charitable Trusts. The Pew Scholars Program in the Biomedical Sciences provides funding to early-career investigators of outstanding promise in science that is relevant to the advancement of human health.
Miller’s research focuses on a key phase of cell division, or mitosis, when protein-based machines called kinetochores help chromosomes correctly maneuver between parent and newly forming daughter cells. This process ensures that each cell receives a complete set of accurately replicated chromosomes.
Better understanding of how kinetochores work could lead to the development of genetic interventions or other treatments to reduce the risk of these disorders, Miller says.
"Matt Miller is studying a truly fascinating and red-hot area of research," says Wes Sundquist, Ph.D., a former Pew Scholar and chair of the Department of Biochemistry at the University of Utah Health. "To address this problem, Matt uses an amazing multi-disciplinary combination of biochemistry, biophysics, genetics, and cell biology for which he is almost uniquely qualified owing to his wonderful breadth, insight, and creativity."
Understanding the process of chromosome separation during mitosis is a difficult challenge, according to Miller. That’s because of its dynamic nature and the inability to precisely replicate the physical forces that regulate these activities in cells.
To overcome this difficulty, Miller and his colleagues purify the protein machines involved and have developed techniques which allow them to reestablish their complex activities outside of a cell. This allows the researchers to experimentally control things such as applied physical force and ultimately understand how these factors carry out this process so reliably.
"Kinetochores are incredible protein machines," Miller says. "They move chromosomes within an ever-changing environment and are signaling hubs that help regulate the cell cycle. Biologists have been fascinated with this process for more than 100 years, yet we still don’t know how kinetochores achieve their remarkable feats."
In fact, according to Miller, scientists still don’t have a complete "parts list" for the inner workings of kinetochores. It’s like knowing that an internal combustion engine makes a car run but not understanding that under the hood it is a collection of pistons, spark plugs, and other vital moving parts, he says.
Despite this, Miller and his colleagues are unraveling several key aspects of kinetochores and their role in cell division.
During cell division, the cell’s genetic information, or DNA, is packaged into structures known as chromosomes, which need to be copied and then partitioned equally between resulting daughter cells. To facilitate this process, kinetochores assemble on chromosomes and attach themselves to the mitotic spindle, a molecular machine that forms thin, thread-like strands called microtubules. Once they do this, the duplicated chromosomes can move to opposite ends of the parent cell in preparation for cell division.
If kinetochores don’t do their job correctly, then the chromosomes won’t divide evenly, and one cell could end up with too many or too few of them. As a result, harmful imbalances and mutations can occur, Miller says.
Fortunately, these types of errors are rare. So what keeps the chromosomes attached to the right microtubules? It all boils down to tension, Miller says.
To accurately segregate replicated chromosomes to daughter cells, the chromosome must attach to microtubules from opposite sides of the cell. This pulling from opposite sides generates tension, telling the cell it has the correct attachment configuration and can proceed with cell division. Miller and colleagues recently discovered that kinetochores have an intrinsic mechanism that "senses" this tension. It acts, Miller says, like a child’s finger trap, a simple puzzle that traps fingers in both ends of a small cylinder woven from bamboo. The harder a person tries to pull their fingers out, the tighter the device gets.
In much the same way, the tension created by the force of opposing microtubule pulling keeps the chromosomes aligned properly. When the kinetochores "sense" the right amount of tension, they give the "go-ahead" signal and then move each of their chromosomes to opposite sides of the parent cell, enabling accurate cell division.
Using an array of cutting-edge tools in biochemistry, biophysics, and gene editing, Miller hopes to determine which "parts" of the protein machines are responsible for chromosomal attachment and segregation.
"We will then reconstitute the activities of these protein machines in a test tube to discover the mechanisms these protein machines use to carry out this process," Miller says. "This work could lead to novel strategies for reducing the chromosomal segregation defects that give rise to many human diseases, including cancer and developmental disorders such as Down syndrome."
The 2022 class of Pew scholars—all early-career, junior faculty—will receive four years of funding to explore some of the most pressing questions in health and medicine. They were chosen from 197 applicants nominated by leading academic institutions and researchers across the United States.