June 14, 2022, 8:00 a.m.
Matthew Miller, Ph.D., assistant professor of biochemistry at the University of Utah Health, has been named a Pew Scholar Fellow in 2022 for his research on cellular machines that help accurately separate and divide chromosomes during cell division. This work is crucial, as even the smallest mistakes in this process can have harmful consequences, including birth defects, miscarriages and cancer.
Miller is one of 22 scientists nationwide honored by Pew’s charity trusts. The Pew Scholars in Biomedical Sciences program provides early-stage funding for researchers with outstanding promises in science that are important for improving human health.
Miller’s research focuses on a key phase of cell division or mitosis, when protein-based machines called kinetochores help chromosomes to maneuver properly between parental and newly formed daughter cells. This process ensures that each cell receives a complete set of accurately replicated 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 said.
“Matt Miller is studying a really fascinating and hot field of study,” said Wes Sandquist, Ph.D., a former Pew Fellow and chair of the Department of Biochemistry at the University of Utah. “To tackle this problem, Matt uses an incredible multidisciplinary combination of biochemistry, biophysics, genetics and cell biology, for which he is almost uniquely qualified for his wonderful breadth, insight and creativity.
Understanding the process of chromosome division during mitosis is a difficult challenge, according to Miller. This is due to its dynamic nature and the inability to accurately reproduce the physical forces that regulate these activities in cells.
To overcome this difficulty, Miller and his colleagues purified the protein machines involved and developed techniques that allowed them to restore their complex activities outside the cell. This allows researchers to experimentally control things like applied physical strength and ultimately understand how these factors perform this process so reliably.
“Kinetochores are amazing protein machines,” says Miller. “They move chromosomes in a constantly changing environment and are signal centers that help regulate the cell cycle. Biologists have been fascinated by this process for more than 100 years, but we still don’t know how kinetochores achieve their remarkable achievements.
In fact, according to Miller, scientists still do not have a complete “parts list” for the inner workings of kinetochores. It’s like knowing that an internal combustion engine makes the car run, but not realizing that under the hood is a collection of pistons, spark plugs and other vital moving parts, he says.
However, Miller and his colleagues reveal several key aspects of kinetochores and their role in cell division.
During cell division, the genetic information of a cell or DNA is packaged into structures known as chromosomes, which must be copied and then divided equally between the resulting daughter cells. To facilitate this process, kinetochores are assembled on chromosomes and attached to the mitotic spindle, a molecular machine that forms thin, thread-like filaments called microtubules. After doing so, duplicate chromosomes can move to opposite ends of the parent cell in preparation for cell division.
If the kinetochores do not do their job properly, then the chromosomes will not divide evenly and one cell may end up with too many or too few. As a result, harmful imbalances and mutations can occur, Miller said.
Fortunately, these types of mistakes are rare. So what keeps chromosomes attached to the right microtubules? It all comes down to tension, Miller says.
To accurately segregate replicated chromosomes to daughter cells, the chromosome must be attached to microtubules on opposite sides of the cell. This pull on opposite sides generates tension, telling the cell that it has the correct attachment configuration and can continue with cell division. Miller and colleagues recently discovered that kinetochores have an internal mechanism that “senses” this tension. It works, Miller says, like a child’s finger trap, a simple puzzle that catches the fingers at both ends of a small cylinder woven of bamboo. The harder a person tries to pull his fingers out, the tighter the device becomes.
In the same way, the tension created by the force of the opposite pull of the microtubules keeps the chromosomes properly aligned. When kinetochores “sense” the right amount of voltage, they signal for “activation” and then move each of their chromosomes to opposite sides of the parent cell, allowing accurate cell division.
Using a range 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 restore the activities of these protein machines in a test tube to find out the mechanisms that these protein machines use to carry out this process,” Miller said. “This work could lead to new strategies to reduce chromosomal segregation defects that lead to many human diseases, including cancer and developmental disorders such as Down syndrome.
The class of Pew scientists for 2022 – all junior teachers at the beginning of their careers – will receive four years of funding to study some of the most pressing issues in health and medicine. They were selected from 197 nominees nominated by leading academic institutions and researchers in the United States.
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