UW Scientist Discovers Genes Directing Hectic Cellular Expressways

Mutants and a superpower used by a University of Wyoming molecular biologist led to discovering certain genes implicated in cancer, genetic diseases and birth defects can serve as traffic cops directing complex transportation superhighways inside cells.

This discovery by scientists working in the laboratory of David Fay in the Department of Molecular Biology led to his lab receiving a $2.7 million, five-year grant from the National Institutes of Health (NIH).

“As it turned out, I probably got the grant by the skin of my teeth,” Fay says. “It tends to be a very competitive process.”

Fay, a professor, also is associate director of the Wyoming IDeA Networks for Biomedical Research Excellence grant. The $17.5 million NIH award broadly funds biomedical research and training at UW and throughout Wyoming.

Fay is not alone in bringing research dollars to the university among the professors in the department.

“I don’t think a lot of people realize our department’s something of a powerhouse when it comes to bringing in ultracompetitive outside funding,” Fay says.

Several members of the department have hit the grant jackpot since the first of the year. Associate Professor Dan Levy was awarded a $1.7 million, five-year grant from NIH to study how cells control the size of the nucleus, and Associate Professor Jay Gatlin recently was notified of a $1.2 million, four-year award from NIH to study how cells distribute their chromosomes during cell division.

Others in the department have secured multiple grants, including Professor Don Jarvis, whose six external grants fund a diverse array of projects, ranging from HIV research to therapeutic protein production. The funding portfolios of Jarvis and Associate Professor Grant Bowman include dollars to support local biotech companies started while at UW.

All 11 research-active faculty members in the department are externally supported, including its assistant professors.

Department Head Peter Thorsness credits the culture of the department in helping attract the high level of talent.

“I expect the individual talent possessed by each of our faculty members would allow them to be successful in most places, but the supportive atmosphere in the department is not to be undervalued,” he says. “One key is that the department is committed to hiring new faculty who are better than we perceive ourselves to be. We have really bought in to the aphorism ‘A rising tide lifts all boats.’”

The Fay lab, which started at UW in 2001, uses nematodes -- tiny roundworms -- to analyze gene functions conserved across many species, including humans. This “basic” scientific research relies on organisms that, although perhaps less complex than mammals, carry out many of the same fundamental processes at the cellular level and have advantages researchers can use in the lab, Fay says.

“The beautiful thing about basic scientific research,” he says, “is that you can never really know at the beginning how your work will play out or the ways in which it might become relevant to human biology and disease.”

Fay and the scientists in his lab were studying a process common to the growth of many worms and insects -- molting. As tiny larva develop into adults, a growing worm needs to trade in its old skin for a larger, roomier new skin.

A new skin has to be synthesized underneath the old one, and then the old one must be rapidly shed. The timing is tricky, as are the underlying mechanics of the process, Fay says.

To better understand molting, Fay enlisted the help of defective mutant worms unable to molt and then flexed what he calls a geneticist’s superpower.

Most scientists work with a hypothesis, a testable proposed explanation based on limited evidence and a starting point for more investigation.

“As molecular geneticists, we get to ask ‘How does this work?’ and then let the organism tell us,” Fay says.

Researchers found several genes critical for the bulk movement of proteins and lipids inside cells by tinkering with those important for molting. These proteins and lipids are important building blocks -- for the skin of the worm and for other structures, he says.

“The inside of a cell is a ridiculously complex set of highways but without obvious medians and guardrails,” Fay says.

During molting, molecules are constantly being sent outside the cell or being brought back in to be recycled. Fay’s research indicates some of the genes critical to molting act as very busy traffic cops directing what goes where and when. And the genes discovered in worms have correlates in humans, where they carry out many of the same functions.

Before these studies in worms, these disease-associated genes had not been known to have a crucial function in cell trafficking.

“We were skeptics ourselves, and it wasn’t until the last few years that we really started to believe what our data were telling us,” Fay says.

He says a particularly convincing experiment was taking human versions of the worm genes and showing that, when placed in the molting-defective worms, they could fully substitute for the missing worm genes; the worms molted just fine.

Fay is now collaborating with several groups outside UW to examine the trafficking functions of these genes in human and rodent cells, where they are looking for additional parallels. He looks forward to seeing where the worms take him and his research group over the next five years.

Despite the current pandemic situation, “the energy and enthusiasm in the department these days are great, and work continues to get done,” Fay says.

More about Fay’s laboratory and research is at www.uwyo.edu/molecbio/faculty-and-staff/david-fay/index.html.