The future of neurodegeneration

0:00This is Stanford Engineering's The Future of Everything, and I'm your host Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. and it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:37In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, co-workers as well. My lab works a lot on Huntington's disease. It's a disease where you have a mutation in one protein that causes that protein to aggregate and misfold. So the idea for that is if you could lower the levels of that misfolded protein or keep it from misfolding, you can help with the disease.

1:14This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying The Future of Everything, please follow it in whatever app you're listening to right now. That'll ensure that you're always notified of new episodes and you never miss the future of anything. Today, Judith Friedman will tell us that in diseases like Alzheimer's, Parkinson's, ALS, there's a defect in the cellular machinery that makes and breaks down proteins. It basically creates junk, and that junk mucks up the cell and leads to these terrible diseases. But we're starting to understand those changes, and it's suggesting new potential therapies.

1:48It's the future of neurodegeneration. Today, we're continuing our new feature, the future in a minute, and at the end of my interview with Judith, I'll ask her a few rapid fire questions and she'll give us some rapid fire answers. Before we get started, remember to follow the Future of Everything podcast in whatever app you're listening to so that you can always be alerted to new episodes.

2:16So proteins are key pieces of the cell. They're encoded in our DNA and our genome, but they're the beautiful three-dimensional objects that do all the functions of life. They contract in your muscles. They digest your food in your stomach. They monitor light in your eyes and tell your brain when a photon has hit the back of your eye. So proteins are just wonderfully important, and they're key in the brain where they do communication and signaling to create all the phenomenal capabilities of the human brain. But we know that in terrible diseases like Alzheimer's, Parkinson's, ALS, and others, something goes wrong in the brain.

2:56And it turns out that one of the things that goes wrong is the ability of cells in the brain to make good-looking proteins, to break down bad proteins that have defects, and to keep things neat and tidy degrades over time. And in aging, we start making faulty proteins. They don't achieve the beautiful three-dimensional structure. They don't look right. And they're hard to get rid of. So they kind of accumulate like junk and mess up the cells. Well, Judith Friedman is a professor of biology and genetics at Stanford University and an expert at how proteins are made, distributed throughout the cell, and broken down.

3:34She's now studying aging cells in not only humans, mice, rats, and the normal experimental organisms that you may think of, but also in a rare and amazing African fish that has a lifespan of three months. And in those three months, it goes from healthy to aged. And it starts having symptoms very much like those that we see in people with these cognitive disorders. Judith, you're an expert at how proteins are made, distributed, and eventually broken down in the cell. How did you connect that to aging? Okay, so as many people know, aging is a condition, which we all hope to have someday, that increases your risk for many diseases.

4:23And in particular, there is one big class of diseases that is associated with aging, which is neurodegenerative diseases, including Alzheimer's, Parkinson's, frontotemporal dementia, so many diseases that affect cognition and brain function. And they're on the rise and they're terrible. Yes. Well, as lifespan expectancy increases, then they are increasingly prevalent in the population. They are a huge economic and social and emotional burden for society. So they are really on the rise and really it's urgent to be able to find ways to delay them, to treat them, to kind of do something about them, both to treat them, but also to prevent them from starting early in life.

5:20So all of these diseases are characterized by the appearance of these entities called plaques. Plaques, neurofibrillary tangles, and all of these are accumulations of misfolded proteins. So actually, it's amazing how long it took for people to figure out that these plaques and amyloids caused by many different proteins that when they function normally look completely different. Tau, which forms neurofibrillary tangles or alpha-synuclein that forms Lewy bodies in Parkinson. When they are correctly folded, which is what my lab started studying, they look completely different. But when they are misfolded, they all look the same.

6:11They form these clamps which it's debated whether they are the toxic species or whether they are kind of like the cannery in the coal mine that there is something wrong with your folding machinery, meaning they accumulate, but they are kind of like a garbage can where misfolded proteins are put, but the damage and the toxicity comes not from the plugs, but from something else. This is a big debate in the field. So anyway, it became clear that during aging, the folding machinery, the machinery that monitors all your proteins to make them, to get rid of them when they are damaged, stops working.

6:56And this doesn't just happen in humans, it happens in yeast, in worms, in flies, in fish, in every organism. So clearly this is a general phenomenon. And this could explain why aging makes you vulnerable to all these diseases. So this is why we started to look at this. So, yes. So great. So just for people who don't think about proteins every day, I thought it would be useful for you just to review. We have our genome and people know that the genome is a big, long list of DNA letters that encodes proteins. And the miracle, to some extent, is that these one dimensional, you can think of it as like a string of pearls or whatever you want to think.

7:38But that string of pearls, because you've used the word folding several times, that string of pearls actually folds into a complex three-dimensional shape somewhat and quite reliably. And as you said, into a bunch of very different and actually quite beautiful three-dimensional structures. And then what you also said, however, is that that folding process sometimes needs some help. It needs cellular support. And that it can go wrong. And then they don't fold into these beautiful structures. They fold into these structures that kind of all look alike and can be maybe damaging to the cell. So I just wanted to get that out so that people who don't think about proteins know that this is a fundamental set of molecules inside cells that need to have this three-dimensional shape to do their thing.

8:23Okay. So then you went on and you said some really interesting things about all these other organisms. So this is a universal phenomenon in aging where you get these kinds of defects? Yeah. Actually, this is quite interesting, and this is even yeast, the organism we use to make beer and bread. Very important. It's very similar. Very important. Most useful organism ever. It's very similar to us in many aspects. Simpler, so it's easier to understand problems, but very similar. So yeast ages and becomes full of aggregates and has problems folding their proteins. worms, flies, fish. I mean, we recently did a study in fish aging, where, of course, fish have brain and have behavior, so they are much more complex and a really great system to study aging to mice and humans.

9:21So all organisms seem to age in a similar way. So tell me about the fish study, Because as you said, in previous work, you've done yeast and mice and other things. But why was fish such a good system for you to do the most recent set of studies? And then tell us what you found. Yeah. So there is a class of fish called the African killifish that lives in these seasonal ponds in Africa that are only, let's say, ponds for about three to six months with seasonal rains. So these fish have a very short lifespan, maybe three months or six months, depending on the species. So they are a great model for aging because the problem with studying aging in mice or even in rats, let alone molecularly studying it for humans, is they have very long lifespans.

10:25So an aging experiment that takes three years is really very hard to do any kind of interventions. So these fish have become a really beautiful model for aging. and there are colleagues at Stanford that work on this. But I actually, the last meeting I went to before the pandemic, I met this scientist that was then in Germany, now is in the US, Alessandro Ori. And we had a conversation. We were studying how aging impacts a process called translation, which is the process that makes proteins, the process that you say makes these linear strings from the genome and converts them into proteins. And we had really cool data about how aging impacts translation in yeast and in worms in very similar ways.

11:17So he had a really beautiful model of killifish and aging and was doing molecular studies. And, you know, this is a project that started maybe a bit virtually during the pandemic, and then slowly we started to accumulate experiments. And we focused on the killifish brain. So during aging, killifish become disoriented when they are swimming. So really, they have cognition problems. And so we decided to look at the killifish brain and we looked at the molecular signatures of the killifish brain when they are young, when they are middle aged and when they are aged. And we looked at the RNA, so what comes from the genome.

12:08We look at the proteins in the killifish brain. And we looked at proteins that aggregate, that form these clumps during aging. And what we found in these initial studies is something that has been found in, actually, in human studies of post-mortem tissues in mice, which is that with aging, there is a disconnect between the RNA complement, the information that comes from the genome, and the proteins. And then we hypothesized that this disconnect may be due to this faulty translation, what we had already observed in yeast and worms. So we tested this. We did a technique called ribosome profiling, which measures how the ribosomes read the information from the genome to make proteins.

13:03And we saw that. Just to interject here, the ribosome is actually the amazing molecular machine that actually builds the protein from the genome instructions. And so it's an ancient molecule. It's unbelievable. It's huge. And it's a little tiny factory that makes proteins. Is that a fair? That's perfect. perfect right and it's very complicated to make and so what we saw is that the same type of defects that we had observed in yeast and worms also happened in the brains of these fish with aging and the proteins that were defective that were made defectively were very similar to the proteins that we see forming clumps with aging, connecting defects in production with these problems with folding and forming of clumps in brain aging.

13:58So this is really kind of very, very important because it suggests that one of the problems that you have with aging is that you, the machinery, this amazing machinery, the ribosome or something in the process to make proteins starts to be defective. And you can imagine in a society, if the machines you need to use all are to be defective, you will overwhelm everything. You will overwhelm your, let's say, disposal systems, which is what happens. You will start to make things work less well. We said it was a factory. And if the factory is putting out bad cars or bad iPhones, chaos will reign. Exactly.

14:46Exactly. And you will overwhelm. And as time goes by, it will be worse and worse. And, you know, it's interesting because many of the interventions, genetic and maybe even pharmacological, that are now considered to extend lifespan, all interfere with the process of translation. You know, so people take rapamycin or metformin or caloric restriction. These are all processes that attenuate or lower the levels of translation. So in a way, what you do is you produce less proteins trying to give the cell an opportunity to deal with the fault you want. So let me, if I can just pause, because it's amazing to me.

15:34So let's take humans and these killifish. Humans last for 70, 80, 90, we all hope a long time. And over a three-month period, I'm presuming that we don't have a lot of evidence of aging and damage. Like when you go from one years old to one and a half year old, you're still perfectly fine. And yet these killifish in three months seem to recapitulate what takes 80 years in humans. So is this some kind of like fundamental rule that I'm just amazed at the difference in the time scale, and yet you're telling me it's very similar observations? Yeah. You know, this is one of the interesting open questions about aging.

16:11Why we age, right? I mean, clearly different organisms age at different rates. Yeah. I mean, there are theories that this is something called antagonistic pleiotropy, meaning, okay, this is a very fancy word. Great phrase, great phrase. I know. But it means that in order to make everything work together, some processes are less effective or work less well. And then the whole process is kind of doomed to crash at some point and that this set point is different. It could also be there are other theories that the set point of aging is evolutionarily determined from other reasons. There are many theories at this point.

16:57It's very hard to test them. But clearly, you know, there are organisms such as the naked mole rat that basically don't age. You know, what does it mean they don't age? People have done studies where they, if you define aging as risk of mortality, the risk of mortality of naked mole rats doesn't increase with the passage of time. meaning they don't age. The females that are fertile stay fertile until the end of their life. I mean, they have a weird colony structure. Other small animals like guinea pigs live eight years. You know, mice live a couple of years. So the set point doesn't necessarily have to do with the size.

17:44Clearly, larger animals live longer lifespans, but there must be some other set point. And the conservation, the cool thing about the conservation is the genetics that determine aging in the organisms where it has been looked at are kind of very similar. So you can use simpler models to study aging. Yeah. It's really amazing. And I know that this needs to be tested carefully. But it gives you the sense that what's happening in these killifishes, if you don't pay a lot of attention and put a lot of energy into quality control at your factory, in three months, everything can be out of control. Whereas for humans, my instinct, although I'm sure you have to test this, is that we must be putting a lot of time and effort and energy into not letting those things happen so that we can go for 70, 80 years.

18:33Yes. And in fact, you can see that, I mean, in a way what aging does is allows all these mutations we have that, say, make you at higher risk for heart disease or for Alzheimer's express themselves. Because it's kind of like the system that keeps it all going together kind of starts to decay, decay, decay, and then your mutations start to be expressed, right? But when you're young, everything works well. And all these quality control systems work well. This is The Future of Everything with Russ Altman. We'll have more with Judith Friedman next.

19:30Welcome back to The Future of Everything. I'm Russ Altman. I'm speaking with Judith Friedman from Stanford University. In the first segment, we learned about ribosomes and we learned about aging cells and how the proteins in these cells are messed up and can foul up the ability of the cell to function. In this next segment, I'm going to ask Judith, what about the details of what we understand and do those details at the molecular level give us ideas about potential new treatments in the future for these terrible neurodegenerative diseases. Don't forget, we'll end this segment with the future in a minute, where I will ask Judith some rapid fire questions, and we'll get her thoughts on the rapid fire answers.

20:11So at the end of the segment, Judith, you talked about this idea that the cell is being overwhelmed with errors, and it's making mistakes, and it can't really keep up. And I know you study this at a molecular level, and you have kind of an understanding. So could you describe to me What's actually happening in the cell that is kind of overwhelming it and leading to these bad proteins? Okay. So in the cell, the machinery that deals with proteins is super highly interconnected. Okay. The ribosome, this amazing machine you described, makes proteins. Then a set of machines also called chaperones or molecular chaperones, which a little bit like human chaperones help guide young problematic entities to their correct fate, help proteins fold and they monitor that everything is okay.

21:03And when proteins are damaged, misfolding, get in trouble, chaperones communicate with disposal systems that eliminate these proteins. And so you have this entire system that is constantly monitoring the health of the cell. And this system normally works at almost capacity, has a little bit of excess capacity. When you get in trouble, too much heat, misfolded protein, the system can up the capacity up to a point. So one of the implications of our study is that when the ribosomes start to put out faulty proteins, then the system starts to become overwhelmed. So instead of folding and disposing and dealing with the proteins, it starts to generate all these bad proteins and the cells tend to put these bad proteins in these clumps.

22:05You know, I mean, we think that many people also think that these clamps that you see in neurodegenerative diseases are kind of a protection mechanism. And actually, one, this might date me, but there is a episode of I Love Lucy, where Lucy and her friends are working on a conveyor belt. And, you know, they are in a way the quality control system. And they I mean, people can YouTube it and they they cannot keep up. And then everything, all hell breaks loose. She starts eating. She starts eating the candy so that it won't fall off the edge. And she starts throwing it in the garbage. And this is the image we should have for the ribosomes that are overwhelmed.

22:46They're like Lucy. Exactly. And the quality control machinery. And in fact, many of the mutations, for instance, that cause Parkinson's disease are in machineries that take care of misfolded proteins. or in one of the organelles or, let's say, systems that is important for degrading misfolded proteins. So in a way, the whole system is interconnected. And you can think of this type of diseases or even aging as a condition, as a kind of systems failure. You kind of overwhelm the machine. One of the things we see happens during aging is these ribosomes are these little machines that are reading the genome and spitting out proteins and then chaperones will fold them.

23:33But when this machine starts to kind of stutter at some places, they start to bump into each other. And this is very bad, right? This is called ribosome stalling and they start to have collisions. And then there is a machinery that kind of puts apart the collisions, like maybe Lucy eating candy. And this machinery also becomes overwhelmed. So the whole system starts to become overwhelmed. And then you start to have an overload of that. Yes, this really makes sense. So given this kind of detailed molecular understanding that you're starting to gather, Um, um, what we're, of course, what we're all thinking is, does this give us clues about potential therapies for these terrible diseases that you mentioned at the very beginning?

24:21Yeah, I mean, absolutely. I mean, you know, in, in terms of therapies, obviously understanding the problem is the first step in solving the problem. And of course, some therapies, what they do is they upregulate the disposal machinery, So the drugs that enhance the function of the two major machineries that degrade proteins. Another approach is to upregulate chaperones. I told you that chaperones can be upregulated under certain stressful conditions. So some people have thought of upregulating chaperone levels to increase the capacity. and of course understanding what is the problem at the level of protein production would be very important right to fix to fix it right we really yeah you were talking about these the crashing into one another or going the wrong speed or hesitating and then restarting and so it's like we have to get so so this is very exciting because you just already act uh you already outlined three different approaches and of course we could also try to do all three to kind of get the synergies As you think about this, are you imagining that this is going to be like small molecule drugs or do you think we're going to have to do genetic engineering on the genome or all of the above or too early to say?

25:43What's your instinct about how these therapies might be developed? Yeah, I think some therapies that can be developed short term will be at the level of protein. So for instance, now one thing that people are trying to do is for diseases such as Huntington's disease, where you have one misfolded protein. So Huntington's disease is a really, my lab works a lot on Huntington's disease. It's a disease where you have a mutation in one protein that causes that protein to aggregate and misfold. So the idea for that is if you could lower the levels of that misfolded protein or keep it from misfolding, you can help with the disease.

26:27And so this can be done using a kind of genetic interventions. I think for a disease such as Alzheimer's or Parkinson's or generally aging, which are so prevalent, it would be prohibitively expensive to have either a genomic or, let's say, personalized intervention where you need to inject into the spinal cord, a very expensive reaging. I think for these large, very prevalent millions of people affected by these diseases, really of people will age, hopefully. Right. And for Alzheimer or Parkinson, a small molecule will be eventually the way to go. Because these what you want to have is an intervention that you can start to take, say, in your 50s.

27:21that doesn't really interfere a lot with the normal function of your body, of your tissues, but that enhances capacity or reduces the damage or the output of bad proteins. So I think ultimately this will have to end up being probably a small molecule, but you know, a lot of steps in between. Now the small molecule, we do have some good news there. As you know very well, we have a history of having small molecules that do interact with the ribosome. So as you know very well, we have antibiotics. Fortunately, the bacterial ribosomes are different enough from the human ones that we can mess up the bacteria and kill them without messing up our own, generally speaking.

28:09And so that's a little source of optimism because we know that we can get small molecules into the areas where the ribosome operates and we can get them to bind it and hopefully do things that increase its efficiency and effectiveness. Yeah, absolutely. I mean, obviously, the ribosome is very druggable. All the factors that help the ribosome make proteins are also quite druggable. The factors that regulate how often you start to translate proteins. I mean, I think, you know, if one can understand better the molecular event that is problematic or maybe a set of molecular events, it is possible to drug them.

28:56Yeah. So in the last minute, I just wanted to end by asking you, what is next for you at the research level? So we were talking about therapies, and of course, you're working towards that. But in the lab today, what are the next steps that you're most excited about? So obviously we want to understand that for these using model organisms like flies or worms or even geese is essential. We want to understand the molecular events that lead to these defects in translation, in protein quality control. So this, you know, you need to be able to go very deep into aged cells to be able to understand molecular mechanisms.

29:38We have also developed a system to look at aging in humans using skin fibroblasts. It's really, really amazing. You can take skin from human donors that have Alzheimer's or have Parkinson's or have Huntington's or young or aged. And they do have signatures of aging in the skin fibroblasts. Wow. That's amazing because the brain is hard to get, you know, nobody wants to give up a piece of their brain for science. But they might be willing to give up a piece of their skin for science. And you can even transform them into neurons without losing the aging or Alzheimer or Parkinson's signature. And you can study molecular defects on these human cells.

30:23This is, I mean, of course, this is very small amount. So you cannot do the kind of biochemistry or structural biology we want to do to understand molecular mechanisms. But it is a very exciting system to study how these insights convert to human molecular insights in the cell. So we are also very excited about that. Well, that's fantastic. And thank you so much for telling us about your work. I'd like to move now to our new segment, which is the future in a minute. And I think we've briefed you before. I have a few questions to ask you, kind of rapid fire. And you'll give me rapid fire answers.

31:02So I'm just wondering if you're ready to go. Yeah. Okay. First, what is one thing that gives you the most hope about the future? Compared to when I started to work in research and now, it's amazing the discoveries that science has been able to do. So things that when I was a grad student would be a whole five years PhD. Now an undergrad, a high school student can do them in a week. This is incredible, right? It's such an incredible power to solve problems. What is one thing you want people to walk away from this episode remembering? Aging and neurodegenerative diseases arise from molecular defects in the protein folding and quality control machinery.