Perseverance, payoff and potential in research

For non-scientists, Dr. Terra Arnason’s latest published work has a daunting title—The SNF1 Kinase UBA Domain Restrains its Activation, Activity and the Yeast Lifespan.

But when she explained it in layman terms, the paper is revealed as a story of important research focused on human health benefits, and a tale of perseverance, payoff and future potential.

Arnason, a practicing endocrinologist with a particular interest in diabetes research, has been working on this paper since she joined the U of S College of Medicine in 2008. With help from PhD students, post-docs, lab technicians, and summer and honours students, she has been looking at an enzyme that is turned on and off in cells in response to energy levels in the body. When energy levels are low, as they are when a person is fasting, dieting or exercising, Arnason said the enzyme switches on and goes to work creating energy by burning body fat, using fat from the liver and stopping cholesterol production.

People with diabetes, she explained, often have difficulty losing weight, have cholesterol production that is unregulated and suffer from high blood glucose, all of which would be helped by the enzyme being switched on. "If I can figure out how to turn on this enzyme in people with diabetes, I think you'll see real health benefits."

But to do her research aimed at helping humans, Arnason studied the on-off enzyme function in yeast. "In yeast, there are three possible forms of this enzyme," she said. "In humans, there are 12 and they vary by tissue type and are regulated by hormones which yeast don't have. Yeast is so simple it lets us look at the fundamental processes."

Her focus was on a particular string of amino acids, called a motif, which exists in the enzyme and is found in organisms from yeast and plants up to and including human liver, fat and muscle cells. By manipulating the motif, Arnason showed that it actually puts the brakes on the enzyme's ability to turn on, thus negating the benefits for diabetics. Her research also established the motif has the potential to enhance the ability of cells to withstand stress and aging "which I fully expect to be applicable to human health.

"It's the result I was hoping for seven years ago; it just took me a long time to get there. My longest-term goal is to find a drug that targets and blocks the motif, and activates the enzyme, resulting in health benefits."

Arnason said she first sent her paper to a scientific journal in September of 2014. It was rejected; too specialized, the editors said. Other submissions and rejections followed, but she remained optimistic. "I've had papers go through half a dozen journals until I found one that was just the right fit. And yeast is not very sexy."

Finally the editors of the Journal of Biological Chemistry realized its potential. And along with its acceptance for publication came its selection as a paper of the week. That means the editorial board determined it to be in the top two per cent of the more than 6,600 papers the journal will publish this year based on significance and overall importance.

"It's a huge honour," said Arnason. "When I read the email, I was happily shocked. Who said you can't study diabetes in a yeast cell?"

The paper is already on the journal's website and will appear in print in June. The journal editors also offered to consider using an image from the research on the cover but "yeast is not very photogenic," she said with a laugh. "We have before and after shots, but they're identical."

For Arnason and the paper's first author, PhD student Rubin Jaio, the long road to publication has ended, but there may well be many more chapters to be written in this story.

In addition to seeing her findings offering significant health benefits to diabetics, Arnason has recently turned her mind to how manipulating the amino acid motif in plants could enhance resistance to stressors.

"I haven't even talked to anyone about this yet but imagine if we could come up with crops that could better resist drought, or elevation, or if we could drain a salty marsh and grow something edible, all by mutating a single amino acid in an enzyme."
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