画外音
欢迎 实验室围墙之外, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned Research Institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries in cutting edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it.
在索尔克研究所，我们正在揭示生命的奥秘，并将这些发现传播到实验室之外。.

伊莎贝拉
Today, we welcome Pam Maher, who is a trained biochemist and cell biologist that spends her time at the Salk Institute studying the intersection between aging and neurodegenerative disease. Welcome to the podcast, Pam. We can get started at the very beginning. Where were you born?

Pam
Well, I was actually born in New York City and I lived there for about six months. And then my parents moved to the suburbs of in Connecticut, in Fairfield County.

伊莎贝拉
And did you stay in Connecticut for college?

Pam
I went to McGill University in Montreal because I wanted something really different. And I also didn’t want to be in a school that was—at that time there were still all female schools, and it was not my idea of a good time. And also I wanted a city rather than a small town because I had grown up in a small town and I didn’t like the environment of small towns where everybody knew everything about you.

伊莎贝拉
Moving to Canada, you must have liked the snow?

Pam
Well, I had grown up with snow, so it snow didn’t particularly bother me. I was used to that—cold winters—although Montreal was definitely colder than Connecticut.

伊莎贝拉
Do you remember being interested in science or plants or anything when you were a kid, or did that start later on?

Pam
Actually, as kind of—so I was really interested in science and then I had a couple of science teachers and in middle school and high school that I didn’t really like. And so I got kind of turned off from science. And when I went to college, I was thinking of majoring in political science. The woman in the room next to me was going to major in science, and she would come back and tell me about her classes every day.

And she was so excited about learning all this new stuff and I was not very excited about my classes. So I thought, well, maybe I’ll just try some classes because they sound a lot better than mine. So I just started going to her genetics class and then decided I’d transfer into biology.

伊莎贝拉
Was it difficult to switch majors?

Pam
That presented some hurdles because the genetics class was actually a second year class and she had taken Advanced Placement biology, so she was able to skip that but my school didn’t offer it, my high school. And so I had to at the same time I was taking genetics, I had to go backwards and take first year biology. And then I decided—

So, in the biology area at McGill, there were all sorts of options you could major in marine biology or cell biology, but biochemistry was sort of considered the most rigorous. And I figured if I’m going to do this, I might as well challenge myself.

伊莎贝拉
So, at what point did you decide you wanted to pursue research after college?

Pam
Well, the people around me, they were all pretty serious students, so I was surrounded by people who were planning on continuing—a number of them in either medical field or in basic sciences. So, I think that kind of became the direction I figured I would take as well.

伊莎贝拉
Did you consider medical school?

Pam
I did, but I’m really not—I don’t have a lot of empathy. And so I just didn’t think I was going to be very good. I would not be very good with patients. I wanted something where there was more discovery, I think. But staying in biochemistry, cell biology offered more opportunities for exploring and discovering.

伊莎贝拉
And then did you stay in Canada for your Ph.D.?

Pam
Yes, I did, yeah.

伊莎贝拉
And what were you looking at during your Ph.D.?

Pam
I ended up in the lab of a guy who really mostly interested in the eye, but he was just setting up his lab at the time, so he was open to exploring newer areas and I was more interested in nerve cells. One of the things he had developed was a technique for labeling cell surface receptors and being able to visualize them.

So, you would tag little spheres with antibodies or other molecules and look at their distribution on the cell surface and how that was changed with different types of treatments and stresses and things. So, that was one of the areas that I pursued, was to look more at how different types of stresses change the distribution of these different receptors on nerve cells.

And that led me to San Diego because one of the people at the time who was at the forefront of looking at the interaction between cell surface receptors and intracellular network of actin and microtubules was John Singer, who was at UCSD.

伊莎贝拉
And how was the experience coming from New England and Canada and going to San Diego?

Pam
So, I had been in Vancouver, which for Canada is kind of the San Diego of Canada, I guess you would say. It’s more temperate and it rarely snows there. So, I had already kind of moved from really cold winters and a lot of snow to Vancouver, where the winters weren’t really that cold, but they were pretty dreary. So, it was actually nice to come here and have more sun.

Yeah, and obviously I liked it because I’m still here a lot, long time later.

伊莎贝拉
Yeah, I was going to say you, you’ve stuck around so San Diego has grown on you. So, what was it like at UCSD and other places that you were in San Diego that weren’t Salk.

Pam
So UCSD was—Singer had a pretty big lab, I think. It was great because they were from all over the place and different a variety of different backgrounds and in general, pretty sociable, really welcoming. There always somebody seemed to always be organizing something and so that was it was it was a really good experience. And then the lab kind of, over time, shrank a bit.

And then I ended up going to a small place that was at the time affiliated with Scripps Memorial Hospital called the Whittier Institute, which I don’t think it exists anymore, but the reason I went there was that Roger Guillemin, who had moved there, and we were we were working specifically on fibroblast growth factor receptors, which had some of that early work had come out of Guillemin’s lab.

Then the Whittier, I guess you would say, kind of fell apart. The person who had started it retired so we were able to negotiate moving to Scripps Research Institute, and so we did. And then I was there for about eight years, I guess.

伊莎贝拉
And how was it there at Scripps?

Pam
The person who had taken this agreed to take our group in is was in the cell biology department at Scripps. He died and the new departmental chair wanted to take the department in a different direction. And she basically told me, I’m not interested in your work, so you should leave. So, at the time my husband was working, Dave Schubert was working at Salk, and he said, Why don’t you come here?

So, I did as initially as a senior staff scientist, so it was much better to come here and work in Dave’s lab with Dave and pursue my own interests, which were more closely aligned with Dave’s. And I think it gave me a lot more opportunities to expand in the areas that I was more interested in.

伊莎贝拉
So, what exactly was it that you were studying in those years as you transitioned into Salk?

Pam
I ended up focusing more on fibroblast growth factor receptors and their signaling mechanisms and particularly one of the fibroblast growth factors called it fibroblast growth factor 2, or basic FGF.

伊莎贝拉
Fibroblast growth factor receptors are little proteins that live on the services of cells, which are crucial in regulating the development of cells, then maintaining cell function once they’re mature. Fibroblast growth factors are the key to the fibroblast growth factor receptor lock and the interaction of the two is frequently implicated in cancers.

Pam
That led me to begin to start asking questions, which there was some evidence that this could be a protective in nerve cells. At the same time, we were doing some studies, Dave’s lab and then I was interested in this, too, of developing models of of nerve cell death. One of the obvious things to start looking at was fibroblast growth factors.

It turned out they didn’t help at all in protecting the cells, and then Dave had a postdoc in his lab who was really interested in in natural products. He started looking at the protective effects of natural products and I thought this was really interesting and I was really impressed by some of the data he was generating. And so that was the beginning of our work with looking at natural products as neuroprotective compounds.

伊莎贝拉
And when you came to Salk, you were in your husband’s lab? How did you meet?

Pam
We were both doing triathlons at the time and we were in a master’s swimming program at UCSD, and we were both in the slow lane because neither of us were very good swimmers. So, Dave and I were in the slow lane, and so we would talk between, while we were catching our breath between sets and it turned out he was at Salk and did some interesting research.

And it turned out from talking, obviously we had an and both had an interest in triathlons, and we also had a common interest in science.

伊莎贝拉
What was it like collaborating scientifically at Salk?

Pam
His lab, and now my lab is out in what were the temporary buildings that were first put up when they were building the original buildings of the Salk Institute. So, I had a separate lab within his lab, and as a senior staff scientist, I could apply for my own grant funding and everything. I mean, we worked together, but I had my own independent group, and I had my own postdocs and things within his group and then interacted with the postdocs in his lab as well.

伊莎贝拉
And you eventually became a research professor.

Pam
Yeah. So, Dave died in 2020, in August of 2020, so he hadn’t really been feeling very well. But because of the pandemic, he was really reluctant to go see a doctor. And by the time he did, it turned out he had B cell lymphoma, which at that by that point was untreatable. So, he died pretty quickly, actually. I mean, by the time he was diagnosed until he died, it was very quick.

The question at that time was what’s going to happen to the lab? And I really wanted to keep the science going for me, for Dave, because he had been the impetus, behind a significant portion of what was going on. I realize as head of a lab, if I’m not a faculty member, I’m really not part of conversations that are really important to running a lab here.

So, I asked if I could apply to be a research professor, and they said yes.

画外音
If you’re enjoying this episode of Beyond Lab Walls, be sure to check out our other channels at Salk.edu. There you can join our new exclusive media channel, Salk Streaming, where you’ll find interviews with our scientists, videos on our recent studies, and public lectures by our world-renowned professors. You can also explore our award-winning magazine Inside Salk and join our monthly newsletter to stay up to date on the world within these walls.

伊莎贝拉
So now you’re a research professor, you have your postdocs and your science, and you’re still looking at a lot of natural compounds. Can you tell me what a flavonoid is?

Pam
So, we all have certain metabolic processes where we make things like sugar, glucose, and make energy, and we make the building blocks of RNA and DNA and we make proteins, which is all called primary metabolism. But plants have a whole nother set of metabolic pathways called secondary metabolism, and they make thousands of molecules that are not essential for basic survival.

But they play all sorts of roles in plants, like protection against various insults, can be attracting pollinators, the colors in flowers. And so, among these products of secondary metabolism are a group of compounds called flavonoids, which are what are called polyphenols. They’re a group of three ring structures. The plants make six or 8000 different ones of these.

伊莎贝拉
Polyphenols are small chemical compounds found in nature. Each are made up of carbon rings and other chemical elements like oxygen and hydrogen.

Oh, interesting. So, we’re actually eating flavonoids all the time?

Pam
So, you can actually, depending on the flavonoid, get a fair amount in your diet. People were interested in them as potentially as antioxidants, but it turns out they they do a lot more than that and the antioxidant activity is probably not particularly relevant in humans because you just don’t eat that much of it. In the plants, it may be relevant because they’re concentrated in the plant cells.

伊莎贝拉
And what drew you to study flavonoids specifically?

Pam
It turns out that they have one of the things intrigued me about the originally and that still interests me is that they seem to have multiple activities, so they are able to interact with several different targets that are relevant to a number of age-related diseases. Historically, mainly plants were the source of all medicines. For thousands of years, people, different groups identify plants that can provide beneficial effects, and they knew which ones were helpful for fever or which ones were helpful if you had chest problems or which ones would be helpful in childbirth.

A number of our drugs that we still use were based on these, like aspirin, is based on willows. Some of the heart medicines—digitalis comes from digoxin, which is a plant product. So, there’s this long history of use but chemists had turned—medicinal chemists—away from this. They made lots of synthetic chemicals. And one of the problems with the flavonoids, they would stick in these dishes nonspecifically and give false positive results.

So, a lot of medicinal chemist would, those are horrible to use because they’re they give all these false positive results, but it doesn’t mean there’s anything wrong with them. It turns out now there there’s been a return to interest in natural products because chemists have now realized that there are a lot of what are called the scaffolds of different chemical structures.

So, the sort of the basic architecture. There, plants may have actually conceived, many more than chemists have been able to conceive. So even if the final drug candidate isn’t identical to natural products, the natural product provides a really good starting point. And so that’s one of the avenues we’ve taken. We’ve both been interested in the natural products themselves, but also made what we call derivatives, which are based on them but now are new, what are called new chemical entities.

伊莎贝拉
So, one fruit you’ve been looking at in particular is strawberries, which produce a flavonoid fisetin.

Pam
I studied that molecule for a long time. It’s not that abundant in strawberries, but that was kind of a selling point at one point. But you would have to eat quite a lot to, to get the kind of doses that seem to to have effects in humans. But it was rediscovered in the context of aging as what’s called a senolytic.

So as organisms age, one of the consequences can be that cells develop senescent cells. So, these are cells that are not dead, but they’ve stopped dividing and they’ve changed what’s called their phenotype, so they’re no longer doing their normal day job in whatever tissue they’re in. Instead, they start secreting a number of factors that can be damaging to other cells.

And so some people think that senescent cells are the drivers of aging. I think others think they are contributor, but it’s more complicated than that and I would come down on that side, and there have been a number of studies now testing it. So, for a clinical trial where it’s a natural product and you don’t have to go through all of the toxicology studies, I’m not sure it’s actually worked very well.

I do think it has potential.

伊莎贝拉
In addition to flavonoids, like fisetin, and Pam also looks at cannabinol. Cannabinol is a molecule derived from the cannabis plant and is commonly referred to as CBN. Like CBD, cannabinol is non-psychoactive and studies have begun emerging that demonstrate cannabinol may be a good tool for managing anxiety and pain.

And how is your research on cannabinol going?

Pam
We did a study in aging mice, and not so much for the effects, again, more in the context of loss of cognitive function. And there seem to be some beneficial effects in giving the mice CBN, cannabinol. We have a collaborator, Kim Finley, who works at San Diego State, who’s an expert on Drosophila, on flies. So we’ve been doing some studies with CBN and some of these derivatives in flies with you can do as is I quicker with flies in terms of effects on aging or effects on other types of neurological insults that she has developed.

I was contacted by a company up in Oregon called Flora Works that is interested in in CBN and related natural products. And so I’ve been testing some of the ones that they have in our cell-based assays and they’re interested in potentially identifying something that they could eventually test in humans. So, I’m not sure what the regulatory environment would be in terms of what kinds of approvals would be needed to take CBN into to humans.

But hopefully since it’s also a natural product and it’s not psychoactive, it wouldn’t be too difficult or something related.

伊莎贝拉
What does it take to bring something from your lab to clinical trials?

Pam
One of our approaches has been to take natural products and to work with chemists to modify them to improve their efficacy and their ability to to get into the brain. So, Dave’s work was focused on this curcumin derivative he called J 147, and he licensed that to a small company and they took it into phase one trials.

伊莎贝拉
Curcumin is a polyphenol derived from turmeric.

Pam
Originally it was for Alzheimer’s disease, but it looks as if now they’re switching focus to stroke for various reasons. To take something into humans, you first have to get what’s called IND approval, investigational new drug approval, which involves a whole bunch of both cell-based assays to look at various aspects of toxicology and inhibition or effects on various enzymes that are involved in drug metabolism, as well as animal toxicology studies that have to be done in two different species.

And if those are clean, then you can apply to the FDA to get this IND approval and that allows you to go into at least phase one clinical trials, which is where in humans you test safety and tolerability.

伊莎贝拉
Have there been any other derivatives since curcumin?

Pam
We developed a number of fisetin derivatives and ended up focusing on one of them, which we called CMS 121. I then ended up partnering with another scientist, Bill Raschke, who had a very small company here in San Diego, and we managed to fund research on first the fisetin derivatives in general, and we’re just finishing up a phase one clinical trial of CMS 121 and we’re trying to get funds to go into a phase two trial where we would test efficacy of the compound in Alzheimer’s.

But it’s a long road, it’s and it’s expensive, but it’s been a very much a learning experience, which is good.

伊莎贝拉
So, then the real question is the drugs are going to take a while: how many turmeric lattes and strawberries do I need to consume to become immortal?

Pam
Well, I would I as I said, for instance, fisetin is available as a supplement. You can buy it. So, I would suggest potentially taking that. With respect to both aging and Alzheimer’s disease, there are genetics involved, but there’s also physiological factors, lifestyle factors, environmental factors, all of those that appear to play a role in disease development. And those are factors that you can pay attention to and in many cases may adjust. In terms of physiological factors related to Alzheimer’s disease, but related to aging as well, obesity is a risk factor, type two diabetes.

In terms of lifestyle, getting exercise, eating a healthier diet, both of those play into both aging and Alzheimer’s disease, whether as well as other age-related diseases. Social interactions are important and I read a study a year or so ago that people who read rather than just watching TV or watching movies or something, they had better cognitive performance as they age.

伊莎贝拉
Wow, really?

Pam
Because when you read particularly and this was particularly fiction, so when you read novels, you have to keep all these characters in your head and you have to remember what they did five chapters ago, and and all of that it really makes you have to have much more cognitive engagement than you realize. Another study I read recently that as people with developed sort of cognitive problems, they tend to move from fiction to nonfiction because nonfiction is much more straightforward, and you don’t have to keep track of all this stuff that happened five or ten chapters ago.

So, all of these can contribute not only to maintaining cognitive function, but also healthier aging as well.

伊莎贝拉
That’s so interesting. Do you have other advice for promoting health and healthy aging?

Pam
One of the things coming out of a lot of research now is that some of these changes particularly, well, in the context of Alzheimer’s, but this would be relevant to aging as well again, is that even though we think of Alzheimer’s as an old person’s disease, a lot of the physiological factors say it’s diabetes, obesity, atrial fibrillation, they’ve met, the—

The biggest impact they have is actually when you’re say, have type two diabetes in midlife or obese in midlife, not when you’re older. So, it’s actually something you need to pay attention to and that’s something that’s not getting out there. And I think it’s really important that going forwards that people realize that maybe the diseases manifest themselves later, but your body is setting the stage for that much sooner.

伊莎贝拉
Speaking of the future and going forwards, how do you like running your own lab and helping out fledgling scientists?

Pam
I enjoy working with them and seeing them develop from often when they come, even though they have gotten a Ph.D., sometimes they’re still pretty unformed, I guess, and helping them to learn to write and writing is is critical to success in science. And if you can’t convey your ideas well, no matter how good the ideas are, you’re going to struggle.

伊莎贝拉
From Connecticut to Canada to San Diego, flavonoids, bench work, mentoring. You’ve accomplished so much. Do you have any free time or what do you do if you find yourself with a little bit of it?

Pam
I do a lot of gardening. I like hiking, so I do a fair amount of hiking. We have a really wide range of native plants here. San Diego County is actually one of or is the most diverse county in the U.S. botanically, I think probably because we stretch from the ocean to the desert. So, there’s a lot of interesting native plants and that’s also particularly this year has been really fun on hikes because so many things are blooming this year and there’s been waves of different types of wildflower or different blooming plants.

伊莎贝拉
Wow. I had no idea. That sounds very beautiful I’ll have to check it out. Thank you so much for talking to me. It was great getting to know you, your science, your life. I’m glad we got to have you on the podcast.

Pam
Well, thanks.

画外音
Beyond Lab Walls is a production of the Salk Office of Communications. To hear the latest science stories coming out of Salk, subscribe to our podcast and visit Salk.edu to join our new exclusive media channel, Salk Streaming. There you’ll find interviews with our scientists, videos on our recent studies, and public lectures by our world-renowned professors. You can also explore our award-winning magazine Inside Salk and join our monthly newsletter to stay up to date on the world within these walls.