The Science of Aging (And Why Research May Hold the Key to Longevity)

Why do some people age faster than others? That question has intrigued scientists for centuries as they try to unravel the mysteries of longevity. This episode of the Princeton Pulse Podcast highlights breakthroughs in genetics, molecular biology, and genomics that are helping researchers understand the biological process of aging and, in turn, how we can not only live longer, but also healthier. 

Host Heather Howard, a professor at Princeton University and former New Jersey Commissioner of Health and Senior Services, is joined by two guests: Professor Coleen Murphy, director of Princeton’s Lewis-Sigler Institute for Integrative Genomics and the Paul F. Glenn Laboratories for Aging Research, whose work explores the molecular underpinning of longevity and age-associated diseases; and  Professor Jeremy Berg from the University of Pittsburgh, who formerly served as editor-in-chief of Science magazine and director of the National Institute of General Medical Sciences. 

The panel discusses how scientific research could hold the key to longevity. They explain how studying worms and other organisms may lead to discoveries that improve women’s reproductive health, slow down cognitive aging, and prevent or manage certain chronic and degenerative disorders. They also underscore the impact of federal research funding on this important work.

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Learn more about Coleen Murphy’s research on the process of aging: Coleen Murphy | Lewis-Sigler Institute 

Learn more about Jeremy Berg’s current research at University of Pittsburgh: Jeremy M. Berg, PhD - Department of Computational and Systems Biology

The Princeton Pulse Podcast is a production of Princeton University's Center for Health and Wellbeing (CHW). The show is hosted by Heather Howard, a professor at Princeton University and former New Jersey Commissioner of Health and Senior Services, produced by Aimee Bronfeld, and edited by Alex Brownstein. You can subscribe to The Princeton Pulse Podcast on Apple Podcasts, Spotify, or wherever you enjoy your favorite podcasts.

Transcript

Episode #23 -- The Science of Aging (And Why Research May Hold the Key to Longevity)

SPEAKERS

Coleen Murphy, Heather Howard, Jeremy Berg

Heather Howard 

Hi, and welcome to the Princeton Pulse Podcast. I'm Heather Howard, professor at Princeton University and former New Jersey Commissioner of Health and Senior Services. On campus and beyond, I've dedicated my career to advancing public health. That's why I'm excited to host this podcast and shine a light on the valuable connections between health research and policy. Our show will bring together scholars, policy makers, and other leaders to discuss today's most pressing health policy issues domestically and globally. We'll highlight novel research at Princeton, along with partnerships aimed at improving public health and reducing health disparities. I hope you'll listen in as we put our fingers on the pulse and examine the power and possibilities of evidence-informed health policy. 

Heather Howard 

Why do some people age faster than others? That question has intrigued scientists for centuries as they try to unravel the mysteries of longevity. An answer finally may be within reach. Thanks to advancements in genetics, molecular biology, and genomics, researchers are beginning to understand the biological process of aging, and in turn, how we can not only live longer but also healthier. 

Heather Howard 

On today's episode, we welcome Princeton Professor Coleen Murphy, Director of Princeton's Lewis Sigler Institute for Integrative Genomics and the Paul F. Glenn Laboratories for Aging Research. Her fascinating work explores the molecular underpinning of longevity and age-related decline. To that end, she and her team seek to identify genes associated with the biological functions that contribute most to our quality of life. We'll dive into her research and the progress she's made with funding from NIH, or the National Institutes of Health. Also joining us is Professor Jeremy Berg from the University of Pittsburgh, who formerly served as editor in chief of Science Magazine and director of the National Institute of General Medical Sciences. He'll share his views on the current state of federal research funding and the widespread impact of cuts to NIH grants for studies on aging, mental health, cancer, Alzheimer's, and other diseases. Coleen, Jeremy, welcome to the show.

Coleen Murphy

Thanks for having us.

Jeremy Berg 

Glad to be here.

Heather Howard 

Coleen, before we dig into the topic at hand, can you just tell us a little bit about your background and research interests?

Coleen Murphy 

Well, my background is actually in biochemistry, genetics, genomics. Before I came to Princeton, I had done my graduate work in biochemistry and enzyme kinetics, and then I went to do a postdoc with Cynthia Kenyon, who was basically the first person to really explore, discover a longevity mutant, and that was in C. elegans. I built microarrays there, so I could look at 1000s of genes at once that are changed in a longevity mutant. Then I came to Princeton, where I've been really focusing on studying not just aging and longevity, but things that we care about with humans, for example, loss of our cognitive function with age and reproductive aging as well. But using a small model system called Caenorhabditis elegans, C. elegans, to do that, because it's very well conserved. So, what we find in these little worms is often directly applicable to humans. That's the model system we use in our lab.

Heather Howard 

Great, so we'll get back to the worms. But first, Jeremy, you've had an illustrious career. Can you tell us briefly about that background and what you're now doing at the University of Pittsburgh?

Jeremy Berg 

I am a chemist by training, and sort of drifted from chemistry into biochemistry and biophysics when I was at Johns Hopkins. I was doing well there, working on gene regulation, structure, and function of proteins, and then got a call out of the blue asking me if I would be interested in applying for the position of Director of the National Institute of Journal Medical Sciences at NIH, which had been the agency that had funded me, actually, since I was undergraduate all the way through. I looked into it a little bit, decided I could never figure out what the job was until I just did it, so I decided to jump in, and I loved it. I was there for almost eight years. It was the best job I ever had, and also the hardest job I ever had. Then my wife got recruited to the University of Pittsburgh, and I was dragged, not quite kicking and screaming, but I was definitely the trailing spouse when we were recruited here, and we've been here for going on 15 years now. So I'm a professional professor of computational and systems biology, and still research active, still working on some molecular computational problems. But also, courtesy of Vladimir Putin invading Ukraine, I'm now a born-again biostatistician, helping my wife, who does breast cancer screening trials, because her statistician was from Ukraine and went back to Europe to try to figure out what to do with his parents when Putin invaded. She didn't have any money for a statistician and needed stuff done, so we just published our sixth paper together, I think. 

Heather Howard 

That's wonderful. Congratulations, and you also have played a part in Coleen's research, right? 

Jeremy Berg  

Yeah, so when I was at NIH, the first year I got there, they started a new program called the NIH Director's Pioneer Award, which was intended to be for proven, innovative scientists who wanted to work on some big ideas. It was sort of an experiment, because people had said there were all these incredibly talented people who just couldn't get their projects funded because they were a little bit too out there, or too high risk, or they came from weird directions. That program has been great, but the first year there were nine winners, there were nine male winners, and about half the people were very well established at NIH funding, doing interesting science, but it didn't seem like they fit the profile for the program very well. And I was complaining to the NIH director that this seemed like a lost opportunity. I dutifully went back and wrote a long email to him explaining what my concerns were, and two days later I was invited to run the program, so I should have realized I was filling out a job application. A couple years later, the program was doing well, Dr. Zarini was very focused on early-stage investigators and how to support them more, and the Congress had really liked the Pioneer program. So, in the middle of February one year, I got called into a meeting with the budget director and the NIH director, saying, "You guys think you can set up a program in the next six months to do sort of junior pioneers to early-stage investigators, but give them freedom to do stuff?" That was called the NIH Director's New Innovator Program, and we got it done and got lots of applications and funded not nearly as many applications that we would have liked. One of the best parts of that job, which I sort of took on myself, was actually calling the winners of the New Innovator awards and telling them that they got an award. One, I wanted them to know. Two, it was just an opportunity to sort of make connections between these young scientists and the NIH. And three, it was just really fun because you could watch people's lives change over the phone, just really excited that they could finally do what they really wanted to do. So I called Coleen and told her that she won one. I didn't realize that her husband, who also won one, was actually in the car, and she was very anxious about how much stress there was going to be in the family if things didn't go well on the other phone call.

Heather Howard 

Coleen, can you tell us what did that call mean? 

Coleen Murphy

Oh, it was fantastic. To this day I still have trouble getting the regular bland sort of R1 funding because I think a lot of things I want to do are kind of weird. That particular grant was about reproductive aging, and at the time, that was 2008, not a lot of people were focused on that. I remember I even had the word "chick-lit" for chick literature. It was nice; you could write an essay, basically, and I love writing. So it allowed me to really explain what I wanted to do, but not be constrained by some of the ways that we normally give grants. That was really helpful for getting my lab off the ground. And, as Jeremy said, it was really nice because I worried for a moment. It was great to get the call, but Zamar and I had both only started labs two years before. So it was a little tense both going up for the same awards. Luckily the NIH was generous, and we both won those awards, so that was fantastic.

Jeremy Berg 

Yeah, I should say one of one of the most poignant things about that program, that's been sort of depressing in some ways, is like every year I got at least one email from somebody saying, "I didn't get the award, but it was so nice to be able to write about what I really want to do, as opposed to what I think I can get funded to do."

Coleen Murphy  

That's right.

Jeremy Berg

It was, on the one hand, very satisfying that we created the program. On the other hand, it was really damning about the system. We've managed to create a system where we take these super talented young people when they're full of crazy ideas and aren't experienced enough to know that none of them are going to work, so they just go ahead and propose them anyway. Giving them an opportunity to think big and spread their wings and sort of try to do something important, as opposed to do something fundable, which might be important, too, but...

Heather Howard 

So let's go there on the important work you're doing. Coleen, tell us about your lab and what you're studying, and what you're finding.

Coleen Murphy 

Okay, so we've had the lab for about 20 years now. When I started the lab, the whole field at that time, that was 2005, was really focused on the idea of just studying aging and longevity, and kind of getting the world record for, if you're in worms, how long they could live. I was not really interested in that. I realized when I was a postdoc that there were two things I really cared about. No matter how long I lived, I would want to keep my brain working as long as possible. And, particularly for me, I didn't have kids yet, I felt like I was going to need to make a decision about when I was going to have kids pretty soon. So those are the areas that my lab focused on, and it was fun. The reason this was relevant for a New Innovator award was because there are a lot of misconceptions about the field at the time. For example, even C. elegans. People thought that worms could reproduce forever, but what we found was that worms, like humans, can only reproduce for a certain amount of time. That's because their oocytes degrade with age. Once you get that key, then you can ask, "Well, what are the molecular mechanisms that change with age?" It turns out they're all super well conserved. And how can you manipulate this so that you can actually keep oocyte health longer. That worked as well, so we were able to really make a lot of progress in C. elegans to the point that now we've kind of dropped the entire C. elegans arm of this. We're really interested in women's reproductive health. We're to the point of actually developing a diagnostic to predict how long women can have kids. That's kind of the arc that started with the crazy stuff that we got funded early on by the New Innovator award.

Heather Howard 

So you came at it from the perspective of this was an area that had been overlooked, and then you found not just that it needed attention, but that it actually might be key to the question, right? I mean, help me understand that. Help our listeners understand why understanding reproduction helps in understanding healthy aging for everyone.

Jeremy Berg 

Okay, so there's two facts. It's still frustrating to me when I hear people talk about reproduction. They mix up menopause and reproductive aging, but for women there's a 15-year gap in those two things. So we really shouldn't think of them as interchangeable, because if you keep doing that, you'll never study the right thing. Okay, so that's one thing. Their mechanisms are largely regulated independently. The other interesting thing, though, if we look at humans, and this is one of my favorite facts from a study from Tom Pearl's lab. He looked back at historical records, before artificial reproductive technologies and IVF and things, [and found that] women who naturally were able to have kids after the age of 40 were more likely to be centenarians than women than women who couldn't. This is exactly what we saw in C. elegans, that the long-lived forms actually could reproduce longer. What it tells you is that, at a systemic level, animals or people who are very healthy basically extend all of their systems. I don't want anyone to misunderstand: having a kid late will not make you live longer. But the women who are able to do that naturally are more likely to be centenarians, which gives us an insight into the systemic regulation of longevity that you can't get late in life. You really get it early in life.

Heather Howard 

And what is that connection?

Coleen Murphy  

Okay, in C. elegans, it's actually regulated almost entirely by the insulin signaling system. So long-lived signaling mutants can reproduce very long because they keep their oocytes healthy. And to the other half my lab, they actually have really fantastic maintenance of their neurons and memory as well. So that's the other direction that the lab went in. What we're seeing, because evolution happened, is that for all these animals, their molecular genetics are extremely well conserved. So, when we find something that's key for one of these regulatory mechanisms in C. elegans, often we look and we see that actually true in mammals as well.

Heather Howard 

So, you said you're developing a diagnostic. How do you translate that research into something applicable to us?

Coleen Murphy 

Right. So, just taking that logic, that it's a system level difference that will allow you to both live long and have kids later, that means you should look for a signal in the system, not necessarily in the ovary itself, for example, which is super invasive. Instead we should ask if there is something, for example in our circulating blood, that will actually give us a signal that might indicate your reproductive aging status. That's the test that we're developing now, but it's based on the basic idea that you get signals in blood that indicate overall health and could predict longevity. That's kind of an accepted idea in the aging field for a while, but I think, as far as I know, we're the first people to apply this to the reproductive system,

Heather Howard 

And once you know that, you know your status, can you affect it? Can you change it?

Coleen Murphy 

That's a great question. So that's going to be the second question we'll ask. Anecdotally, we know that people who are being treated for PCOS -- which I think got a new name change just today, I have to look that up, PMOS, or maybe POMS -- people who are treated for that, often with things like metformin, which is of course also a diabetes drug...

Heather Howard 

That's polycystic ovarian syndrome?

Coleen Murphy 

That's right, but today it got a new name. I'll have to look that up. People who are treated for that often see a rescue of their fertility, and often that overlaps with metabolic syndromes. And just another anecdote is that every time I give a talk or present a poster about this, someone will come up to me. Like not too long ago, a woman came up to me and said that her daughter went on one of these GLP 1 agonists,  Ozempic or something, and now they're having a baby. So it's all anecdotal, but there's an idea that you could alter your metabolic system and help rescue fertility. That's more a systemic thing than these direct ovarian things, which are perfectly worth doing, but I think that's very different from what we're looking at.

Heather Howard 

And I've read you used the term "healthspan," right? What do you mean by that?

Coleen Murphy 

I think everyone's a little bit rightfully allergic to the idea that you would live longer without maintaining your health. All of us, I think, would like to be as healthy as possible as long as possible, and that's really what we're interested in, rather than just, like, you know, winning the record for a long life.

Heather Howard 

So this is about identifying the mechanisms, and then thinking about how to change them so that we can live longer and healthier.

Coleen Murphy 

That's right. And so the other half of my lab is really focused on cognitive decline. We made up a memory, we have short-term, long-term memory assays for C. elegans, which again people hadn't done before, because they thought worms couldn't learn anything. It turns out worms are smart. Like any animal in the wild has to figure out where there's food, where there's danger, they have to do all these things. In order to do that, they have to use their neurons appropriately. And it turns out the long-lived animals do this better and longer. So we were able to find mechanisms to keep the neurons healthier. That's evolved now. We've been able to apply this in mice by basically making the same molecular change in neurons, and now we've done with the Chemistry Department a very large compound screen to look for activators of that same pathway. So the hope is that we will be able to find a drug that will slow down our cognitive aging.

Heather Howard 

What's your timeframe on that? 

Coleen Murphy 

Yeah, everybody wants to run back to lab and bother my students again. 

Heather Howard 

We want to explore with Jeremy the current state of NIH funding. We started by talking about the New Innovator award that you got early in your career. How important has NIH funding been in all this research?

Coleen Murphy 

Well, the other awards that Jeremy mentioned actually have been super important. I've managed since then to get two Pioneer Awards and also a transformative R1 with a team here at Princeton. Those have really fueled the research that we have been able to do, and again, because they're kind of off the wall ideas, you know, those don't do so well in the normal R1 pathway, but they've been fundamental for getting all the work done in our lab that we've been able to do. I also have to thank, you know, like the Glenn Foundation and the Simons Foundation, which has allowed me to start something called the Simons Collaboration on Plasticity in the Aging Brain. It's a mouthful, but that's all about cognitive decline, and so that's been the other component that has complemented the NIH funding that has allowed our lab to get a lot of work done.

Heather Howard 

But do you think having received these NIH awards presumably made you more attracted to these foundations? 

Coleen Murphy 

Absolutely right, because without NIH funding to start the lab, you can't do the work until that attracts other funding. So it's all super important. And I worry about younger faculty now, because with the NIH problems, which you're going to talk about, they're not going to be in a position to be able to build their research programs. 

Heather Howard 

So, Jeremy, it must be music to your ears to hear Colleen talk about this, right? Maybe you can pull us back and tell our listeners, who are not scientists, why the federal government should be funding research into worms. Can you help us understand that? 

Jeremy Berg 

Sure, but let me take a step back before we start. When Dr. Zaruni was at NIH, the framing that he used is that the goal is to die young as late as possible, which I always thought was a really good way of putting it. The other thing is that things can come out of left field in all sorts of ways, certainly C. elegans. But the other thing that certainly has the aging and Alzheimer's field thinking differently is this sort of crazy, mostly insurance-based situation in Wales in the UK., when the national health system made shingles vaccination available. The way the rules work, there was a particular day. If you were older than that day, you weren't eligible. If you were younger than that day, you were eligible. And it turns out that, like 50% of the people who were younger than that age got vaccinated. No one older did. So, you have this incredibly clear mark that would be impossible to do in any sort of trial on purpose.

Heather Howard 

It's a natural experiment that you would never do, because you wouldn't deny people.

Jeremy Berg 

Yeah, I mean, there has to be a date for insurance coverage, and they just picked a date. When they looked at data after seven years, it turns out the people who were born after that date were close to 10% less likely to get dementia, which I don't think was on anybody's radar screen. But just because of the design experiment, it was really obvious. It was like this huge step function. It was like, wait, what happened here? So sort of speaking to Colleen's work, that presumably something systemic with inflammation related to neurotrophic virus infection, or something, who knows, that is contributing to Alzheimer's risk. And rather than just worrying about the things that Alzheimer's researchers have been worrying about, there are presumably a lot of people who are now both trying to figure out how to implement this and really pushing people to get shingles vaccination, because it's doubly good for you. You don't want to get shingles either. Or maybe there are mechanisms that you can sort out that could be even more powerful. 

Jeremy Berg 

So in terms of why people should be interested in supporting C. elegans or other organisms, there are sort of two threads that come together. One is just a biological fact, which I still think is one of the most astounding things around. It's very easy for biological scientists not even to tell people this, because it's so obvious to us at this point, and that is what Colleen said. If you look at organisms, the whole level, we're obviously looking really different than a couple of millimeter long worm. You could tell us apart pretty easily. But if you start looking at cells, it gets a little tricky. When you start looking at biochemical pathways, it becomes next to impossible, because there's so much stuff that evolved early in evolution and has just been maintained -- biochemical path with biochemical proteins, biochemical pathways. I mean, evolution is wonderful, but it's pretty lazy. It basically takes stuff that works and tweaks it to make it a little better or adapts it to a different set of circumstances. But they very rarely sort of invent totally new technology, because that's really hard to do. So because of that, pathways that work in humans turn out to have counterparts in mice and counterparts sometimes in worms and sometimes have counterparts in yeast, in single cell organisms. And researchers just move back and forth between these organisms and don't even give it a second thought.  

Jeremy Berg 

When I was at Hopkins, I was training a fundraiser, and we went to a seminar together. I was bringing her to exciting seminars, so she could get the hang of what basic science was, and a guy was giving a talk about sort of going back and forth between mice and humans about something fairly clinical. It was a great talk, and I walked out with her, and I said, "What do you think?" And she looked very upset and very concerned, and sort of said, "Is he okay? You know, should do we need to call somebody? He doesn't seem to understand that people and mice are different." And I was like, we need to talk. It seems crazy, but it turns out it's true at a pretty deep level, a lot of the time, not always. But the other thing was that in 1945, there was a document written by Vannevar Bush, who was an MIT engineer who had become a big government advisor during World War 11. And he was also a pretty effective bureaucrat, so he was wondering about how to fund science after the war ended. During the war, it was very contract driven. The government would say, "we really need this," and they would find people to do it, and they would give them a contract, and they would do it. 

Jeremy Berg 

But he also discovered that a lot of problems, like better fuses for detonating bombs, or the Manhattan Project, there was all this off-the-shelf stuff that had come out of academia that had nothing to do with what they were working on, but just turned out to be exactly what what they needed at the time. So he asked President Roosevelt to ask him to put together a group to write a report about how to fund science after the war. As far as I can tell, he never asked anybody else, but he wrote the report. I don't know if he had that in mind all the way, or whether he got more advice. Then as the war was wrapping down, and President Roosevelt had died, he delivered to President Truman this report. It was called "Science: The Endless Frontier," and it is one of the most amazing, forward-looking documents ever written. Basically, what he said was, what the government should do is fund curiosity-driven research in academia; they should not decide what the problems are. They should just let academicians pick the problems that they're most interested in and most curious about, and work on it, and publish their work. And that was the best way to support the military and industry, and everything else, because by the time you figured out what you needed, it would take too long to do the research. If you funded 100 scientists doing things they just thought were really interesting, you couldn't figure out which one of them would be useful, but one or two of them would be really useful. That idea became the basis for the funding models in the U.S. and led to the founding of the National Science Foundation and basically the grant program at the NIH. It's been incredibly productive. That, and the fact that the Nazis sort of chased all the Jewish scientists out of Germany and Europe, were the powerful drivers for American science for decades and decades. People wonder why we, America, does so well in terms of Nobel prizes and leading discoveries, and so on. A lot of it is that model.

Heather Howard 

Where are we today in this NIH funding?

Jeremy Berg

So what's been unbelievably disheartening and sort of disorienting, and so on, has been the current Administration has been, in my view, using science and science funding as leverage against universities, so it's not that they have a problem with science per se. There's some things that they're uncomfortable about, like climate change, which they think is detrimental to the fossil fuel industry. But it turns out that when you have $35 or $36 billion of NIH funding going to universities, it basically gives the executive branch a huge amount of leverage to put pressure on universities to do other things that they want them to do, and that's been going on at a scale bigger than I ever anticipated, with grants being terminated because they were on subjects that the Administration thought were politically not up their alley. Or they would argue they weren't going to be productive, although there was no evidence to support that. Or they just turned off the money flowing to institutions like Northwestern, didn't tell them why, didn't even tell them they were doing it; they just weren't getting reimbursed for expenses for months. All of a sudden they were short $40 million a month. And then they go back to the universities and say, you know, have we got a deal for you, we'll give you the money back as long as you sign this letter saying that you'll change how you admit students or change how you develop your curriculum, or whatever. It's putting university leaders in a very tough spot, because their core values of maintaining the financial viability of the university's they're responsible for, and protecting academic freedom, and letting scientists do their thing without interference from the government, are in conflict. They've been trying to navigate that--in my view, some much better than others -- but it's hard. 

Jeremy Berg 

In terms of the tangible effects, there were lots of grants that were just terminated, particularly around DEI issues or climate change. People just got an email one day saying, "Your grant is terminated. Please stop spending any money." The good news is that some courageous people decided to fight and litigated, sued the NIH or the NSF and said this is illegal, which the courts have ruled it was. So a lot of the money has been, not all of it, has been reinstated, although the Supreme Court eventually weighed in on the NIH rulings and issued a very frustrating split ruling, namely that the grant terminations were almost certainly illegal, but the lawsuits were brought in the wrong court system -- they should have been brought in the court of federal claims instead of where they were brought. So NIH was not required to reinstate the grants, although some of them were, most of them were. The other things that have been going on are various threats, which are sort of in the weeds about indirect costs and so on, which are hugely important to universities. That was one of the very early things, which got everybody's attention, but again was litigated, and the government lost. 

Jeremy Berg 

And then the most recent thing was toward the end of last fiscal year. The fiscal year runs through the end of September, and the last few months NIH finally was way behind in grant making. They got a lot of grants funded, but one of the things that they did was what's called multi-year funding grants. Normally, the way NIH funds most of its grants is like this... If Coleen gets a four-year grant, she gets one year's worth of money from that year's appropriation. Then she writes a progress report, and if all goes well, she gets what's called a non-competitive renewal, and she gets the next year's worth of money. She works for another nine months or 10 months, and submits another progress report, and so on. So the money comes out of multiple appropriations. What NIH started doing was funding all the years of a grant out of last year's appropriation. What that meant was it basically cost four times as much to fund one grant. You could have spent the money [differently] and funded four grants, one year at a time. There's a little bit of an advantage in that. NIH doesn't have as many commitments going into the next fiscal year. But the most tangible thing is, in the year that you're doing that, it decreases the number of new grants that you can fund. That number turned out to be about 20% So, there were 20% fewer new grants that were funded last year compared to the previous year.

Heather Howard 

Hence Colleen's concern about younger researchers being most harmed. Do you share that concern?

Jeremy Berg 

Absolutely. So early-stage investigators got hurt by it, you know. NIH has 27 institutes and centers, 24 of which have funding authority, and one is the National Institute on Aging. They fund not all, but the bulk of the work on aging and Alzheimer's disease, and so on, and they, for whatever reason, did a lot of multi-year funding, and the consequence of that was that the number of new grants that they funded dropped dramatically. So in fiscal year 2024, the overall success rate for new and competing renewal grants was about 15 or 16%, so more or less 15 or 16% of the grants that were submitted got funded. Last year, it was a little under 6% ,so that was about the worst case for NIH. But it's incredibly frustrating, because, you know, if you get a grant funded in the top percentile, that's normally more or less a sure thing for funding. I mean, you get that kind of a summary statement, a review of your grant. You go back to the lab with a big smile on your face. The money isn't in the bank yet, but you're pretty confident. You start thinking about what to do with the money, for sure, and the success in 2024 for those grants was, you know, 90% 95% across all the institutes. Last year it was around 50%. 

Coleen Murphy

That has a real impact. I feel bad for the scientists who are not getting their funding, especially the ones that in previous years would have been funded, but we also do a lot of work to review these grants, so we go to what's called study sections. A group of us will all read the grants, we spend a lot of time ahead of the meeting, then we talk about it in the meeting. We spend a ton of working hours evaluating these grants, so the ones that come out at top really are good. And then to find out that, like, that was all for naught, like we might as well not have had a study section. We wasted everyone's time, because really only like one grant out of that study section ended up getting funded. It's just incredibly frustrating at all levels for the scientists... the scientists who wrote the grants, who evaluated the grants, everything. And we know on the other end, the people who are surviving still at the NIH are working incredibly hard, but it's been very frustrating, I imagine, for them as well.

Jeremy Berg

The other thing is, you know, I've only gotten a couple of grants that were in the top 10 percentile over the course of my career, and you get the summary statement back, and it's glowing. This is wonderful, this is going to change the world, this guy is brilliant, everything is wonderful, wonderful. And then it doesn't get funded, and you're supposed to resubmit it after fixing it, and what are you supposed to fix? You sort of say, I agree with the reviewers, it is brilliant. It's the best thing I've ever thought of, or you just sort of randomly try to change things to see if you can hit some invisible target or something. It's very detrimental, sort of psychically as well. The sense of the NIH before, and you know, Colleen can disagree with me, but the system was very competitive, but it was basically reasonably transparent and reasonably fair, or about as fair as it could be. You knew what to do. You took your shot on goal, and some of them went in, and some of them didn't. When you got a critical review, you were furious and thought the reviewers were complete idiots. And then you'd go back and read it two days later and realize, yeah, they had a point.

Coleen Murphy 

I could fix that, yeah.

Jeremy Berg 

But there was never a sense that this was completely unfair with some arbitrary decision. It really had something to do with what I wrote and how important it is and what mistakes I made. 

Coleen Murphy 

And even so, if that was like from one review, you could resubmit it and address all those points. I will say the I do think the NIH always, even before this, needed more money. And the reason I say that is because at some level, with those study sections, it is very difficult to tell the difference between grants that are like at the 10th and the 15th percentile. So if you were at a funding agency where they're making that cut off, it was really hard as a reviewer to tell the person you're giving the review to. That didn't feel quite fair. And so that's the kind of thing where once it gets to a point where we can't distinguish between a certain level, but because of funding levels being tight, we can't give out all the money. That gets frustrating. And so I think even before this, we needed more money because there's plenty of good research that probably could have been funded all along. And now it's even worse. 

Jeremy Berg

When I was at NIH, I discovered that NIH had all this data about grants and so on, which they just weren't analyzing as much as they could have. So one obvious question, which turned out no one had ever tried to look into, was, "Do percentile scores actually predict future productivity?"  Is there a difference between a fifth percentile and a 10th percentile and a 15th percentile in terms of the number of papers that are published or the number of highly cited papers that are published or anything like that? So I just did the experiment and got the data and did the analysis and the answer was exactly what I thought it was, which was, there ain't much difference. The difference between a 10th percentile and a 15 percentile is not possible to measure by any tool I could come up with, exactly. And that's always been true. I mean, it's basic, and it's not surprising. You're getting three people to look at a complicated, forward-looking document, you know? I mean, it's like picking stocks. If it were easy, everybody would be wealthy. But you know, the people who can pick a few more stocks that are going to do well and a few that are going to do less well end up being very, very successful.

Coleen Murphy

A few days ago, someone put out on BlueSky, what do you miss from the 1980s? Of course, a lot of people had music.

Heather Howard 

Big hair!

Coleen Murphy 

Someone wrote, NIH funding levels, which were above 30th percentile back then. 

Heather Howard 

So, Jeremy, you painted a fairly bleak picture. Before we wrap, can you leave our listeners with something that gives you hope?

Jeremy Berg  

Well, one of the things, which I talked about earlier, is what a tough situation university leaders are in. And the same thing is true for scientists, because even if you think you're getting treated badly, or your whole field is disappearing, or something else, people are reluctant to speak out publicly or talk to the press or anything else, because they're worried about painting a target on themselves and getting hit even worse. So, there's been sort of remarkable quiet from a lot of university leaders and from scientists who are just reluctant to speak out, for understandable reasons.

There has been a lot of progress on finding people who are willing to stand up and fight. Sometimes they're people like me, where my career is mostly behind me, and I'm not NIH funded at this point, so I don't really have that much to lose. I would have a lot to lose if I didn't speak up from my perspective, in terms of my ability to look at myself in the mirror. 

Coleen Murphy  

Yeah, Colette Delawalla formed Stand Up for Sciences. She's a great voice.

Jeremy Berg  

I was just going say that one of the people who's become a sort of hero of mine is a woman named Colette Delawalla. She is a graduate student at Emory, who is in psychology, works on addiction, who's defending her thesis this month. She's been writing her dissertation, and she just decided that she was not going to sit there and watch her scientific career and the scientific career of her peers disappear before they got started. So back in March of 2025, she started this organization, Stand Up for Science, and organized a rally in DC, and got such good response that she said, "Let's just do it all around the country." So they organized rallies in like 40 or 50 different places. I spoke at the one in Pittsburgh, and then she started pestering me about getting involved in other things. I sort of said, "Who is this person?" I didn't know anything about her, and got to know her, and now I'm on the advisory board for Stand Up for Science. They've done it again last year, and they're doing all sorts of other things, and they're pushing really hard. They're very engaged politically, they're very engaged on communications. They just worked with members of the National Academy to release a statement about the National Science Board being disbanded, and they're really just a force. Occasionally, scientists will say they're really busy and don't have time to do any activism. You know, you can't spare an hour a week? Really? Colette has been finishing her dissertation work, writing her thesis, has a two-year-old, and founded and set up this organization. 

Coleen Murphy 

If we're not careful, all of us will have too much free time on our hands, so we really do need to do something about it.

Jeremy Berg 

Well, I think that's the argument for standing up. If a university sits back and tries not to paint a target on itself, they will definitely decrease the chances that they're going to be the 10th university that gets clobbered. But they're probably increasing the chances that they're the 20th, because no one else was standing up. Everybody just needs to defend everybody. And the same thing is true inside NIH. 

It does take a group working together, and you know, supporting each other, and you know creatively solving problems. I mean, I've involved a bunch of different groups like that, and it's really very empowering. I mean, I think people are committed to trying to do what they can. People have lots of creative ideas, you know. Taking a shot at academia, one of the nicest things about it is no one cares a whit about who gets credit for anything. So, it's just, you know, anybody got an idea? Let's just brainstorm this together. And then everybody forgets whose idea it was. So that's kind of refreshing. 

Heather Howard

And Coleen, what about you? You'll go back to your lab after this, back to the worms. Actually, you said there had just been a breakthrough. That work continues, right? Can you give us hope that we're going to unlock more secrets about aging, hopefully in our lifetime?

Coleen Murphy

Well, you know, I have a group of researchers in my lab, students and postdocs, and every day they come in excited to find something new. Some days it's actually true. We do find something. So we'll have to work our way around the funding situation, always, but as long as we can get the money to be able to support the research in the lab, we'll keep going, because it's always fun. I mean, the reason I do this is because it's just the best job. I just love going into the lab and finding something new whenever we can. And it's exciting to work with young people. This is fun for them as well. But it's always a worry in the back of my mind. I want to make sure that they have the next job to go to, and so that's why it's really important for us to keep trying to make sure that the funding in the United States is well supported.

Heather Howard

Well, Coleen, Jeremy, such an important conversation. Thank you. Thank you for joining the Princeton Pulse.

Jeremy Berg

Thank you.

Coleen Murphy

Thank you.

Heather Howard 

Thank you for listening to the Princeton Pulse Podcast, a production of Princeton University's Center for Health and Wellbeing. The show was hosted by me, Professor Heather Howard, produced by Aimee Bronfeld, and edited by Alex Brownstein. We invite you to subscribe to the Princeton Pulse Podcast on Apple Podcasts, Spotify, or wherever you enjoy your podcasts.