Science Friday
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This important breakthrough and other research projects have lost funding because of Trump’s cuts to the NIH.
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Science Friday is supported by MathWorks, creator of MATLAB and Simulink software for technical computing and model-based design. MathWorks, accelerating the pace of discovery in engineering and science. Learn more at mathworks.com. Hey there, it's Ira Flatow, and you're listening to Science Friday. Today on the podcast, a breakthrough in understanding Alzheimer's disease.
This was so surprising that we didn't believe it at first. In the subpopulation of aging individuals who start to show memory loss, lithium levels significantly dropped in the affected brain regions.
Scientists have been working for decades, as you know, to untangle the mysteries of Alzheimer's disease, the debilitating brain disorder that over time robs people of their memories and overall function. New research points to lithium being a possible key to this puzzle. In a first-ever finding, scientists discovered that lithium naturally occurs in the brain, and that taking it away can trigger Alzheimer's symptoms in mice. So how could this translate to lithium being a treatment for Alzheimer's in humans? Joining me now is a senior author on that paper, Dr.
Bruce Yankner, professor of genetics and neurology at Harvard Medical School in Boston, Massachusetts. Welcome to Science Friday.
Thank you, Ira. Delighted to be here with you.
Now, I know that you have been studying Alzheimer's for decades. What is it about this disorder that has kept your interest for so many years?
Well, first and foremost, it's a disorder of higher cognitive function in humans, which is arguably what distinguishes our species on this planet. And it is a disorder that is uniquely human, although we see some changes in other aging mammals. Alzheimer's disease, as an entity, only occurs in humans. So I suspected early on that by understanding Alzheimer's, we might be understanding something very fundamental about the human brain.
So let's talk about this new finding involving lithium. Walk me through what you learned here.
So we came about this in a, in an indirect way. About 10 years ago, we found that there was a transcription factor, a protein that regulates which genes are expressed in the brain called REST that played a role in aging and Alzheimer's disease. And we were studying this protein. And we found that this protein was regulated by another protein called WIND, which signals to cells and causes this REST protein to become activated. So we were trying to activate this pathway. And a classic approach to this was to incubate cells with lithium in the laboratory. So we started doing this in cells and also in
animal models of Alzheimer's disease to study this pathway and observed, as others have, that lithium was able to reverse many of the pathologic and cellular features in these mouse models of Alzheimer's.
What, what features are those?
The amyloid and the tau, the memory loss. At very high concentrations, you could see just a general improvement in all features that these animals exhibited associated with Alzheimer's.
For those of us who don't quite remember the connection between Alzheimer's and amyloid plaques, can you give us a quick crash course on that?
Sure. So back in the early 1990s, this was a contentious issue. It was well known that the amyloid plaques were a hallmark of Alzheimer's disease from Alois Alzheimer's initial observation in 1906, but their role was unclear. So some studies by a number of groups suggested that genetic changes in the precursor protein to Alzheimer's disease could give rise to the disorder. We at that time contributed some of the initial data suggesting that amyloid could have toxic effects in the brain.
And that became the reigning hypothesis. But there have been concerns about that. And the major concern is there are some people whose brains are full of amyloid and their memory function is completely intact. And others who have less amyloid, who are severely demented. So there's not a clear relationship necessarily between the amount of amyloid in the brain and the dementia. Furthermore, there are other genetic factors that predispose to Alzheimer's disease in different ways. And lastly, the therapeutic interventions being used for Alzheimer's disease only modestly affect the clinical symptoms.
So in the last year or two, a revolutionary change is the first treatment that actually affects the cause of the disease rather than just ameliorate the symptoms. Lecanumab and venanumab, which are immunotherapies designed to get rid of the amyloid in the brain.
So why look at lithium?
So one day, we asked the question, could lithium in fact be part of the disease mechanism? Because until that point, lithium was not thought to be a normal, natural substance in the brain. Just a drug with pharmacological effects at very high concentrations. So we set out to try to determine whether lithium was a naturally occurring substance in the brain. And to make a long story short, we had to modify some new technology to make it very sensitive and specific. And we were able to find that lithium could be detected at low micromolar concentrations
in the brain and the blood, was dynamically regulated during aging. And most interestingly, in the subpopulation of aging individuals who start to show memory loss, what we call mild cognitive impairment.
Lithium levels significantly dropped in the affected brain regions. And as this progressed to full-blown Alzheimer's disease, this reduction in lithium in the affected brain regions became much more pronounced.
Wow, so the absence of lithium led, it looks like, to the symptoms of Alzheimer's?
Well, we couldn't say that initially because it was a correlation. And in fact, this was so surprising that we didn't believe it at first. And we set out to replicate these findings using Alzheimer's postmortem samples from many different brain banks across the country. And finally, we were able to broadly replicate this finding and believed it. But we had this correlation. And to determine whether the change in lithium was a biologically meaningful effect or simply a downstream result of pathological process,
we depleted it from the mouse diet. So we devised a mouse diet that was identical calorically and nutritionally to the normal diet, with the exception that it was 90% reduced in lithium. So when we fed that to mice, that dropped the amount of lithium in the blood by about 90% and in the brain by only about 50%. And that didn't change whether we fed it to the mice for a week or a year. But nonetheless, that drop of 50% was enough to spur the pathology of Alzheimer's disease. And furthermore, the mice showed accelerated memory loss.
If lithium does indeed stop these mechanisms of Alzheimer's, wouldn't there be a reduction of dementia in a population of people who've been taking lithium for years to treat, let's say, bipolar disorders?
Yes, there would. And so there are a few studies years ago which showed that the bipolar disorder population has a three to fourfold higher incidence of Alzheimer's disease than controls.
And those who were treated with lithium did not show this increased incidence of Alzheimer's disease. But I think one of the most compelling studies in this regard is an epidemiological study out of Denmark in 2017, where the entire population was surveyed for dementia and the amount of lithium in the local drinking water. And this could be done in Denmark because they had such good public health registry records. And what they found was that there was a very significant correlation between individuals who lived in areas with high levels of lithium in the drinking water and reduced levels of dementia as determined by hospital records.
Yeah. So what, where do we go from here in terms of possible human trials or the future of use in people?
I think it's important at this point to determine whether we can determine who might be deficient in lithium at a very early stage by developing diagnostic markers, measuring lithium as well as other markers of lithium function in the blood or other accessible tissues, and determining if there are populations that are uniquely responsive to lithium and that are, that are therapeutically improved by lithium.
So practically speaking, we need to find the effective dose in humans. We found it in mice, but that needs to be translated to humans. We haven't done that yet. We had very encouraging results that treating aging mice for as long as a year with this physiological dose of lithium orate was not toxic. We need to determine if that's also the case in humans. So people shouldn't rush out and start taking lithium. That would be a big mistake. We need to wait until the clinical trials are done. But I think this has the potential for early intervention with safer lithium salts that are non-toxic.
It suggests that lithium homeostasis might be important in normal aging, and it makes a case for possible preventative trials in the general aging population.
Right. Now, I know you're at Harvard, which has been targeted by the Trump administration's funding cuts. Is your work on Alzheimer's and the lithium and all kinds of related subjects affected by these cuts?
Yes. So, a major NIH grant that funded this work was terminated as a consequence of the overall termination of federal funding to Harvard University. And that has caused us and other laboratories to have to scale down our efforts and will be a limitation in progress going forward. In addition, I've been director of the Harvard Neurodegeneration Training Grant, Harvard Medical School's oldest grant. It's a training grant that trains students and postdoctoral fellows who are working in brain diseases of the aging. We've trained some people who have made major contributions since the grant was started
in 1991, and that grant was also terminated. This will affect the training of the next generation of scientists.
Yeah. As I said before, you've been studying Alzheimer's for decades. Are you happy with the progress that's been made over the decades to understand it?
I think it's fair to say that Alzheimer's has turned out to be a tougher nut to crack than people expected. If you had asked me when I first started out as a junior assistant professor, where would we be therapeutically at this point? I would have thought we'd be further along than we are.
So Alzheimer's continues to be?
A great mystery.
Yes, I think it's fair to say that. It's an incredibly important disorder, both socially, societally, and economically. And it's going to become even more important as this century moves forward.
Well, Dr. Yankner, that's about all the time we have for today. It was a great conversation. Thank you for your work and for sharing it with us.
Sure. Happy to be with you.
Dr. Bruce Yankner is professor of genetics and neurology at Harvard Medical School in Boston, Massachusetts.
After the break, Bruce's grant isn't the only one that has been slashed due to Trump's NIH cuts.
You know, all of these things that make America healthy again, and RFK say they support, but it's really hard to see that when all of this infrastructure is being cut down at the same exact time.
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The Department of Health and Human Services announced this week that it's cutting some $500 million in funding for research into mRNA vaccines, the kinds used to combat COVID and the flu. HHS Secretary Robert F. Kennedy Jr. said his agency would focus their funding on a so-called "universal" vaccine. He said that research into other uses for mRNA technology, including cancer therapies, would continue. We'll have more on this story next week on the program. Meanwhile, the Trump administration continues to dismantle the National Institutes of Health, the agency that helped to fund those mRNA vaccine therapies.
Aside from the COVID-19 vaccines, the NIH has been responsible for health successes like fluoride for dental health and life-saving cancer treatments. If you don't work in science, it can feel like these cuts are happening in some far away place, but the trickle-down effects for everyone are becoming evident.
Joining me to help break this down is Dr. Caitlin Jetelina, author of your local epidemiologist newsletter. She's based in San Diego. Dr. Elizabeth Marnik, an immunologist and director of science education and outreach at the MDI Biological Laboratory in Bar Harbor, Maine. Welcome both of you to Science Friday.
Thank you for having us. Thanks for having us.
You know, to an outsider, the inner workings of the NIH can feel opaque. So give us an idea of how it all works.
Yeah, it does. It does feel pretty distant, but it impacts our literally everyday lives with scientific discovery. How does it work? Well, the NIH is not just one agency. It's a collection of 27 institutes and centers, and each of them are focused on different areas, like cancer, or infectious diseases, or aging, or mental health. And it, like you said, is the largest research engine, not only in the United States, but in the world. It's by far the biggest. And what we have seen is research funding budgets, they rise and they fall with every fiscal year, and new administrations come and go, and congressional priorities are different.
But this year is dramatically different. At the NIH, approximately 5,500 fewer research projects are being funded due to executive decisions, which is just significantly lower than we've seen any other year.
Wow. So Caitlin, how does that work that's done there affect everyday people? Do they feel it yet?
No, I don't think they feel it yet. And this is what's really killing me. You know, when I, as a researcher, worked with police officers and looked at, as police officers are impacted by their traumatic offense, and then thus how they engage with communities they serve. And a lot of these NIH grants helped me co-develop solutions with police officers, who are our dear friends, but also a lot of MAGA supporters. And They didn't know that NIH was this, really this invisible engine behind a lot of this magic and this movement towards better mental health for them at their police departments.
And this is just one example of a lot that are being discontinued pretty quietly, pretty stealthily. And I don't think people will necessarily feel it until it's too late and we don't make progress in a lot of these areas.
Right. Liz Marnik, is the work that you do affected by these cuts?
Yeah, so one of the things that I do now is I work to develop K through 12 outreach programs. And I was actually in the middle of writing a grant to submit to the NIH that no longer exists. And that was one of the few options for funding this kind of science education work out there. And so far, there's really nothing to fill that gap yet. So it's concerning in terms of what's going to happen in the future with these kinds of grants. And then the institution that I work at, where Maine is a really rural state, and because of that, we actually have a special grant, we're an idea state, and this is a grant that was designed by the NIH to help rural states like Maine have more ability to do high quality scientific research. And we're head of that grant for the state of Maine.
And as of right now, we had a five year grant awarded last year, and we were supposed to get our non competitive renewal back in the spring, and we still haven't gotten it. So a lot of things are just uncertain right now. And exactly what is going to happen next is unknown.
You know, what's really interesting here is that some of these cuts are because of ideological things this president doesn't believe in, like climate change, LGBT and gender studies. But some of the research that's been cut, some of it is part of this make America healthy again agenda. Caitlin, isn't it? Can you give me some examples of how you're sort of shooting yourself in the foot here?
You're so right. A lot of politicians are portraying these cuts as trimming waste or targeting these fringe projects don't really apply to the average American. And sure, some projects are niche, but a lot of them aren't. Just like you said, Maha, right? Make America Healthy Again. More than 100 clinical trials have been cut that supported research around chronic disease and cancer and diabetes and mental health. You know, all of these things that make America healthy again, and RFK say they support, but it's really hard to see that when all of this infrastructure is being cut down at the same exact time.
So what does this signal to you? What's really behind this?
Yeah, so some of it kind of seems like it's just chaos. And a lot of it seems to be there's this lack of understanding over what the NIH and what research dollars are actually being spent on. So sometimes I think it's hard because the project might seem, if you just go off of the title or the abstract, it might seem not important. But the way that research builds off of each other is that you have to have a foundation of knowledge to develop a new cancer therapy or to develop a new treatment for asthma. And a lot of times that early research that's so foundational doesn't seem important, but it is. It's kind of like if you were building a house without a solid foundation, if you
take that foundation away and try to build anywhere, the house is going to collapse. So taking away some of these research projects, and they might think they're just cutting waste, but in reality, it's going to impact cures that we could have had maybe three or five or 10 or 20 years down the line. We just don't always realize it at the time.
And that's part of the issue here, I think, is the messaging problem. If you asked anybody, hey, do you want us to cut back in cancer research, heart disease, whatever, they'd all say no. Right? Well, who's going to, who in their right mind would want to do that? But it seems like we're having a communications problem here, too.
You know, this invisibility has consequences, right? And I think that, yes, all of this is happening quietly and strategically and very politically. But we in science and in public institutions also kind of have to own our part, right? That we haven't done enough to make this work visible to the people it impacts. And so while, yes, this destruction is happening, I think one thing Liz and I really call out on your local epidemiologist, the article we wrote, was that we also need to really start engaging with the communities, that the community is not merely like a research target, but it's an active participant.
Liz, is this the end of the bleeding, do you think? Is anything more going to be happening?
That's a great question, and I don't think we know right now. So last week, the Senate Appropriations Committee did vote to bring a bill out of their office. So in case people aren't aware, the Senate Appropriations Committee, they're in charge of kind of setting different batches of money for different things. And National Institute of Health, their funding comes from the Budget for Health and Human Services, HHS. And last week, the Senate Appropriations Committee overwhelmingly voted yes in favor of advancing this bill to the next step. And that bill actually rejected a lot of the things that Donald Trump wanted in terms of cutting the NIH budget. They actually increased it by a very small amount.
They did not restructure the NIH to the degree that Trump wanted it. So all of those are positive signs, but it's not over yet because the House has their version of the budget bill we have to wait for. And then we have to get a final budget approved by both houses over a majority vote. So there's a lot of things that still have to happen between now and getting an actual budget approved.
Do you think that the public, many times over, I get a phone call that would say, "What can I do as an individual? Do I have any power?" Liz, what would you say to our listeners?
Yes, you do. I think that's one of the things right now is that you have a voice, and you can use that voice in different ways. You can call your representatives because they do care about that. I've been spending a lot of time on the Hill recently, and overwhelmingly, I hear that they appreciate knowing what their constituents care about. Even if your representative is politically aligned with you, even if they're not, it doesn't matter. Call them anyway because it helps them to know what issues you care about. And then beyond that, talk to the people around you because, again, as Caitlin and I have said, a lot of science is invisible. So if you benefit from a new cancer drug, or if you benefit from any sort of scientific advancement, if you have a friend with a chronic disease
or with Alzheimer's, talk about those things and talk about why research matters to you because that will help make these things more obvious to people who maybe aren't thinking about it.
Are any of these scientists optimistic about the future? Is it a matter of waiting out this administration? Or have we turned the clock back to 80 years ago, right before we had this great run of science and research at NIH?
I think it really depends on how the next few months unfold, like Liz saying, if they can start getting the money out the door, if the congressional budget refuses the 40% additional cut to NIH for fiscal year 26. You know, I do still have a little hope. I think it's because of what Liz said around last week, the Appropriations Committee really sticks standing up in ways that we haven't really seen in other topics. And the other thing that I'm seeing is this topic is becoming increasingly bipartisan. We can see it in the polls, right? More people, regardless of Democrat, or Republican, or Independent, really support scientific research when asked.
So I actually do have some hope, but we'll see what happens. I mean, it's definitely a possibility that we are set back decades, and it's gonna take a long time to recoup that. I think Liz, and I, and scientists, and institutions, and academics are doing all we can, so we don't do that. But I don't want to lie. I mean, it is a possibility.
Thank you both for taking time to be with us today. Dr. Kaitlin Jetalina, author of Your Local Epidemiologist Newsletter. She's based in San Diego. Dr. Elizabeth Marnick, epidemiologist and Director of Science Education and Outreach at the MDI Biological Laboratory in Bar Harbor, Maine.
Thanks for having us.
Thank you.
Hey, thanks for listening. If you have a comment or question or a story idea, our listener line, it's always open. Call 8774-CY-FRY, 8774-CY-FRY. This episode was produced by Kathleen Davis and a lot of people helped make this show happen. Jordan Smadick.
Emma Gomez. Praise Aguchi. Santiago Flores.
I'm Ira Flatow. Thanks for listening.
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