Introduction:

Welcome to the Salk Institute’s Where Cures Begin podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.

Allie Akmal:

I’m here today with professor Ron Evans, who is director of Salk’s gene expression laboratory, and the March of Dimes chair in molecular and developmental biology. As a molecular endocrinologist, he studies hormones, both their normal activities and their roles in disease. Professor Evans, welcome to Where Cures Begin.

Ron Evans:

Thanks for having me here, Allie. Appreciate it.

Allie Akmal:

You’re known for your discovery of a large family of molecules called nuclear hormone receptors. That’s not nuclear as in nuclear bomb. Can you tell us what it refers to and what nuclear hormone receptors are?

Ron Evans:

Well, nuclear receptors basically are receptors for common hormones, such as steroid hormones, estrogen, androgens, cortisone, the anti-inflammatory molecule. Sometimes people put that on their skin to reduce itching and that sort of thing. These are all hormones and they act in the nucleus of a cell, which is why we call them nuclear hormone receptors.

Allie Akmal:

Okay.

Ron Evans:

So it’s not like the nuclear bomb, rather the information that they act on is in the nucleus. So we call them nuclear receptors.

Voiceover:

Hormones, like estrogen, testosterone, or the thyroid hormone, thyroxin, are genetic switches that control almost every aspect of growth and metabolism in humans. In a cell, once a hormone attaches to a nuclear hormone receptor, the switch is flipped and genes start turning on. We’ll hear a little later about how the Evans lab discovered the first nuclear hormone receptor in 1985, but first we’ll explore some of the labs more recent discoveries.

Allie Akmal:

One of the very exciting breakthroughs you had about nuclear hormone receptors was a genetic switch called PPAR-δ. And your discovery was that this switch can turn on genes that usually require physical exercise, like training for a marathon. And in reading about this, it was just really hard for me to get my mind around the fact that a genetic switch could accomplish something that would normally take a sort of a physical act on a person’s part. Can you explain why that’s possible?

Ron Evans:

PPAR-δ, it is one of 48 nuclear receptors we discovered in 1995. Like other nuclear receptors, it resides in the nucleus waiting for a signal. And the signal that it responds to is actually common dietary fats. These typically comprise 20% of your daily calories a day. People don’t often think what they eat is really controlling body function, but in this case, it does. Now, PPAR-δ is a metabolic switch [which] in the presence of dietary fats is activated and will begin the process of burning fat. What we discovered is if we made a chemical, that is, a compound that is not a fat, but is able to activate the receptor, and we just screened for drugs basically in our lab and found chemicals that are not fats, but they mimic fats, and when they bind to PPAR-δ, they activate it. And so what happens is that just like in normal exercise, when PPAR-δ is activated, these compounds that we call exercise mimetics, they activate the same genetic network as real exercise. And the muscle doesn’t know what’s causing it to turn on. It just is turned on.

Voiceover:

I want to emphasize what Evans is saying here. When we exercise, various genes are activated, genes that help us burn fat, for example. But a chemical compound made by the Evans lab was able to activate the same genes that would normally be activated by exercise, but without requiring any exercise. It was essentially exercise in a pill.

Ron Evans:

And so, as a result, if you give a mouse, let’s say an injection or in their food, the compound every day or one injection a day, but in another case, you exercise mice every day, at the end of a month of training a mouse on a treadmill, they can increase their running performance about 90%, almost double. Now we take mice that didn’t get any exercise, but we gave them our pill every day, once a day. And those mice actually could go to a hundred percent, that is double, of the other mouse that was getting trained. So they basically behave very similar to training, almost identical—training or the drug gave you the same benefit in terms of improving performance.

Allie Akmal:

Now, your research on this has been done in mice. Is your sense that it should work the same way in humans?

Ron Evans:

Well, first of all, we know it’s going to work the same way in humans, because hundreds, maybe even thousands of humans are taking it, mostly athletes, all the time. The Russians got caught doing this, and that was a big scandal, especially when Russia was hosting the Olympics.

News clip:

Russia is facing a doping scandal. The country’s shocking the world this week over allegations of state sponsored athletics doping. The world antidoping…

Ron Evans:

But in fact it will work in people. But we already have two different forms of the drug that are in new trials and in people. And those trials are up and running.

Allie Akmal:

Oh, great. So clinical trials.

Ron Evans:

With this drug and two different drugs, one for kidney disease, type of kidney disease, and another for kids with Duchenne muscular dystrophy.

Allie Akmal:

Did you find when you were doing the work in mice, that mice lost weight when they were on the drug as well? So could this be beneficial for obesity?

Ron Evans:

Well, that’s a very spot-on question and exactly that’s what happens because the main source for getting the energy for the muscle to burn, when you give PPAR-δ, is the adipose tissue. And muscle and fat communicate very well with each other. And so when the muscle gets the signal to burn fat, the [fat] gets a signal to release it. And so we do find that the mice are getting the drug do lose weight, even though they’re not exercising.

Allie Akmal:

Wow.

Ron Evans:

And so that’s another benefit. We also find that if those mice are on high fat diets or they have any signs of diabetes, it lowers blood sugar as well.

Allie Akmal:

Wow. So lots of benefits, it seems like.

Ron Evans:

These are benefits because what muscle likes to burn is sugar and fat. And so when you activate that program, it mostly wants to burn fat, but of course it’s happy to burn sugar as well. And these are two things that you really want to keep at low levels, naturally in your blood. You don’t want to have high lipids. You don’t want to have high sugar and these high-energy compounds, but you need them to be stored safely. You don’t want them in your blood for a long time because they’re reactive with other kinds of molecules.

And so basically, it’s one of the reasons why diabetes is a problem because you have chronically high sugar and sugar then interacts with other proteins.

Allie Akmal:

Your lab, actually, along these lines, just published a really exciting paper about a new stem-cell-based therapy for type 1 diabetes.

Ron Evans:

Type 1, or juvenile diabetes, occurs typically in kids, although it can occur in adults as well. And it’s an autoimmune disease where part of the body attacks—the immune system—attacks the cells in the pancreas called islets. And the islets are the insulin-producing cells. They’re called beta cells. If you have type 1 diabetes, the cells that produce insulin, the beta cell, is gone. So you have no way of controlling your glucose. And in adults with type 2 diabetes— which is linked to obesity, typically—that cell because of the obesity is working overtime 24/7, and it basically just fades out. It’s just overworked and becomes less and less efficient.

Allie Akmal:

And now your lab has developed synthetic islets, which you call HILOs. What were the challenges in developing them?

Ron Evans:

Stem cell technology has long been thought to be a way to create new kinds of therapy for people. And it’s held this promise of being able to create healthy new cells as replacements. But it’s been very difficult to actually make that happen. And what we did is, using stem cell technology, is we created cell clusters that come from basically a generic human cell that’s an FDA approved human cell. It’s called an embryonic stem cell. But we can do it from any cells. What we did basically, is use a series of what are protocols, or methods, to take that sort of generic cell and encourage it to move and progress down a series of steps that transforms it.

And one of the problems with the existing protocols, all of them, every single one, is that it does produce beta cells that make insulin, but those cells don’t respond to sugar, they don’t release the insulin. They just sit there, happily, smiling at you saying “I’m a beta cell. I’m loaded with insulin, but I’m not giving it up.” And so that doesn’t help.

Allie Akmal:

Okay.

Ron Evans:

And what we discovered is—through molecular genetic analysis—is that cells that work have an energy switch. Think of it as you’ve built a house, but you go in and there’s no light switches. So at night, it’s just completely dark. It’s like, okay, you got the beautiful house that you want, but you can’t live in it really. It’s not doing what it’s supposed to do. So what we basically found is a molecular light switch. It’s a nuclear hormone receptor, again, one that we discovered, I hate to say it, back in 1988. And it’s able to release the insulin in the cell very quickly—just like a normal islet would do that—now in the blood stream.

Allie Akmal:

Okay.

Ron Evans:

And so we had this major advance, the discovery of the power switch was key. That essentially, might call it turbocharges, the whole process. And the other previous cells were kind of in idle. They were there, they just couldn’t get anywhere. The secret was having the right nuclear receptor. And so that’s the first part of this advance that we’ve made. And the second was that the reason that kids have this problem of type 1 diabetes is their own body is rejecting beta cells with the immune system. The immune system’s on attack.

Allie Akmal:

Okay.

Ron Evans:

So if you put new beta cells in, even if they’re functional, it’s going to take them out. Every one you put in will be taken out, basically that day.

Allie Akmal:

There are medical protocols that transplant these beta cells into people and their own immune system destroys them, so they can’t really function.

Ron Evans:

That’s correct. The challenge with that kind of rescue is that you have to be on immunosuppressives the rest of your life.

Allie Akmal:

Oh, gosh.

Ron Evans:

Because you’re getting foreign cells and the body’s just going to reject it very quickly. And so it can work, but then you have to have this immune suppression going on.

Allie Akmal:

Okay.

Ron Evans:

So what we did is, understanding that the immune system was going to take cells out, especially if you’re putting a human cell in a mouse. And what we did to address that problem is we created kind of a molecular shield that is an immune protection shield. You put it on and the cells become invisible to the immune system. These synthetic islets, even though they’re human, start rescuing diabetes in diabetic mice, with human insulin, on the day that we introduce them into the mouse.

Allie Akmal:

Wow.

Ron Evans:

And they keep going, day after day after day, 10 days, 20 days, 30, 40, 50 days and great glucose control, that was completely rescued by a human cell in a mouse without a device.

Allie Akmal:

Wow.

Ron Evans:

And so that means that because the cells are not rejected—and it’s very challenging to get the cell not to be rejected—But it means we’ve kind of solved two major problems, which is why this new technology is really, I would say, a major step forward in trying to create a potential cure for type 1 diabetes. So we would like to gear this up to be able to get to people soon, which is challenging. Can you scale it up? We’re not rescuing diabetes in a mouse. A human is a lot bigger than a mouse. And so can you produce a thousand times more and can they all be quality controlled?

Voiceover:

We’ll be back in just a moment. If you liked this interview and want to hear others, be sure to subscribe. For instance, you might enjoy hearing about the power of stem cells in season one, episode six. And if you’d like to get regular updates about Salk discoveries, sign up for our monthly newsletter at salk.edu/news.

Allie Akmal:

Now I’d like to switch gears and ask how you got interested in science to begin with.

Ron Evans:

Oh, you’re going back now a hundred years ago. Yeah. So I was always interested in science. And so that, it may not be surprising, and as I went into it, my dad was a physician, although I have to say he was the first person in his family to go to college.

Allie Akmal:

Oh, wow.

Ron Evans:

And the only person for a long time until my brother and I then went to college as well.

Voiceover:

Evans got his undergraduate and graduate degrees from UCLA, at the start of the molecular biology era, an era that’s revolutionized the study of genetics.

Ron Evans:

My interest was in gene control, trying to understand how the logic of genomic activity is regulated. I studied viruses, I was a virologist by training, RNA viruses like the coronavirus. Then I did DNA viruses for my postdoc.

Allie Akmal:

After completing his postdoctoral training at Rockefeller University, Evans came to Salk as an assistant professor and switched from working on viral genes to working on cellular genes.

Ron Evans:

I thought cellular genes could be the goal for gene expression. And I decided to work on two receptors that were genetic regulators, one’s called the glucocorticoid receptor, and the other’s called the thyroid hormone receptor. And so one’s a steroid receptor, and one’s a receptor for thyroid hormone, which is a modified amino acid. Thyroid hormone controls basal metabolic rate, controls your temperature. It controls your heart rate, that controls your alertness. Glucocorticoids control sugar, that’s the glucose part in the name. That’s the major trigger for the fight or flight response. But the way they work is strictly controlling genes. And I thought if I could get one of these two genetic regulators for hormones, because the advantage of these, you can turn them on and off with the hormone, this steroid, the genes turn on and take it away, a gene goes off.

And so I set my sights on isolating these receptors. There were no manuals for it. I knew how to do RNA sequencing before I came in and no one else that was working on it, had these tools. And because of that, I had an intrinsic advantage. I also had, a double bonus is that I used a network of people to help advance what I wanted to do. And in a relatively short time, we were able to get the first steroid receptor, called the glucocorticoid receptor. And I won’t go through all the details of that. But basically, that was a landmark in the hormone field. Having the first hormone receptor, we’d have the hormones for basically a hundred years, but no one had the target.

Voiceover:

When Evans talks about isolating the first hormone receptor, he means identifying the gene for it, within DNA. And knowing what the exact DNA sequence of the gene was, was a big deal because it was a familiar sequence. This suggested genes for other hormone receptors might be similar and could also be found within the genome.

Ron Evans:

And so we then said, there’s got to be more out there. And very quickly, and I won’t go through a lot of the details, we discovered that there were quite a few unnamed receptors in the genome. Thyroid had been discovered back in 1914 and glucocorticoids in 1920, and retinoids in 1915. These molecules had been known, basically all of the classic endocrine hormones were known 50 to 60 years ago. No one had the targets and everyone thought that targets would all be different. But in fact, they’re all just variants of each other. And that led to what I call the super family of receptors.

Allie Akmal:

You’ve obviously found a lot to keep you excited in going into the lab every day. Do you have hobbies or activities that you do that are not about science?

Ron Evans:

I’m not a great tennis player but I love playing tennis. So being physically active. But another big hobby of mine was planting flowers.

Allie Akmal:

Oh, okay.

Ron Evans:

I like to plant and I used to come home from lab every day and have it setup where I would have a pot, something to plant, soil. And before I come in, I just go out to the planting area and plant a plant. I really like dirt, getting into the feel of the earth kind of thing. And still do that. Don’t plant every day, but do a lot planting.

Allie Akmal:

You must have an incredible garden.

Ron Evans:

Well, my wife is really avid about that as well. It’s a shared passion. The other thing is I play guitar. Guitar is an instrument that I have adopted since I was a young teenager. I played many kinds of, they’re all basically acoustic. I have two electric guitars, but most learned it as acoustic guitar. And then mostly in kind of in that learning phase, like the James Taylor and the Bob Dylan and that kind of, Paul Simon kind of thing. I just love, they all their personalities, different sounds, different feel. So yeah, they’re again, endlessly interesting. And when you’re playing music, you can’t have anything else in your brain. It just takes you offline completely.

Allie Akmal:

You have to be really present.

Ron Evans:

You have to be present. And it really is a way to unplug, one thing and it’s a surefire trick. It always works.

Allie Akmal:

That’s fabulous.

Ron Evans:

And I like to play for myself, but I’m starting a little bit more for other people. I used to not want to do it, but I had a heart problem a couple of years ago that I wasn’t aware of. I was just getting weaker and weaker and dizzier and dizzier. And I was fainting. I was having all sorts of cancellations on trips. I was going to many, many doctors, they couldn’t figure out what it was. But turned out to be that my right coronary artery shut down completely without my knowing it. But because I work out all the time and play tennis all the time, I had these collateral vessels that came in to help rescue that right side. But it was still getting weaker and weaker. And finally, and I had to go for open heart surgery.

Allie Akmal:

Wow.

Ron Evans:

They unplugged three additional parts and my brain came back online. I suddenly had twice as much oxygen.

Allie Akmal:

Oh my gosh.

Ron Evans:

And so after that, it’s funny that I started playing guitar more for people as well. It was one of my ways to get out of the harshness of surgery. I think the heart and heart surgery is different than other organs—[this] may not be fair to other people that had surgery—but there’s so many things about the heart. It’s like ‘heartfelt,’ and ‘healing your heart,’ ‘heartwarming.’

Allie Akmal:

So metaphorical.

Ron Evans:

‘Warms the cockles of my heart’ and the heart of the matter,’ all these things in which you don’t have it for any other organ. You don’t have the liver or your pancreas or whatever. It was very philosophical to have the surgery and the recovery. I do feel that the benefit of having it is that you think more deeply about yourself in life. And so the gift is that I appreciate things more. So there’s always everything that’s bad, there’s always something that gets good, and guitar got me into all that.

Allie Akmal:

We’ve covered so much ground today. It’s been fascinating. Is there anything you’d like to add that I didn’t ask about?

Ron Evans:

Things that I think about and that I enjoy is trying to encourage the next generation of young scientists that are coming forward. Science is so powerful now that many, many things are possible. But in the end, it comes down to having your ideas, when to know and go into something and what you want to pursue. And so it was not only what Francis Crick told me, because Francis Crick was at the Salk when I was there as well. I had all these great mentors.

Allie Akmal:

Yeah. Francis Crick, one of the co-discoverers of the structure of DNA.

Ron Evans:

One of the co-discoverers of the double helix. And he was known for being able to ask the right questions. And for me, it’s a very humbling lesson because you can ask many questions. There’s hundreds of ways that you can be curious about things, but Francis would get down to what’s the key question. I don’t want to have a good question or a pretty good question, what is the key question? He had ways of distilling things and also pushing you—and pushing me. I talked to him about certain things and he’d say “good idea” or he’d say, “No, Ron. You should let someone else do that. Good idea, not for you.”

So he was very helpful actually. All of the mentors that I had made me step up my game. And I think it’s a good lesson for young people that are coming on, and there’s so much to do. It’s a great year in science. And so it still comes down to knowing what to ask. That’s going to be the key.

Allie Akmal:

Well, Professor Evans, thank you for leaving us with some words of wisdom. This has been a great conversation and thank you so much.

Ron Evans:

Allie, thank you very much for having me.

Ending:

Join us next time for more cutting-edge Salk science. At Salk, world-renowned scientists work together to explore big, bold ideas, from cancer to Alzheimer’s, aging to climate change. Where Cures Begin is a production of the Salk Institute’s Office of Communications. To learn more about the research discussed today, visit salk.edu/podcast.