Matt Miller Pew Scholar has been named University of Utah Health Biochemist

June 14, 2022 8:00 p.m.

Matthew Miller, Ph.D., an assistant professor of biochemistry at the University of Utah Health, was named Pew Scholar in 2022 for exploring cellular machines that help accurately divide and differentiate chromosomes during cell division.

Matthew Miller, Ph.D., an assistant professor of biochemistry at the University of Utah Health, was named Pew Scholar in 2022 for exploring cellular machines that help accurately divide and differentiate chromosomes during cell division. This work is critical because even the smallest mistakes in this process can have detrimental consequences, including birth defects, abortions, and cancer.

Miller Pew is one of 22 scientists from across the nation who have been honored by the Charitable Trusts. The Pew Scholars Program in Biomedical Sciences provides funding for early career researchers who are promising in science, which is important for the advancement of human health.

Miller’s research focuses on a key phase of cell division or mitosis, when machines based on proteins called zinetochores help the chromosomes to maneuver properly between parents and newly formed daughter cells. This process ensures that each cell receives a complete set of accurately repeated chromosomes.

A better understanding of how kinetochores work can lead to the development of genetic interventions or other treatments to reduce the risk of these disorders, Miller says.

“Matt Miller is exploring a truly fascinating and red-hot field of research,” says Wes Sundquist, Ph.D., a former Pew Scholar and president of the Department of Biochemistry at the University of Utah Health. “To address this problem, Matte uses an amazing multidisciplinary combination of biochemistry, biophysics, genetics and cell biology, and he has an almost unique ability to do so because of his versatility, vision and wonderful creativity.”

Understanding the process of chromosome separation in mitosis is a difficult challenge for Miller. This is due to its dynamic nature and its inability to accurately repeat the physical forces that regulate these activities in cells.

To overcome this difficulty, Miller and his colleagues have developed techniques that allow them to purify the protein machines involved and restore their complex activities outside of a cell. This allows researchers to control experimentally, such as the applied physical force, and ultimately understand how these factors carry out this process.

“Kinetochores are huge protein machines,” says Miller. “In a constantly changing environment, chromosomes move and are signaling sites that help regulate the cell cycle. Biologists have been fascinated with this process for more than 100 years, but we still don’t know how filmmakers achieve outstanding feats.”

In fact, according to Miller, scientists do not yet have a complete “list of parts” for the inner workings of kinetochores. It’s like knowing that an internal combustion engine is starting a car, but not understanding that there is a collection of pistons, spark plugs, and other key moving parts under the hood, he said.

However, Miller and his colleagues are shedding light on their role in key aspects of cell and cell division.

When the cell divides, the genetic information of the cell, or DNA, is collected in structures known as chromosomes, which must be copied and then evenly distributed among the daughter cells that are created. To facilitate this process, kinetochores join on chromosomes and bind to the mitotic axis, a molecular machine called the microtubule, which forms a thin, thin, wire-like chain. Once this is done, the duplicate chromosomes can be moved to the opposite ends of the parent cell to prepare for cell division.

If the kinetic cells do not do their job properly, then the chromosomes will not be evenly distributed, and a cell may end up with too many or too few of them. As a result, imbalances and harmful mutations can occur, Miller says.

Fortunately, these types of mistakes are rare. So what keeps chromosomes attached to the right microtubules? Everything is reduced in tension, Miller says.

In order to accurately separate replicated chromosomes from daughter cells, the chromosome must bind to the microtubules on the opposite side of the cell. Pulling on the opposite side creates tension, saying that the cell has the correct attachment configuration and can continue with cell division. Miller and co-workers recently discovered that filmmakers have an intrinsic mechanism that “feels” this tension. Miller says he acts like a child’s finger trap, a simple puzzle that catches his fingers at both ends of a small bamboo-woven cylinder. The harder a person tries to pull their fingers out, the tighter the device.

Also, the stress generated by the tensile force against the microtubules keeps the chromosomes properly aligned. When kinetochores “feel” the right amount of tension, they signal “forward,” and then move each of their chromosomes to opposite sides of the main cell, allowing for accurate cell division.

Using a number of cutting-edge tools in biochemistry, biophysics, and gene editing, Miller hopes to determine which “parts” of protein machines are responsible for chromosomal attachment and segregation.

“We will then reconstruct the activities of these protein machines in a test tube to learn about the mechanisms that these protein machines use to carry out this process,” says Miller. “This work may lead to new strategies to reduce chromosomal separation defects that cause many human diseases, including cancer and developmental disorders, such as Down syndrome.”

The 2022 Pew Research Class — all early career teachers — will receive four years of funding to study the most serious health and medical questions. They were selected from 197 applicants nominated by major academic and research institutions in the United States.


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