The future of Parkinson's disease
Biochemist Suzanne Pfeffer is an expert on the molecular roots of Parkinson’s disease.
Her work focuses on mutated proteins linked to Parkinson’s risk. She’s discovered, for instance, that drugs inhibiting one of the proteins can help neurons regrow primary cilia and stave off cell death, reversing disease progression. Since similar drugs are in clinical trials, her findings bring great hope for people with a subtype of Parkinson’s and hopefully can be linked to earlier detection through warning signs like REM sleep disruptions and loss of smell. “This is precision medicine,” Pfeffer tells host Russ Altman of the future of Parkinson’s disease on this episode of Stanford Engineering’s The Future of Everything podcast.
Transcript
[00:00:00] Russ Altman: This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. Since we started this show eight years ago, it's become an archive of amazing and impactful work by my Stanford colleagues. Research is not something that just happens in the lab, and as you'll hear on this show, the research at Stanford can impact areas like health, technology, law, and business, and many other topics that can affect everyday life. We hope you'll tune in to learn more about how research has the potential to help your life and to help the lives of people you care about in your family and your community.
[00:00:32] Suzanne Pfeffer: And what we found was the antennas grew back, the cells began again to make those neuroprotective factors, and this cell, which was retracting its axon on its pathway to death, actually came back.
[00:00:46] Russ Altman: Wow.
[00:00:47] Suzanne Pfeffer: And we actually saw restoration of talking between these two neurons, restoration, back to normal. So it wasn't just stopping disease, it was reversing the process.
[00:01:05] Russ Altman: This is Stanford Engineering's The Future of Everything, and I'm Russ Altman. Today, Suzanne Pfeffer from Stanford University will tell us that our understanding of Parkinson's disease at the molecular level is increasing, and we have a better understanding of what's going on in the brain, so much so that we can now detect early signs of Parkinson's 20 years before the big, bad symptoms really occur. This is leading to new opportunities for treatments that are quite exciting. It's the future of Parkinson's disease.
[00:01:33] You wanna help shape future episodes of the podcast? Leave a review and tell us what you would like to hear next. We'll see what we can do. In fact, today's episode with Suzanne Pfeffer was suggested by a reviewer who said, "How about a little bit more on Parkinson's disease?" it affects millions of people. We, many of us know someone, a loved one or a friend, who suffers from the disease. So we found a local expert, Dr. Suzanne Pfeffer, and we're gonna be talking about Parkinson's disease today. In addition, today we're continuing our feature, The Future in a Minute. At the end of my conversation with Suzanne, I'll ask her some rapid-fire questions, and she'll give us some rapid-fire answers.
[00:02:08] And again, before we get started, remember to rate and review the show. It helps us, and it helps others learn about the show
[00:02:22] Parkinson's disease is a terrible disease that affects millions of Americans. It's thought of as a motor disease, a, a motion disease. People get problems with walking smoothly, they get a tremor, they get a lot of motor disturbances, and it can progress over the years to become worse and worse.
[00:02:40] The treatments are not very good. There's deep brain stimulation, which can last for about seven years, and there's medications which last for about five years, but then the side effects of those medication outweighs their benefit, and we often have to stop them.
[00:02:54] Well, Suzanne Pfeffer is a biochemist and a professor of biochemistry at Stanford University, and she's an expert at the molecules that go wrong in Parkinson's disease. She's studying them, and she's learning more about what goes wrong in the disease, and importantly, she's generating hypotheses about new ways to treat the disease, not just when the symptoms come on in your older age, but very early when you're first showing signs that you might have a risk for the disease. It's very exciting, and she'll be telling us about it.
[00:03:25] Suzanne, you're a biochemist. What led you to make the decision to do deep dive in a disease like Parkinson's disease?
[00:03:32] Suzanne Pfeffer: I was actually really lucky. So we were studying a small, set, a family of proteins called Rab proteins, and they control how proteins, are put in the right place in cells.
[00:03:44] And, our collaborator, Dario Alessi at the University of Dundee, made a discovery that an enzyme that's really important in Parkinson's makes a change to my favorite protein. And he didn't know about my favorite protein, and out of the blue, I got a phone call, "Suzanne, we need your help. We wanna understand how your proteins are part of Parkinson's."
[00:04:05] And that is a, was a totally life-changing experience, and he's the most wonderful collaborator. So, now we're celebrating our 10th year of direct collaboration, and I have learned so much and, and the work is really so meaningful. So, it was serendipity that his discovery led to my set of proteins and, and here we are.
[00:04:24] Russ Altman: So biochemists, just to stick on this topic for a couple minutes, biochemists are known for their kind of commitment to basic science, you know? In fact, you were probably studying these proteins, and they were probably interesting to you biochemically, and they did interesting things. Is it a big, hard decision to say, "I'm now going to think about this as the understanding a disease and maybe even getting involved in the development of treatments," where before it was just the, the pure kind of curiosity-driven research?
[00:04:51] I'm just very interested in your decision about how to balance those two. I'm sure they're both passions for you.
[00:04:58] Suzanne Pfeffer: So the reason I'm a biochemist is I wanna understand how proteins, these tiny little molecules, make us able to do all the things that humans can do. So I'm, fundamentally, that's the reason I'm interested in these molecules.
[00:05:12] But so, any connection to disease makes the work all the more meaningful. 'Cause it's not just working out just the picture of a cell and what it is, it's, has real consequences for people, and that has been one of the most wonderful parts of the last 10 years, is the work is super meaningful.
[00:05:28] Russ Altman: Great. Okay, so I think it would be good for us to have a little tutorial on like what we need to know about Parkinson's disease to appreciate the current frontier challenges and the work that you're doing.
[00:05:38] So maybe tell me a a little bit about the disease. How should we think of it? What do we know about the causes of, just for starters.
[00:05:46] Suzanne Pfeffer: Okay. So let's start with the causes. So most of the causes are probably environmental. We absolutely know that, pesticide exposure can greatly increase your risk of Parkinson's, even trigger it directly. And, so that's bad news for farmers and people that live in regions.
[00:06:05] Russ Altman: Wow.
[00:06:05] Suzanne Pfeffer: Even living near golf courses may be dangerous, right? We never think of that. You think of getting a, a retirement home, a condo facing the golf course. Well, that may not be the best plan.
[00:06:15] Russ Altman: So these are actively used pesticides, not just-
[00:06:17] Suzanne Pfeffer: Yes
[00:06:17] Russ Altman: historical ones.
[00:06:18] Suzanne Pfeffer: And in the US they have still not been, outlawed. The Europeans are ahead of us, but it's very, our, our environment is for sure linked to Parkinson's disease. Now, for scientists, that makes it difficult because, a person comes at age 65 with disease, we don't know where they've lived and, and, and what they might have been exposed to.
[00:06:38] So when there are genetic causes of disease, it gives us an inroads to study the process and especially if those genetic forms, the, the the kind that are inherited in your family from your parents or grandparents, when those forms, come on in a way that doctors, identify very similar to the ones caused by, pesticides, it gives scientists a a really important clue that we can zoom in exactly on that specific form of disease, understand what's gone wrong with that particular gene change to cause the disease, and then see how does that link to the other forms of disease.
[00:07:16] Russ Altman: So, is it the case that some people have the genetic predisposition to Parkinson's, but that other people just have the environmental exposures and perhaps don't have the genetics and still get the disease?
[00:07:28] Suzanne Pfeffer: Absolutely. But what's important is even if you have a genetic predisposition, it doesn't... it's not a guarantee that you'll get disease. So we call this penetrance. And so at, in some populations, in some mutations, it may be you have a 50/50 chance of getting Parkinson's. So then if you have that 50/50 chance, plus exposure to pesticides or smog or other unknown, environmental factors, also the, the chemicals used for dry cleaning, those can be, problematic for...
[00:08:00] So workers who've worked in a dry cleaning store, for example, may be at increased risk. Also, if you're a boxer, you got hit in the head or too many football concussions, that can also increase your risk. So it's gonna be a combination.
[00:08:14] Russ Altman: Okay, and so tell me a little bit about what actually goes wrong. It's a, we know it's a brain disease. It is. what, what happens in the brain?
[00:08:21] Suzanne Pfeffer: So, so, and this is really important, and it actually guides our work. So the two most common forms of neurodegeneration, in people are, number one, of course, Alzheimer's disease is the most, prevalent, but the second most common one is Parkinson's.
[00:08:37] And we always try to say, what's the difference between them? So Parkinson's is classified as a movement disorder. So, you may, people, you may know someone who has what we call a resting tremor. That's what people usually think of, where a hand at rest is showing a tremor, only at rest, or it may be the head has a shake, or the foot has a shake, or the tongue.
[00:09:00] So people think of Parkinson's as being a tremor disease, but it's actually a movement disorder. And what it is, it's, it's related to how smoothly you're able to initiate movement, stop, keep your balance, and not walk rigidly. So walking slow and highly rigid is a, a, a very predominant sign of actual Parkinson's disease beyond the, the resting tremor.
[00:09:24] Russ Altman: And do we, have we isolated the areas of the brain that are, that are, preferentially-
[00:09:30] Suzanne Pfeffer: Important
[00:09:31] Russ Altman: ... damaged?
[00:09:32] Suzanne Pfeffer: Yes. So, again, this is what we're trying to understand. There's a specific circuit in the brain that controls movement, the starting and stopping of movement and the rigidity, and this is called the nigrostriatal circuit. And in Parkinson's, it's the nigrostriatal circuit that is, vulnerable, that is, the cells die and are unable to do this process of, of controlling movement, and that's different than Alzheimer's.
[00:09:59] Alzheimer's can be different regions of the brain, and people with Alzheimer's, present in very different ways. So some people may get very angry, very hostile. Some people just lose their memory. Some people have trouble, swallowing. So again, in Alzheimer's, it could be different regions of the brain, and we're trying to understand in Parkinson's, why is it specifically this circuit that's especially vulnerable? And that's the focus of our work.
[00:10:26] Russ Altman: Great. And, and one more question, and this comes from my personal, you, you mentioned that many people have family and friends and, and in fact-
[00:10:31] Suzanne Pfeffer: Yeah
[00:10:31] Russ Altman: ... I did, my, my uncle. And, and what, two of the words that, two of the, diseases that were bandied about when they were making a diagnosis on my uncle was both Parkinson's disease and Lewy body dementia. So can you just tell us a little bit about, like, what, what, what is, what are the differences and similarities? Are these the same disease or are they different diseases? It was very confusing to the family since both of them were bandied about
[00:10:55] Suzanne Pfeffer: So, Lewy bodies are these accumulations of a protein called synuclein that that are seen and typically found in Parkinson's disease. Now, late stage Parkinson's often will develop into Lewy body dementia, and often there's a crossover in symptoms where you can have Parkinsonian symptoms in outright Alzheimer's. But let's just focus to keep it simple.
[00:11:22] Russ Altman: Yeah.
[00:11:22] Suzanne Pfeffer: In Parkinson's, the brains you see have Lewy bodies that are full of synuclein, and it's not at all for sure if they're the cause or the consequence, but they are characteristic of most, but not all forms of Parkinson's, and people would like to call it a, a Lewy body disease. But, Lewy body dementia is where you have, Lewy bodies in other regions of the brain that that are consistent with the dementia, the inability to remember things and, and to have that kind of brain function.
[00:11:56] Russ Altman: Great. Well, thank you very much for this tutorial. So now we, now we all have a kind of a shared understanding of these circuits. But you made some intriguing comments about some molecules, and I think we should try to understand where you are in your research and what we've learned.
[00:12:09] So, tell me a little bit more. You said there were some molecules that are involved in, I think, I well, I've reviewed your your papers, to what they call the trafficking of proteins, where it it tells the proteins in the cell where they need to be to do their job. So, tell me about how those things, are, are involved with the disease, and then of the other molecules that are important.
[00:12:30] Suzanne Pfeffer: So, we were talking before about how scientists use genetic forms of disease to really understand what's going on. So we studied two proteins that are, when mutated, the most common, risk factors for Parkinson's. And that's an enzyme called leucine-rich repeat kinase 2, or LRRK2. We call it LRRK2.
[00:12:52] Russ Altman: LRRK2
[00:12:52] Suzanne Pfeffer: And the other,
[00:12:53] Russ Altman: Nice and easy to say.
[00:12:54] Suzanne Pfeffer: Yeah. And the other is a lysosomal enzyme. I'll say what that is. It's a protein called GBA, glucocerebrosidase. And if you have, so the problem with the LRRK2 is you have a mutation, LRRK2 becomes what we call hyperactive.
[00:13:11] So LRRK2 makes a change on a protein. It puts a little charged molecule, a little charged piece, a, a little modification, changes the structure of a protein. And if the mutation does this too often, okay, too much of it.
[00:13:26] Russ Altman: Right.
[00:13:26] Suzanne Pfeffer: And so, when it happens too much, what happens is it blocks a process in the brain that we discovered, which is generating a little antenna on the surface of the cell.
[00:13:37] And that antenna is called a primary cilium. It's involved in signaling. So it's it's listening for signals, chemical signals that require the antenna that make the cell change.
[00:13:50] Russ Altman: It's a very fun idea that cells would have antennas, and it's very attractive 'cause of course they need to communicate, so it's fun that there's actually kind of like an antenna.
[00:13:58] Suzanne Pfeffer: It's a physical antenna. It's and they're beautiful little structures. Anyway, they're on nerve cells and they're on the supporting cells around the neurons. And what we discovered specifically in the nigrostriatal circuit, the part that's important in Parkinson's, the cells talk to each other.
[00:14:15] So here, this is a cell that secretes dopamine, these are the ones that die in Parkinson's. What they do is they send out a, a long process, a little extension, we call it an axon, to another region of the brain, and they secrete a signal when they are stressed. And the antenna has to receive that signal, and that makes this cell produce protective factors that make this cell happy So normally if this guy's stressed, the job of this one is to send happiness factors so these cells are happier, they're, they're, they're better able to deal with stress.
[00:14:50] Russ Altman: Right, right.
[00:14:51] Suzanne Pfeffer: And what we discovered is if you have the hyperactive form, the too active form of that LRRK2, these cells lose their antennas. So this guy's stressed, he's sending a signal.
[00:15:02] Russ Altman: Oh.
[00:15:02] Suzanne Pfeffer: This guy can't receive, doesn't know it's happening. It doesn't have an antenna, so it can't send back those protective factors. And so, then this cell starts to retract its axon as part of its process to die, and that's something we wanna stop in Parkinson's disease. So we're trying to understand how we can rescue that antenna so it can get the signal to send back the neuroprotective factors.
[00:15:26] Russ Altman: Now, you mentioned these two proteins, the LRRK2 and, and the one that begins with a G.
[00:15:32] Suzanne Pfeffer: GBA.
[00:15:33] Russ Altman: Tell... GBA, thank you. Yeah. what, what, are they on the part of the, are they part of the antenna, or are they part of the distress signal, or both?
[00:15:41] Suzanne Pfeffer: Good question. So what we know is that LRRK2 blocks the process of the antenna being there. So in LRRK2 mutation, half of the cells lose their antennas.
[00:15:52] Russ Altman: Oh.
[00:15:52] Suzanne Pfeffer: In the GBA, the cells keep their antennas, but they're not functional. They this antenna's broken. It can't sense the signal. And we we showed that the GBA mutation changes the structure so it can't signal anymore. So it's there, but
[00:16:08] Russ Altman: Gotcha
[00:16:08] Suzanne Pfeffer: ... and it, it can't do its job.
[00:16:10] Russ Altman: So, you know, one of the things that you you, you said you, you gave a scenario of a 65-year-old, but I know that there's a question about when these, when these, pathological changes in the brain start.
[00:16:22] And, and what, what do we know about this? And, and do... Are we seeing these malfunctioning cilia, if you will, primary cilia? Are we seeing them very early, or, or do we understand how quickly that happens in the disease process?
[00:16:35] Suzanne Pfeffer: We don't know that yet in humans. So, so far we've only looked at brains from, people who passed away at the age of 85 And, we clearly see in all forms of Parkinson's, not just the genetic forms, but the kind that we don't know the cause of that are likely due to environment plus some genetic factors, we see this, the, the antenna go away.
[00:16:57] They go away more in Parkinson's than in control brains from people of the same age. And so we don't know how early in humans. In mice, it's pretty early. In mice it's as, you know, it's at eight weeks we can see the, the problem. But remember, only half of the cells lose their antenna, so the other half are still there.
[00:17:20] And what we think is happening, it's, this is kind of like a, it, the, it's a slow process. So, so you have half the cells, maybe you're making half as much neuroprotective factors, but at, at, by the time you're 65, it's it isn't enough.
[00:17:36] Russ Altman: Yeah.
[00:17:36] Suzanne Pfeffer: Because it's been all those years a slow process. And this comes back to, to earlier symptoms of Parkinson's disease. So we know in Parkinson's, 20 years before you have a resting tremor or rigidity of walking, 20 years earlier, you have a couple of symptoms. One is constipation. Now anybody can have constipation. That's not proof you're gonna get Parkinson's. But you may have something which is called REM sleep behavior disorder. This is where when you're sleeping, you're acting out your dreams, and these are often sometimes violent dreams. So you're, you'll be kicking and punching.
[00:18:14] Russ Altman: Huh.
[00:18:14] Suzanne Pfeffer: And your partner will say, "Hey, you're waking me up. You're kind of dangerous over there. what's going on?" If you have REM sleep behavior disorder, there is a very high probability, and this is 20 years before anything else.
[00:18:28] Russ Altman: Wow.
[00:18:29] Suzanne Pfeffer: There's a very high probability that you will get Parkinson's. It's not a, it's something I wouldn't wanna be diagnosed with.
[00:18:34] Russ Altman: Yes.
[00:18:35] Suzanne Pfeffer: Yeah.
[00:18:35] Russ Altman: So the, the constipation is not very specific. The, the, but, but the, the REM disorder is.
[00:18:41] Suzanne Pfeffer: REM behaviors. And, and also loss of smell
[00:18:44] Russ Altman: Oh!
[00:18:44] Suzanne Pfeffer: So just like in COVID where many people lost their sense of smell, an early symptom of Parkinson's, 15 years before you have any of the movement symptoms, will be a loss of sense of smell.
[00:18:56] And most people don't really notice when they're losing their sense of smell. they may start wearing stronger perfume because they don't realize it, but it's something, it's very subtle unless it's really tested. And something for the future, I hope, is that everyone, when they go for their annual physical exam, will take a scratch and sniff test, which is, costs costs a dollar or something to, to offer people.
[00:19:21] It's, it's very inexpensive, but it's something we should be monitoring, whether people are, how sensitive they, and able they are to sense, odors.
[00:19:30] Russ Altman: Yeah, the, the, the last few minutes of, of your comments, and I know you've written about this, make me understand why, we shouldn't think of Parkinson's as something that just hits us when we're old, but there actually probably should be in as part of your primary care, a certain amount of surveillance for these-
[00:19:45] Suzanne Pfeffer: Absolutely
[00:19:46] Russ Altman: ...different symptoms that you've just, that you've just described.
[00:19:48] Suzanne Pfeffer: Absolutely. Absolutely.
[00:19:50] Russ Altman: This is Russ Altman, your host of The Future of Everything, and I'm speaking with Suzanne Pfeffer. We're gonna move on to treatment as a something I wanted to ask Suzanne about because we now have a pretty good understanding of Parkinson's disease, some of the molecular problems in the brain.
[00:20:04] So Suzanne, what is the current state of treatment for Parkinson's disease, and what's good and what's bad about the current treatments?
[00:20:11] Suzanne Pfeffer: So one of the challenges and, and limitations, the treatments right now are just treating symptoms.
[00:20:18] So basically, you would be given something that will, help the resting tremor or help you be able to coordinate movement a little better. But the problem is, is that after about five years, those, you, with time you need to increase your dose and increase your dose and increase your dose. And then at some point it has a bad consequence, which is it caused something called dyskinesia, which are these movements which you can't control, and it's very embarrassing and very uncomfortable for people to have those.
[00:20:51] There's also, a, a great success with something called deep brain stimulation, where they actually place an electrode into the brain to try to counteract some of the signals, and that works very, very well for about seven years. But then at some point, that also stops. So we need something that's not temporary for these people because-
[00:21:12] Russ Altman: Yeah
[00:21:12] Suzanne Pfeffer: you can live a long time with Parkinson's, and the symptoms, you know, you really would like to be able to button your shirt when you get up in the morning or be mobile but, and independent and, and not worry about a freezing of gait where you, basically cannot move forward. I mean, that would be terrible if you're trying to go about your daily life.
[00:21:33] Russ Altman: Yes.
[00:21:34] Suzanne Pfeffer: So, so you really would like to do better. So we have to do better, not only to, help with symptoms, but also to slow the progression.
[00:21:43] Russ Altman: Yeah
[00:21:43] Suzanne Pfeffer: And that's, that's really the limitation at the moment.
[00:21:46] Russ Altman: You know, in our, in our previous conversation, you were mentioning these symptoms that, that can come 20 years early, the sleep problem, the, smelling problem. And, I take it that if, if you did have all of these symptoms and you told your doctor and your doctor was then worried about Parkinson's, none of those medications that you just described would really be very good 20 years early, would they?
[00:22:08] Suzanne Pfeffer: That's correct. So for example, they will prescribe melatonin to help you sleep better, but it's still not going to address the underlying cause of the, of the symptoms.
[00:22:19] Russ Altman: Okay.
[00:22:19] Suzanne Pfeffer: And, but,
[00:22:20] Russ Altman: Well,
[00:22:20] Suzanne Pfeffer: Yeah. So it's a challenge. So we, we need to try to... We need to learn what's going on at the earliest parts of disease and, try to, try to block it and maybe even reverse it if we can.
[00:22:32] Russ Altman: Yes. And, and because I like to prepare for my interviews, I did look at many of your recent papers, and there are some very, promising directions on some of the molecules you were discussing earlier. So, can you tell us what's the status of, these potential new treatments based on the molecular mechanisms that you and your colleagues are working out?
[00:22:50] Suzanne Pfeffer: So I told you about LRRK2 and LRRK2 being important for a cellular antenna, and there are now 32 biotechs in the space of trying to identify an inhibitor that will bring it down to normal levels.
[00:23:04] I told you it's too active, but all of us have a certain amount of activity, so we just need to inhibit it or bring it down in its activity a little bit. And, one, Phase 2B clinical trial just completed, with a LRRK2 inhibitor, and there are several others that will be, read out fairly soon.
[00:23:24] The the first one, unfortunately, the good news is it showed very good safety profile, but it didn't seem to benefit the people that were included in the trial. And my own feeling is I think it was the wrong group of people.
[00:23:37] Russ Altman: Ah.
[00:23:37] Suzanne Pfeffer: We know that there are people specifically where we know they have too much LRRK2, and that's the best patient population. They're hard to hard to recruit for the trials, but the next trials coming out that we're going to be hearing about, we're, we're very careful to only use those populations, and my fingers are, are crossed. I'm very optimistic that there will be benefit for those people.
[00:24:00] Also, I think a limitation of the previous trial is it was it was using, it, it, it could use more sensitive methods to monitor any success in the trial. And of course, it's a problem, these kinds of, of, if you live for 20 years with Parkinson's, the changes year to year are not gonna be as great-
[00:24:21] Russ Altman: Right
[00:24:21] Suzanne Pfeffer: ... as if you live a very short time. And so it, the readout will, will have to get very, we wanna get more specific so we can actually see the benefit of these compounds.
[00:24:30] Russ Altman: So for the phase 2 trial that, showed good safety and, and, but wasn't able to show a lot of change, was that done on elderly advanced disease, or was it done on these folks who have the early symptoms? What kind of patients did they use?
[00:24:44] Suzanne Pfeffer: They were patients that were relatively newly diagnosed, but they didn't necessarily carry the predisposition, the mutation in LRRK2. And so, if it's a, if it was caused, if it's of unknown cause, we can't be sure that this precise, this is what we call precision medicine. It's a precise drug that will help specifically people with this mutation, but we can't be sure it'll help everybody.
[00:25:10] Russ Altman: Yeah. So so for people who don't think about clinical trials every day, the, I, just to restate what you just said, the idea is that Parkinson's disease might have subtypes. There might be subtypes that are particularly well-suited to a certain drug, and if you mix up the people who are very well-suited to people who are not very well-suited, it may overall look like your drug is a loser, but actually there's a a, a fraction of that population who got a great benefit. And so that's why I, I, I presume that's why they're redoing these trials now with a more focused way.
[00:25:40] Suzanne Pfeffer: Absolutely.
[00:25:40] Russ Altman: And in terms of the mechanism, the the mechanism is actually, I think you've told us everything to, at least at, to a certain level, you were saying before that the LRRK2 mutations sometimes are making these changes to proteins and they're doing it too much. And so I guess these molecules, you might have even said this word, are inhibiting the LRRK2 so that it doesn't quite, it's not quite as robust in its, enthusiasm for making changes to other proteins and kind of brings it down to a normal level.
[00:26:07] Suzanne Pfeffer: That's absolutely. But we had a really exciting result last year, which is we took some of these, drugs, drug candidates, and a, a particular one, and we fed it to mice that have the too much LRRK2 activity.
[00:26:20] Russ Altman: Oh
[00:26:20] Suzanne Pfeffer: ... super enthusiastic LRRK2. We fed the mice for two weeks and we looked at the brains, and there was no change. But we fed them for three months, and what we found was the antennas grew back, the cells began again to make those neuroprotective factors, and this cell, which was retracting its axon on its pathway to death, actually came back.
[00:26:43] Russ Altman: Wow.
[00:26:44] Suzanne Pfeffer: And we actually saw restoration of signaling, talking between these two neurons, restoration, back to normal So it wasn't just stopping disease, it was reversing the process. Now, the thing is, these mice are a model of early Parkinson's, and so our hope is that those same reversal of symptoms will help people if we can get the drug to them at the earliest stage.
[00:27:10] Russ Altman: Yeah, that's why I asked you about the population that was tested, because it, it would be
[00:27:14] Suzanne Pfeffer: Yeah
[00:27:14] Russ Altman: ... hard if somebody is, you know, 40 and just having initial symptoms, it might be hard to get them to be very excited about being in a clinical trial 'cause their-
[00:27:22] Suzanne Pfeffer: Exactly
[00:27:22] Russ Altman: ...their level of disease is not so great. They're not really aware of it yet. and yet, that might be the group that would eventually benefit the most.
[00:27:29] Suzanne Pfeffer: Absolutely.
[00:27:30] Russ Altman: Is that, is that correct logic?
[00:27:31] Suzanne Pfeffer: Absolutely. Absolutely.
[00:27:33] Russ Altman: Okay. Well, so this is great. So in the last two minutes, I just wanted to loop around, 'cause I know you're, you're passionate about this. You know, you you're a biochemist and you, you, you were studying proteins, that you found to be fascinating and, and important to, to understanding basic, neuroscience and other fields. And then all of a sudden, you got a call from somebody who, who was a Parkinson's researcher and and now you, you describe this 10-year, journey.
[00:27:59] This is a really a great story about the value of basic science because when you started studying these Rab proteins that you mentioned earlier-
[00:28:06] Suzanne Pfeffer: Yeah
[00:28:06] Russ Altman: ... I think you mentioned them, but I know-
[00:28:07] Suzanne Pfeffer: Yeah
[00:28:07] Russ Altman: ... they're Rab. You probably weren't thinking that this was gonna be a Parkinson's disease, relevant study. So, what do you take from that whole experience, and what would you tell people who maybe don't understand why you're doing research on molecules that you don't even know what disease they might be involved with? Or if they're even involved with a disease at all, right?
[00:28:27] Suzanne Pfeffer: So I've had-- I've lived both lives. I've lived a life where I study a specific disease for the past 10 years, and the 30 years before that, I studied a general process. And I could tell anybody, it's important in cancer, in immunology, in neurodegeneration. We could make the story relevant to all these things, but it's a completely different world.
[00:28:47] And today what I would say is, I would rather pick a a, a disease and study the molecules, because I can sit, sit on an airplane and talk to the person next to me and say, "I work on Parkinson's," and I can meet with people who have people with Parkinson's, and to, and they, it's just so much more valuable and meaningful-
[00:29:10] Russ Altman: Yeah
[00:29:10] Suzanne Pfeffer: ...to me as a person. I'm making a difference. I am making a difference in people's lives. And sure, I was doing that before, but now I'm doing it in a very concrete way. And, and as a researcher, you know, we work days and nights and hours and, long, so it's a full dedication. I think the extra benefit of studying a disease is just so, satisfying, personally satisfying
[00:29:33] Russ Altman: Well, yes and thank you for your work, which is really giving, many of us who have family, friends who've suffered from this disease a lot of new hope. Before we finish up, I just wanted to ask if you're ready for our segment that we call Future in a Minute?
[00:29:46] Suzanne Pfeffer: I'll try.
[00:29:47] Russ Altman: Okay. So, as you know, we, I'll ask you these questions, and, I'll try to ask them quickly, and then you give me your, your, your answer. Okay.
[00:29:57] What is one thing that gives you the most hope about the future?
[00:30:01] Suzanne Pfeffer: I think our ability to integrate predisposition to disease, the earliest symptoms, and, newly discovered disease biomarkers should really make it possible for us to address neurodegeneration and stop it before it develops. It is a very exciting time.
[00:30:17] Russ Altman: What's one thing you want people to walk away from this episode remembering?
[00:30:22] Suzanne Pfeffer: I think people don't understand about how cures are found for disease. Fundamental research is critical for our ability to identify ways to help people and cure disease for, any disease, both for treating symptoms and for actually curing the disease.
[00:30:39] Russ Altman: Aside from money, what is the one thing you need to succeed in your research?
[00:30:43] Suzanne Pfeffer: I'm gonna tell you two things. First of all, you need a, a, a talented team. It takes a team of people to do the work. But we also need brains, and it's hard to ask people to donate their brains, but please consider it because it, it helps us be sure that what we study in the lab is is directly related to what we see in human disease.
[00:31:05] Russ Altman: If all goes well, what does the future look like?
[00:31:08] Suzanne Pfeffer: I think the future looks like much better treatments for Parkinson's, and hopefully we'll be able to stop, disease progression in its tracks so that we have a world where people really don't have to suffer from Parkinson's disease.
[00:31:23] Russ Altman: And if you were starting over again and you needed to get your degree or your certification in a different discipline, what would that be?
[00:31:30] Suzanne Pfeffer: Well, as you've said many times, I'm trained as a biochemist and a cell biologist, but I study whole brains. And so I think we, I, I could really benefit from, training as a cellular and systems neuroscientist to really understand the consequences of molecular changes in the context of an entire organ that's as complicated as the brain.
[00:31:52] Russ Altman: Thanks to Suzanne Pfeffer. That was the future of Parkinson's disease. Thank you for listening to this episode. Don't forget we have a back catalog of more than 300 episodes. You can spend all day listening to the future of pretty much anything.
[00:32:05] If you like what you hear, follow the show, press that button. You'll be alerted to new episodes, and you'll never miss the future of anything. You can connect with me on many social media platforms, including LinkedIn, Threads, Mastodon, and Bluesky, where I'm @RBAltman or @RussBAltman. You can also follow the School of Engineering at Stanford, @StanfordSchoolOfEngineering, or more briefly, @StanfordENG.
