From the Lab to Treatment: Neuroscience and the Fight Against Parkinson’s

Yong Hwan Kim: Sometimes it costs half a million, electrically stimulating the microchip. The real reason behind this is that they’re losing dopaminergic neurons in the substantia nigra where the midbrain is located. Smoking, you know, they have to prevent or delay Parkinson’s disease. But obviously, they have a 16 times higher chance of getting lung cancer, so we don’t recommend smoking to prevent Parkinson’s disease. Now we drive those cells into particular targets. 

Sam Butler: Welcome back to Bronco Tales season two. This episode, we are hosting Dr. Kim with the neuroscience program. Welcome in. Thank you for being here. 

Yong Hwan Kim: Thank you for inviting me. 

Sam Butler: Yeah, you like to just introduce yourself to the audience really quickly. 

Yong Hwan Kim: Hello, my name is Hwan Kim. I’m a program director of the neuroscience program. And we opened our bachelor’s program in neuroscience last summer. This is a brand new program. And we are quickly expanding and growing. So we’re actively recruiting numerous faculty from biology, psychology, kinesiology, and others. And now biomedical engineering and local hospitals, including St. Luke’s and St. Al, and the VA hospital, are part of the neuroscience program. 

Sam Butler: Awesome. And you primarily–in your lab research on Parkinson’s disease, correct? 

Yong Hwan Kim: Yes.

Sam Butler: What is the main cause of Parkinson’s disease? 

Yong Hwan Kim: So Parkinson’s disease, first of all, maybe 10%, or around 10% of patients are genetic, means familial Parkinson’s, meaning that they were born with some genetic mutation. So some of them are considered autosomal dominant mutations, then you will definitely have Parkinson’s disease in your 40s or early 50s. Some cases are autosomal recessive, meaning that both alleles, one from the mother, one from the father, both of them are mutated, then you will have Parkinson’s disease. Obviously, much rarer than autosomal dominant cases, but then, unfortunately, the onset is earlier. So patients are having Parkinson’s disease in their 30s instead of 50s. But the vast majority of PD cases are sporadic. They don’t know why they got Parkinson’s disease. So then, usually the patient’s onset is around 60 or mid-60s. 

Sam Butler: On average, it’s 60s, and then early onset would be 30s. 

Yong Hwan Kim: Right. 35-ish, but then it is rare. Only one or two percent of Parkinson’s patients are early onset. 

Sam Butler: And what are some of the first symptoms that people start to see, whether it’s regular onset or early onset? 

Yong Hwan Kim: They start to complain about stiffness. Oh, I used to, you know, walk around comfortably, but now my body’s holding stiff. Even my back is kind of crouching a little bit. And then some of them start to show mild tremors. So then, okay, something’s not right. But then some of them may not take it seriously because, you know, hey, I’m 70 years old and, you know, my body’s stiff. I guess I’m getting old, but that’s not a real reason now. You know, the real reason behind it is that they’re losing dopaminergic neurons in the substantia nigra where the midbrain is located. So then dopamine synthesis and release would be reduced. Therefore, their motor control is already deteriorated, but then too late. 

Sam Butler: And how do you see kind of what you just described in research, but also like a diagnosis? Like, how does, you know, what scans kind of–what diagnosis do the people have to go through? 

Yong Hwan Kim: The best way to do it is functional MRI. So we know where your dopaminergic neurons are located, and where dopamine release is happening. So based on functional MRI, certain areas, like substantia nigra, or the pudicodamine, where dopamine release normally happens, that area would be quiet, less active compared to healthy controls, age-matched, and gender matched. Then the neurologist can comfortably conclude, oh, you have Parkinson’s, you are having or progressing a Parkinson’s disease. So then we can test kind of the opposite way, giving some medicine, whether that actually helps their mobility or not. So they can verify that yes, you are having Parkinson’s disease. 

Sam Butler: And what are some of the ways, if any, that have been discovered to help prevent or reduce, you know, maybe push back how…like the age range that you can kind of…

Yong Hwan Kim: We don’t have an excellent way to prevent Parkinson’s disease, you know, at this point. That’s why numerous scientists are studying, you know, Parkinson’s disease. So many reports suggest that nicotine, smoking, you know, prevent or delay Parkinson’s disease. And based on statistics, yes, smokers, you know, have a lower chance of getting Parkinson’s disease, but obviously they have a 16 times higher chance of getting lung cancer or other disorders. So, you know, we don’t recommend smoking to prevent Parkinson’s disease. And after having Parkinson’s disease, mild exercise, including yoga and others, would be beneficial in terms of reducing stiffness. 

Sam Butler: What about in terms of like the tremor, you know, hand-eye coordination exercises, kind of things of that nature to strengthen those…

Yong Hwan Kim: Probably helps, and this–you know, we can say it doesn’t hurt because you know the mild exercise often stimulates dopamine release. So patients feel better with that, and we don’t have any curing method for Parkinson’s disease, and no real, you know, the curing medication either. So everything available in the market for Parkinson’s disease patients is symptom-alleviating medicines, nothing to do with you know curing the disease. 

Sam Butler: Just to help kind of ease the symptoms. 

Yong Hwan Kim: Yeah, right. 

Sam Butler: So, what–you know, we kind of talked about the causes. What does the Kim lab do in terms of Parkinson’s?

Yong Hwan Kim: We try to understand the pathological mechanisms of Parkinson’s disease, and ideally, we want to identify a novel therapeutic target. Particularly, I’m interested in cellular senescence. So we are getting old, and cells are getting old, and at some point, cells stop proliferating, then we call them senescent cells. In neuroscience, we didn’t pay attention to cellular senescence much because neurons do not proliferate. But 90% of cells in the brain are glial cells, which are locally proliferating. So that’s why now we pay attention to the cellular senescence aspect of Parkinson’s and Alzheimer’s disease pathology. We found that brains are experiencing a pathological condition, or progression is already happening; more senescent glial cells were detected based on our observation from human samples and the mouse model. We published one paper related to that, and currently we are running a couple of projects related to that. 

Sam Butler: And what, you know, how do you gather this research? What are kind of the steps that you kind of have to go through, and then you’re able to look at these things? 

Yong Hwan Kim: So we have to get or establish the research tools, which are typically mouse models or cell lines or cell models, or human samples. Sometimes we get human Parkinson patient samples, especially substantia nigra, the frozen samples, and we analyze whether our target or biomarker would be higher or lower in the patient compared to an age-matched control. That’s one way to validate, okay, this is a reasonable target or not. And we manipulate animals, like typically mouse models, for that purpose. We can genetically manipulate that. Something toxic, then we can overdrive, genetically, or we can inject alpha-synuclein of preformed fibros into the brain, where the dopamine release is happening. So then, two to three months later, those animals are experiencing Parkinson-related symptoms. And we can see that progression is kind of quick after some point. We use those animal models for our research tools.

So then, for example, in cell-less senescence, we want to remove senescent cells. Then we orally gavage senolytic, which induces apoptosis for senescent cells to remove toxicated cells to prevent neurons. So we are using a cell model, or sometimes a stem cell model, or a primary cell culture, which means isolating brain tissue from a baby brain, and then we culture it in vitro. Or, as I said, we’re using a mouse model, a transgenic or injection model. 

Sam Butler: So you’re kind of artificially stimulating the brain? 

Yong Hwan Kim: Right, right. Kind of, we generate the neurotoxicity in the animal brain to mimic Parkinson’s condition. Then we can apply a potential therapeutic application, whether that actually reduces the toxicity or prevents the neurons or not. So we can test that in mice. 

Sam Butler: And what’s the overall, like, main goal of your lab? 

Yong Hwan Kim: Well, the ultimate goal is based on our findings, as I said, a potential therapeutic target. We want to use the target for therapeutic application. So we are also working with a biotech company. And, I’m going to discuss, and we found some novel targets, and they design either small molecules or other, like antisense RNA, things like that. So if we take it and we apply it to the pathological mouse model, and we test whether it is convincing or not, really. Then we kind of maneuver, not working, then we redesign the potential drug and possibly a completely different target. So we are mainly interested in developing therapeutic applications for Parkinson’s. 

Sam Butler: So not solving, you know, how you get Parkinson’s and that, but mainly helping patients that already have the disease. 

Yong Hwan Kim: Right. So it can be two different, you know, the root. One way is, if we can prevent–preventive medicine would be the best. But again, we don’t have a good pre-diagnostic marker for Parkinson’s disease. So we have a very limited, you know, access. Second thing, after patients are showing symptoms, we have to help them in terms of alleviating symptoms, and possibly halt pathological progression. That’s the goal. If we can hold, then possibly we can reverse, you know, pathology a little bit. Then everything will be in the right direction because they probably feel better, they can move better, and possibly prevent secondary damage, which is like dementia and depression, because 25% of PD patients in the later stage they’re experiencing depression and dementia. 

Sam Butler: So that kind of just builds off of what develops from Parkinson’s?

Yong Hwan Kim: Right. So, if we can kind of hold the disease progression, then probably the downstream other pathologies would be prevented as well. As I mentioned, like dementia or depression. 

Sam Butler: Which would almost be a form of a cure of some sort. It wouldn’t stop it, but you’re trying to get enough to make it easier to live with. 

Yong Hwan Kim: Right. So, unless we prevent the full damage, maybe not reversing from the pathology developed, but at least hold right there. To prevent further damage, their quality of living would be much better. So that could be a very important application as well. But ideally we can–you know, prevent from the beginning, then we need to identify, you know, the pre-diagnostic tool, which is also lacking in Parkinson’s and Alzheimer’s. 

Sam Butler: And what drew you to kind of choose this research and field? 

Yong Hwan Kim: Well, initially, I studied molecular biology for my bachelor’s degree, and then I studied biotechnology for my master’s degree. But then, right before finishing my master’s degree, my mom got a stroke. And I realized I studied biology or physiology for several years already, but I didn’t know much about the brain. And that was kind of a turning point. I’m interested in neuroscience. I want to study neuroscience. So I decided to study neuroscience for my PhD. So that was my initial engagement with neuroscience. But then–what I studied for my PhD thesis was sex differences in the brain. Why are males responding…differently or behaving differently than females? What kind of gene expression would be different? That was my thesis topic.

But then my last project before I left UCLA was Parkinson’s disease. Patients are a little bit more prevalent in males than in females. So then, whether any genes on the X chromosome prevent the Parkinson’s disease onset on the female side. So we studied that genetically using a mouse model. And then I was deeply engaged with Parkinson’s disease. Then I got my first postdoc job at Johns Hopkins to study that. And then I moved back to California to study Parkinson’s disease continuously at the Buck Institute. So, since then, I studied Parkinson’s disease for the past 20 years or a little bit longer. 

Sam Butler: And was that first at UCLA, was that your choice to choose Parkinson’s, or was that kind of given to you? 

Yong Hwan Kim: That was actually kind of a mutual agreement between me and my PhD mentor. I like that project, so that’s why I was willing to take over the project. So it’s a mutual decision. 

Sam Butler: You also kind of mentioned in your lab that you used–or researched deep brain stimulation. What does that look like in a human–or for a human brain? And, how can that help with Parkinson’s? 

Yong Hwan Kim: I haven’t studied deep brain stimulation in my lab yet, but I’m interested in doing that. But I have interacted with several DBS, the transplanted patients, Parkinson’s patients, and their response was very positive. And I have interacted with the neurosurgeons and neuroscientists in several institutions, including Rutgers, the University of Florida, and Johns Hopkins. So it is very promising. So a simple idea is to surgically implant a small microchip into, in our case, the substantia nigra. Because we know where our target is, which is the substantia nigra, where dopamine energy neurons are dying. So that surgically implant it there, and then put the post-chaser or regulator underneath the skin with a battery-operated system. So then when patients feel stiff, they can push the patch, then electrically stimulate the microchip with the brain, and then they feel better. 

And again, based on my interactions with the patients, they say they like it, and their quality of living is much better. But still, it’s an expensive procedure because it’s a major invasive surgery is required, and insurance companies probably do not support that. So sometimes it costs half a million, things like that. A lot of positive responses from the patient. But one caveat is we don’t know how it works, really. Simply to stimulate the whole region, even though it is pretty narrow, but how it works, really, we don’t know exactly. We assume, yes, stimulating the whole neuron, then the dopamine release would be stimulated as well, but is it really the mechanism? Probably so, but we don’t know the exact mechanism. The second thing is that it doesn’t really prevent further disease progression. So it’s not really curing the disease. So that’s one of those downsides.  

Sam Butler: Like the quality of life. And it doesn’t sound like–do you know how many people–or it’s not a very common…

Yong Hwan Kim: Not that common yet, because again, it’s not covered by insurance companies. And also, it’s not really a disease-modifying application, although it substantially alleviates their symptoms, but it’s not really curing the disease. So, very limited access and limited availability for average patients. 

Sam Butler: So would you say it’s probably not the best way to kind of route to move toward, or do you think in the future it would be? 

Yong Hwan Kim: I think a lot of patients are highly recommending it because they are–many of them are saying that their quality of living is substantially better after surgery. So I think it is probably a good way to go. But again, it’s not really a disease, you know, a curing application. So, you know, theoretically better way is stem cell research, simply patients lost the dopaminergic neuron, 50%, whatever or more. Then the IPSC, an Induced Pluripotent Stem Cell from your own skin, and in vitro differentiation into the dopaminergic neurons, and they can get that neuron in vitro differentiated, you know, in this case, the dopaminergic neuron into their own substantia nigra, and let them reconnect.

So very limited application of stem cells because like same thing extremely expensive, and insurance doesn’t cover and there aren’t many, you know, labs out there that can do it consistently. Because cultured stem cells could be very finicky, because cells of life, you know, I think sometimes they–differentiate it slightly differently, the outcome would be different too.

So a lot of variables in this application, but a friend of mine at McLean Hospital, which is Harvard Medical School. He reported in New England General Medicine about three years ago with a success story. So I think a lot of promise for this application, but we need to decide how we can lower the cost. One way to do it is genetic, you know, not necessarily transplanting my own cell, you know, just like a custom-made cell line, but they are the pulmonary neuron, and then transplant, and then after surgery, we need to get immunosuppressant, you know, to take the cell where someone else’s, you know, the neurons. 

Sam Butler: So you’re artificially growing or the–what you’re describing is like an artificial growth of stem cells. 

Yong Hwan Kim: Yeah, in vitro, on the dish, we can culture either my own cell or someone else’s cell and then differentiate them into, in this case, a dopaminergic neuron, then transplant to the target area, and then wait. And one caveat of this approach is that whole protein aggregation is the main cause for Parkinson’s, Alzheimer’s, and other neurodegenerative diseases. So then, the pathological condition is not cleared, but then giving new neurons. Some people believe those new neurons will take up protein aggregates quickly within several months or within a year, then they will probably lose those new neurons again. Then is it worth it to spend half a million or whatever? 

Sam Butler: So it might not be it?

Yong Hwan Kim: So we still have several hurdles to overcome, but theoretically, this is the most promising approach because the application can cure Parkinson’s disease and Alzheimer’s. 

Sam Butler: And what do you mean by differentiating the cell into the dopamine receptor? 

Yong Hwan Kim: So the IPSC means the induced pluripotent stem cell, so we’re using our own skin, because skin is one of the few cells that still proliferate actively, even though patients can be in their 70s. But then we have to de-differentiate and then re-drive those cells into a particular target, like dopaminergic neurons. So we need to get dopaminergic neurons, right? So that’s why we convert skin cells to dopaminergic neurons.

Sam Butler: So it’s transforming the cell? 

Yong Hwan Kim: Right, that’s what I mean by differentiating into a particular target. Let them lose skin cell characteristics, and then become more stem cell characteristics, and then we can drive them into dopaminergic neurons. It takes two to three months on a dish, but we already have protocols like that, not me per se, but in our community, this is well established. So that part is relatively easy, but the transplant takes time and is costly, and also, after surgery, nothing’s guaranteed. So it’s still a risky surgery. 

Sam Butler: I know you probably get this question a lot, and you’ve kind of mentioned it, but if you were to get Parkinson’s disease, what process would you go through, or would you do it any differently than most? 

Yong Hwan Kim: Practically not a lot of, you know, options. 

Sam Butler: Yeah. 

Yong Hwan Kim: So because, you know, the older medicines available, now are symptom alleviators. So generally, the L-DOPA, which is a precursor of dopamine that works, you know, very well, for most PD patients. 

Sam Butler: That’s a medication? 

Yong Hwan Kim: That’s medication. It has been established, you know, for a long time, more than 34 years. But it does have a side effect. So L-DOPA–90% of patients are saying, oh, L-DOPA works. But, taking L-DOPA for nine years, then 90% of the patients are developing L-DOPA-induced dyskinesia is kind of out of control. So then they need to get another medicine to suppress this kind of side effect.

That’s right, nowadays, doctors are not prescribing L-DOPA or L-DOPA-related medicine like Sinemet because we all know it does have side effects. So then, starting with a mild medicine, like a dopamine agonist, it stimulates receptors–not really, you know, touching on dopamine directly. Or, an inhibitor, which blocks dopamine’s normal degradation. Then the dopamine level would be slightly higher in the system. The patient feels a little bit better, but it’s not excellent medicine. It has a very limited efficacy for many patients. So then what is the choice I–you know, I would have if I’m a patient–again, not much, but a mild exercise based on several studies, yoga or other mild exercise helps dopamine release. So, probably, you know, I will do that. And then, if possible, delay taking L-DOPA because we know it does cause side effects. So, again, very limited, you know, choices. 

Sam Butler: So that’s kind of–not a last resort, but a one you don’t want to immediately go to. 

Yong Hwan Kim: L-DOPA, probably not, you know–and also Parkinson’s disease patients, they live for a while. Many patients live more than 10, 15 years. So you have to think about the long-term effect. As I mentioned, you know, L-DOPA works, but you have to think about what about, you know, five, ten years later. So that’s why many neurologists are reluctantly prescribing L-DOPA medicine, but then patients who complain, you know, still can’t move around. Well, can you help me? You know, then okay, I’ll give you a low dose of L-DOPA-related medicine.

But then, unfortunately, you have to increase the dose over time because of the tolerance issue. The same amount or same dose of medicine doesn’t work after a couple of years, you know, so then you have to increase the dose. Which then elevates the chance of having side effects, you know, like LID or dyskinesia, so that’s the dilemma. Patients like it, you know, initially, but then they will soon experience that effect, so then what is the kind of balance between them? 

So that’s why many patients actually kind of refuse to take any medicine for a while, but after some point, they have to take it. Otherwise, it’s too difficult to, you know, move around their basis. So, depending on the patient and general, they’ll–if health level is high, other than a low level of dopamine. Then maybe they can delay a little bit for taking any major medicines, but some of them start tumbling down. So then, likely, they may not even live another ten years. Then, probably, you know, better to take medicine. So if I’m a patient, then I would consider how many years I have. Realistically, I have probably ten years or longer than I will look at the major medicine. If I don’t feel like you know, I have that much time, then I’ll take Sinemet or another correlated medicine

Sam Butler: Well, I don’t have anything else. 

Yong Hwan Kim: Okay, good. 

Sam Butler: Yeah, thank you for joining me. And thank you, everyone, for watching. It was very interesting to learn kind of the behind the scenes of neuroscience and your lab. 

Yong Hwan Kim: Thank you for having me, Sam. 

Sam Butler: Yeah, thank you. 

Yong Hwan Kim: All right, cool. Thank you.