Announcer:
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 with Salk vice president, chief science officer and professor Martin Hetzer. He uses a variety of approaches to pose questions about how adult tissues are maintained and repaired and why long-lived cells fail to work properly as a cell ages. One of his recent discoveries is the surprising fact that organs such as the liver and pancreas contains cells that are a mosaic of different ages. Dr. Hetzer welcome to Where Cures Begin.

Martin Hetzer:
Hello.

Allie Akmal:
So, tell me how you became interested in science to begin with.

Martin Hetzer:
Yeah. I grew up in a rural area in Austria and my grandparents were close by, so I spent a lot of time with them and my grandpa was a veterinarian. And so he took me different farms in the area. He would mainly treat farm animals. So he worked with horses, cows, and not so much with birds and cats. But this was from a very early age I was exposed to farm life and animals. And, and I think that triggered some interest in nature and biology. I had someone who explained things to me that most people couldn’t because they just saw “here is an animal that is suffering” or “here is a certain occurrence within this farm, but nobody knows what’s going on.” And he would come and explain, “Oh that’s what’s going on and here’s what we’re going to do about it.”

So there’s also this idea that you can intervene. You can, you can do something about it, but you need to know about it. And I was very fortunate that I had him explaining things to me. He just didn’t do it, but he went down into details. And then I thought, influenced by him…I went to med school for two years and I thought I want to be a physician, but then I realized, nah, that’s actually probably not the right thing. I just really got fascinated with research. And then I switched completely because I started [in] a MD/PhD program, but then I really just…I don’t want to, I can’t be a physician. I really want to be a scientist.

Allie Akmal:
So how would you describe your area of research at Salk?

Martin Hetzer:
I started out as a geneticist and cell biologist. When I came to the Salk, I was really focusing on questions that are related to cell proliferation, to cancer. And this was actually the reason I got interested in cell biology in the first place because the cells and especially the nucleus—cell nuclei—are really very highly perturbed in cancer. So that got my interest. Then over the years as my group grew, and we made several discoveries that link cell biology to the longevity of organisms, we got more and more interested in research of aging. And now we’re very much focusing on aging and age-related diseases, and really try to understand how the normal aging process is actually linked to—in some cases—to the development of diseases.

Allie Akmal:
And we have a large population that’s aging, you know, in a big cohort than boomers.

Martin Hetzer:
Yeah. The boomers. So, many societies really already have a very high percentage of elderly people over 65 and older. That’s where we typically see age-related diseases such as cancer, cardiovascular problems, cognitive impairment really increase. There are already some populations, countries, that face that issue, but many, many more will face that issue in the coming decades. So it’s really critical that we understand and are able to distinguish between healthy and pathological aging.

Allie Akmal:
You actually had a paper, I think it was in 2018, where you we’re using machine learning algorithms to try to predict people’s age. Can you talk a little bit about that?

Martin Hetzer:
Yeah. There are many, many model systems and organisms that you can use to study aging, but in the end, we want to understand, how do humans age? And that turns out to be still a very, very poorly understood—certainly—process, but also, and it turns out that we have really not many tools to determine and measure in a very quantitative manner how fast a person is aging. So you start out with some high functional capacity and this deteriorates as you get older. And this gives you—this is typically represented sort of in a linear way, so that it gives you the impression, well, maybe aging is a really linear decline. So basically we age with the same rate as we get older, but we really don’t know that, right? It might be that in our 20s, 30s, we don’t age very much. And then as we get older, maybe hit a certain age, then really aging is accelerated.

And so while we all agree that the chronological age—so the number that is on your birthday cake—is not really useful because you can have an 80-year-old that just qualifies for a marathon and you have an 80-year-old who, you know, spends some time in a nursing home. So chronological age is not useful. And so how do you determine the biological age of a person? But what we wanted to do is seek, can we get molecular signatures? And in this particular case, it was, can we predict a biological age of gene expression patterns that we would find—in this particular case—in skin fibroblasts of people from different ages. And so we analyzed cells’ fibroblasts from the donors of ages less than 10 years up to 90 years of age and used a technique called RNA-seq, which allows you to quantify the levels of a RNA molecules in a given cell, which is very characteristic for a cell type. And then ask, well, are there any changes in this transcriptional profile of a cell that would correlate with age and, amazingly, it does.

And what they found is then that yes, there is a clear correlation between specific genes as they change with age that allow you to sort of predict like how old a person is.

Allie Akmal:
When Hetzer uses the phrase “predict how old” he means that the lab’s algorithm, based on the protein cells are making, can guess the age of the cells’ owner. By looking at this cellular data, their algorithm was able to correctly guess people’s age to within a few years.

Martin Hetzer:
But what’s perhaps even more interesting is that there are some people, some individuals who predict younger or older than the chronological age suggests. And so this is now a tool that we hope we can use to now say, okay, here we have a cohort of 50-year-olds, the chronological age of 50, but they predict younger. And compare them to also 50-year-olds who predict older. And now we can ask, okay, what’s different between them? And so now we have a tool hopefully to use this predictor to drill down on biology and really understand, okay, why do some people age more successfully than others? And the ultimate goal obviously is then to use then interventions…come up with recommendations to change people’s lifestyle, or dietary changes, even pharmacological interventions to improve the aging process of individuals. That’s still far way out, but that’s sort of the ultimate vision behind all this research.

The next step is then to identify a person’s biological age. Now we would like to know, okay, well now what’s the sort of health status or the aging trajectory of individual organs? Because, again, it’s another big unknown how different organs age. And not only my lab, but many other labs have clearly shown that different organs, such as the brain or the heart, they have very different aging mechanisms, which is probably not so surprising, right? Because the brain is largely composed of cells that are…we would refer [to as] post mitotic. So they are typically as old as your are. They never divide. And then you have other tissues such as intestine or skin that is constantly renewed from stem cells. It’s really remarkable that we are sort of a mosaic of cells that are literally as old as we are. And this is still, for me, as a cell biologist, really remarkable that how can a cell, like a nerve cell in the brain, live for a hundred years? And then you have on the other extreme, you have cells such as blood cells, immune cells, or intestinal cells. They can be, you know, a week old. So we have this huge spectrum of cellular longevity that we really don’t understand in the inter overall context of aging.

Allie Akmal:
Do you think we’ll see sort of groundbreaking discoveries and in this area, in the next say 10 years?

Martin Hetzer:
Yeah, I do. I do think the answer is yes. I think there is already, you know, great progress being made in identifying the key areas, almost like in—analogous to the cancer community, who over the last decades identified really the key drivers of cancer. But I think we’ll gain important insights into these early stages of age-related diseases, which I think will change the way we look at many of those diseases, but also hopefully deliver some meaningful interventions.

Allie Akmal:
In your role as Salk’s chief science officer maybe you’ll have a chance to influence the direction of these sorts of studies. Can you talk a little bit about what that position is, what your responsibilities are?

Martin Hetzer:
What I see the CSO office doing is providing a service to the scientists here. Both in the academic world a big part of responsibilities are things that relate to academic appointments—this is from recruitment to retention—making sure people have what they need so that this runs as seamless as it can run. And then the other big part is the operational aspects. So do people have the space they need? That’s a big part, but also that people have access to the technology that they need, both internally, but then we have also a need to access technology that is not located at Salk. So we are involved in developing agreements with other neighboring institutions so that people have all the technological—and also access to clinical samples—for instance, that they need to do the research.

And, so, a lot of my job is also working with our neighbors to think about how we can work together. Because one big advantage that we have here in San Diego is that we have an extremely strong research Institute, biotech and pharma in very close proximity. You know, we literally walk across the street—for everyone who knows La Jolla—across North Torrey Pines and then you’re on the UCSD campus. You walk a minute longer and then you run into Scripps scientists. And you drive a minute and you are in some of the hottest biotech hubs. And so this makes San Diego such a wonderful research environment. And since Salk is a relatively small research institute and very diverse in its research programs, we really want to have as many meaningful partnerships with our neighbors as we can. So this is part of our success.

Allie Akmal:
And then how did you end up at Salk?

Martin Hetzer:
Before I came here, I actually wanted to…I thought I would go to the Bay Area, but because I interviewed at UCF and I really like San Francisco. But then I have to say, when I interviewed here at Salk, really things fell into place for me. And I just immediately not only was impressed by the architecture but really the people I met—I was just really blown away by the depth of the conversations I had with faculty members here. I would talk to not only cell biologists, which was at that time, really my main interest, but I would talk to people about computational neuroscience, which I knew nothing about like what? And, so, I thought, okay, how would coming Salk…how would that change me? And how would that change my research? And I found that so much more exciting than going to a classical cell biology department where I’d be surrounded by, you know, for sure many people who would think like me, but…. I almost looked at this as an experiment, like what would happen to me if I joined the Salk? And so there was the main driver.

Allie Akmal:
What do you enjoy doing when you’re not working?

Martin Hetzer:
So running is something I always enjoy. And then being from Austria, I mean, skiing is an absolute must. At least twice a year we have to go skiing. And I think that’s probably my favorite sport ever. It’s just in part because we—both my wife and I—learned that when we were really young. So it’s very natural to us, but it’s just a wonderful sport. And here in California, well, in the broader US there’s so many great opportunities to go skiing. So yeah, so those are some of the physical parts and another form of for me meditation is to play the guitar. So music has a way to rewire your brain and your thoughts.

Allie Akmal:
Acoustic or electric or both?

Martin Hetzer:
Well, both, but mostly electric guitar. Now, both my son actually and I, we go to the same guitar teacher every other week and my son is much better than I.

Allie Akmal:
So do you have jam sessions with your son?

Martin Hetzer:
Yeah, we do. I mean, it depends on his level of patience. But yeah, we talk a lot about music and it’s so something that connects us.

Allie Akmal:
We’ve covered a lot of ground today. Is there anything that you wanted to share that you didn’t get a chance to share?

Martin Hetzer:
I just want to express again, like how wonderful of a, of a place that is and how wonderful La Jolla and San Diego is in providing an extremely vibrant and rich research environment combined with, you know, being close to the ocean and having a wonderful, relaxed life span.

So I feel…it’s not an advertisement like…advertising Salk, but I really feel very passionate about this. And, and I think…I’m just amazed that I’m able to come to work in a place like this. And I encourage people who don’t know Salk to just to come in and visit us. It’s just a really spectacular place.

Allie Akmal:
Yes, although we’re temporarily close to the public due to the pandemic, people can check our website, salk.edu to see when we’ve reopened. Thank you, Dr. Hetzer, for joining us today.

Martin Hetzer:
Thank you for having me.

Announcer:
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.