In Depth—The Bear Necessities

In Depth—The Bear Necessities

Understanding the functional genomics involved in bear hibernation could enhance human health.

Joanna Kelley, PhD, is an associate professor in the Department of Ecology and Evolutionary Biology at the University of California, Santa Cruz. Her evolutionary genomics laboratory is using the latest genome sequencing and computational approaches to better understand the genomic basis of adaptation, with a special emphasis on extreme environments.

What motivated you to focus on functional genomics and hibernation in brown bears?

I was trained in human population genetics, and I’m really interested in the evolutionary process and differences between different populations at a genetic level. When I was getting my PhD, I realized that extreme environments are a phenomenal place to ask questions about phenotypes, genetics and physiology because we know more about what selective pressures are at work.

When I started my faculty position at Washington State University (WSU), I would often stop by and see the bears at the WSU Bear Center. This got me thinking more and more about hibernation. Charlie Robbins, who started the Bear Center, noticed that I was interested in the bears and brought me into his team working on understanding bear hibernation.

Hibernation is a fascinating adaptation. Bears bulk up and then use that fat all through the winter, and then they do that again every year without negative consequences. We’re trying to find out what changes are happening on an annual basis to facilitate hibernation and then coming out of hibernation.

Could your studies of bears one day help people?

Bears become insulin resistant during hibernation and insulin sensitive outside of hibernation, and this happens over and over again without detrimental effects to their health. Insulin resistance is also a hallmark of Type 2 diabetes. While in bears this insulin resistance is adaptive, it is clearly maladaptive

in humans. Also, during hibernation, bears are barely moving, and yet there’s very little loss of muscle tone, whereas if one of us is on bedrest for even a short amount of time, it can become a huge issue. Muscle atrophy is especially problematic during hospitalization and in geriatric patients.

If we can identify the factors in the bears that restore insulin sensitivity or reduce muscle atrophy, we can use that information to develop therapeutics for humans. Although it may seem kind of wild, bears and humans share a lot of genes, so it’s not so far-fetched to think we might learn something from bears that could be applied in people.

What innovative approaches are you using to carry out this research?

We’re taking a functional genomics approach by looking at how gene expression changes throughout the seasons and the year in the bears. More recently, we’ve been trying to examine whether there are specific regulatory regions of the genome that drive some of the large-scale patterns that we see.

One of our earliest findings showed that in the bears’ adipose tissue thousands of genes change in terms of expression levels throughout the year. To better understand how that regulation happens, my colleague Heiko Jansen at WSU developed an adipose cell culture system based on cells from the bears. Using this cell culture system to complement our organismal studies allows us to ask more specific questions in a controlled environment. It also speeds up our research because we don’t have to wait a year until hibernation occurs again to perform a study.

We’re also working to conduct single-cell RNA sequencing on adipose biopsies to better understand whether the large differences in gene expression we see in adipose are due to changes in cell type composition changes or changes in expression within the same cell type. This is an ongoing project in the lab that I’m quite excited about.

Have you found any surprising or unexpected results?

One of our most exciting findings was showing that serum is incredibly important for the hibernation phenotype. In cell culture, we showed that applying serum from active season bears to cells that were sampled during hibernation shifted those cells into an active state from a transcriptomic perspective as well as a physiological perspective.

We showed that serum from bears that were fed glucose for two weeks during hibernation was sufficient to shift the cell signature back to active season. That was really surprising because the large-scale protein composition in that serum were very similar to hibernation serum. This meant that just a few proteins must be driving these changes.

We went on to identify just eight circulating proteins that seem to be involved in seasonal shifts in insulin sensitivity. We are now thinking about how to manipulate those in a cell culture setting to find out exactly how these serum proteins drive this change.

What makes you and your research a game changer?

It is very humbling to be listed as a game changer. I think I am just lucky. I was in the right place at the right time and found an incredible collaborative group to work with. … It was the constellation of expertise, technology and a collaborative team—all of those things coming together at the right moment.

Interview conducted by science writer Nancy D. Lamontagne.

This article was originally published in the March 2024 issue of The Physiologist Magazine. Copyright © 2024 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.