How MJFF Accelerates Breakthroughs in Parkinson’s Research: A Conversation with Dr. Shalini Padmanabhan

In this episode, I discussed with Dr. Shalini Padmanabhan, Senior VP of Research from Michael J. Fox Foundation (MJFF), the work conducted by the foundation.  She highlighted MJFF's strategic approach to funding across the entire research spectrum, from basic biology to clinical trials, and emphasized our focus on breaking down silos between academia, industry, and patients to accelerate progress. We also discussed current challenges in Parkinson's research, including the complexity of the disease, difficulties in translating preclinical findings to clinical settings, and the need for better biomarkers and clinical trial designs.

·       Biomarker :  is an indicator, something we can measure in our blood, urine, or soft tissues to show that the drug treatment/therapy is showing a response to a therapeutic treatment. These have been hard to find especially for neurological diseases and new biomarkers are being discovered that is helping design clinical trials.

·       Pre-clinical model- to understand a disease in laboratory, scientists need to make a model using animals or cells that looks like the disease.

·       PPMI: MJFF has initiated a Parkinson's Progression Markers Initiative (PPMI), that follows thousands of individuals – those recently diagnosed Parkinson’s participants and healthy controls for clinical and genetic risk factors.

·       Epidemiology— Epidemiology is the branch of medical science that investigates which factors can lead to diseases and disorder.

Transcript

02:29 [Akshata] Welcome Shalini to the show.

03:50 [Shalini] Hey, Akshata, very happy to be here.

03:53 [Akshata] Thank you for joining us today, and I'm really excited to also start off by hearing a little bit about how you got interested in your journey in neuroscience, and then also, what inspired you to join the Michael J. Fox Foundation?

04:12 [Shalini] Sure, happy to share a little bit about my journey. So I actually started my path in science very much shaped by a very traditional Indian family upbringing, where a lot of importance was given to education. And I think this may actually resonate with you, because the main options while growing up was really a career in math or a career in the sciences.

04:34 [Akshata] That's right.

04:35 [Shalini] And I was never really interested in math, so I just kept gravitating towards the sciences from an early age. So that, I would say, eventually led me to pursue a bachelor's degree in pharmaceutical sciences in India, and I think that's when I really started to get interested in how medicines work, how they affect the body, etc. Then I would say my career path really brought me then to the United States, where I became quite fascinated by the brain, how it works, what happens when things go wrong in disease. So during my PhD, I started studying the dopamine system, and that naturally led me towards Parkinson's disease for my postdoctoral training. So after a few years of postdoctoral fellowship at Columbia University, I realized that while I loved the science and I loved the people I worked with, I really didn't see myself staying at the bench long-term. So around that time, my work was actually funded by the Michael J. Fox Foundation.

05:32 [Akshata] Oh, wow. That's awesome!

05:35 [Shalini] Yeah, so I met a few scientists from the foundation, and I started talking to people in my network about what other career paths there might be to contribute in a more meaningful way to the community. So I wanted to have some sort of gratification, you know, from the work that I did. Yeah, so when the position at the foundation opened up, actually, several of my mentors from my network encouraged me to apply, and they thought it would be a great fit for my interests and background, and that was almost, what, now, 10 years ago? And I've truly, I would say, enjoyed every step since. I think it's been pretty gratifying and fulfilling, I would say, to be part of a very mission-driven organization that's really focused on bringing scientists, clinicians, and people with Parkinson's to drive research forward. So it's pretty unique in that sense. So yeah, that's my story.

06:29 [Akshata] That's amazing. I think it's amazing to bring all the different things that are siloed. I do think that, you know, having been in neuroscience and moved from academia to industry, I certainly see the silos that exist, and I think that Michael J. Fox Foundation has done an amazing job of actually making sure we could break some of these and get the people who are studying the same disease in one room, and really learn from each other or talk to each other. So that's amazing. Yeah, and I think that the Fox Foundation is one of the largest non-profits that's funding Parkinson's research. And certainly, I guess from your vantage point, you could probably speak to, you know, how things have obviously changed over the years, and I'm wondering, you know, with so many research avenues, how does MJFF decide where they could focus their research efforts on, or, you know, where their resources are.

07:33 [Shalini] Yeah, I think that's a great question, and honestly, I think it's one of the things that really makes the Foundation pretty unique. Because at the foundation, our North Star has always been impact, right? How can we most effectively and efficiently move the field closer to better treatments. So, I would say we take a very strategic approach to funding. Our decisions are guided by scientific opportunity, but also by what's really most needed to accelerate progress. So, which means we look across the entire research landscape, from early discovery all the way through clinical trials, and then we identify where our funding can make the biggest difference. So we listen closely to the Parkinson's community, we listen to patients, scientists, clinicians, industry partners, because they help us understand both the unmet needs as well as the practical challenges that can slow progress. So I think that's kind of how we evaluate the needs in the field, and I would say, as you've probably experienced also, Akshata, from talking to other people, we don't really just fund projects and step away. We stay pretty deeply involved in the projects that we support, so we always kind of help remove barriers, we build collaborations, we ensure that data is shared, and we ensure that we support has a clear kind of translational path and a path to the clinic. So it's... I would say it's that combination of scientific rigor, you know, collaboration at every step, and urgency is what really defines how we choose where to focus our resources. So it's pretty broad, but that's because we're pretty blessed in the sense that we have those resources to deploy, so it's been very easy to kind of find, you know, what we want to fund and go about funding it in the most impactful way.

09:32 [Akshata] Yeah, no, I think, and to your point about unifying some of these differences, I certainly feel like, you know, as a scientist who's studying Parkinson's, there are lab-to-lab, you know, the procedures and the protocols are so different that it's sometimes hard to directly compare, and I certainly see that MJFF has tried to unify some of those protocols, which does help, because then you can directly compare results and see, you know, what is the rigor in that. So I, yeah, absolutely appreciate from the science perspective what you guys are doing. And as you said, collaboration is certainly key, and it's central to the progress. As all these different groups are independently doing it, but, you know, MJFF certainly has, you know, I know that it's collaborated with academia, but also with industry, pharmas, and then non-profits like Aligning Science Across Parkinson's or ASAP, to drug discovery, and I'm wondering if you could share some of the, I guess, projects that might, you know, to highlight some of those which are happening, especially with ASAP and others.

10:41 [Shalini] Absolutely. I would say collaboration is really at the heart of everything we do at the Foundation. We've always believed that no single lab or company or entity can really solve Parkinson's on its own. So, I think the complexity of the disease really demands that we all work together, you know, across sectors, across disciplines to make progress faster. And I would say, I think MJFF has done a good job of it in Parkinson's disease, because sometimes when I look at other fields, I was like, oh, I wish they were more collaborative, and I wish this was like the PD field. So, I feel that MJFF has done a good job, and that really predates my time at the Foundation, so I won't take the credit for all of it. But I think the foundation has definitely kind of been a leader in that field. And as you mentioned, you know, we partner closely with academia, biotech, pharma, to make sure, as you said, that good ideas don't get stuck in silos. So, for example, we often fund early-stage academic research to help generate the data that industry usually needs to take those discoveries forward into drug development. And we see kind of a lot of collaboration opportunities there, so we kind of always bring together academia and industry groups together early on, so that basic foundational discovery is rigorous, so that it's kind of worth moving it to that next step. But on the other side, we've also supported industry partners directly by helping them de-risk areas of research or providing them with access to tools, data, biosamples that can help move their programs ahead. So I think that's important too, and I think not always, you know, everything is done in a funding manner. I mean, I think people always view us as funders, but I think nowadays we go kind of beyond just, you know, being those funders. We're actually the dot connectors and making sure that people have access to these precious resources so that they can advance their programs quickly. So, I would say as, you know, and as we continue to encourage academia and industry to collaborate, we've realized that on the funder side, we need to model that same spirit of collaboration as well, to accelerate progress. And this is where I think our partnership with the Aligning Science Across Parkinson's, or ASAP, is really a great example, because ASAP really came into the PD field, I mean, well after MJFF was established, but they came with a huge kind of funding commitment to Parkinson's basic science. Something that we were not focused on, and rather than kind of setting up, you know, a completely new entity or saying that they're going to be working by themselves, they chose to partner with us, they chose to partner with the foundation, and they leveraged our scientific and operational infrastructure to manage their programs. Which I think has been really, really powerful, because I think this synergy that combines their focus on open science and global collaboration with our experience in, you know, more strategic grant-making, data sharing, and community building has really been, I think, a win-win for both of us. And I think the findings that we are making through, you know, the ASAP programs are really kind of fueling some of our translational pipelines within MJFF. So I think we've been already, you know, together, been able to invest in large-scale open science initiatives that are bringing global teams of researchers together, but at the same time sharing data real-time to understand, you know, underlying causes of Parkinson's disease. So, I think, as I mentioned, at the end of the day, our goal is to break down barriers, you know, share knowledge, and make sure everyone working on Parkinson's is kind of rowing in that same direction. So I think it's that kind of open coordinated approach is what we think, you know, will truly accelerate discoveries. And ASAP is one of many examples where, you know, this is going really, really well.

14:40 [Akshata] Yeah, no, that's fantastic, because I agree that not any one group can do it all, and I think some of the work around even having, I guess, different understanding the genetic cause of Parkinson's, not in just one population or one area, and, you know, kind of expanding that may not be possible for any one organization, but then certainly through collaboration, mapping it out, and kind of getting a sense of how that could be applied is a really great way of directing it. Yeah, no, that's wonderful, and I think that in terms of, as you said, the early research programs that are funded, and there are also... are there also clinical trials that are funded by MJFF, or there is... Because I know one of the things that you guys are really helping with is development of biomarkers, which for the field is a huge win. And I think that that can really help, you know, as I'm learning more about being in pharma and, you know, what's needed for clinical trial, that's so critical, and if we could look at the field of Alzheimer's and, you know, learn a little bit from there, where having those translational biomarkers has really helped kind of design a better clinical trial, and make sure that some of the same targets that we've been working on for a while can actually move the needle, because now we know what to look at to say, oh, this person's better, or this patient population is better.

16:12 [Shalini] Right, yeah, exactly.

16:15 [Akshata] Yeah, so I'm curious how the research... I guess some of the research targets, are they... how are they complementing some of the clinical efforts that are ongoing with MJFF, or are they kind of separate and, you know, looked at from, okay, these are the research efforts, and they do merge at some point, but then they're not necessarily, oh, this is all the way from preclinical to clinical, or they're kind of parallel efforts, and some of them are more baked, if you will, that they can go to clinical.

16:46 [Shalini] Yeah. Yeah, I would say, I mean, our funding really spans that entire spectrum, right? We fund basic biology, we kind of fund out of the basic biology, new mechanisms, new targets that could be potential drug targets. We fund companies for therapeutic development, we fund, you know, and that's in the preclinical stages, as well as in the clinical stages. And we think that this whole process kind of goes from left to right, but in reality, as a foundation, we kind of see projects coming in, you know, anywhere along the spectrum. And so for us, I think most of our efforts are really kind of spent on making sure that companies that are in the preclinical phases understand, you know, what their clinical development path is going to be. Do they understand, kind of, you know, that patient population? Do they have, you know, biomarkers that can help them understand whether their target or their molecule is, you know, hitting the right target? Is the molecule kind of doing what it's expected to do? So, our job, I feel, is always kind of that backfilling, making sure that those, you know, the right gaps are being addressed at the right time. And sometimes, you know, we also fund, I think, early stages of clinical trials. I mean, we don't have the resources to fund, you know, very, very large clinical trials, but in Phase 1 and Phase 2, sometimes we support that early, you know, exploratory biomarkers work. And I think the goal of our funding is, one, is to, again, de-risk that program with the hope that investors and large pharma come and pick that up. And also, I think, with the hope that if we fund it, that data will be shared more broadly, and that's going to inform other programs, you know, that have similar mechanisms in their pipeline that could be helpful. So the goal is really to ensure that we're sharing data more because we want to prevent any duplication of efforts, and we want to learn from, you know, what's been successful and from our failures. So I would say we fund the whole spectrum. What we fund across that spectrum, I think, varies, and sometimes it's really program-specific as well. So we always say we want to enable programs, and we want to kind of move a program from one step to another. But I think where we really excel is in generating and enabling, you know, the discovery of those field-enabling resources, such as, you know, preclinical tools, you know, be it animal models, be it lab reagents, we generate those, we make those available, you know, to the community, and similarly, in the clinical space, it's the biomarker. So we are really, really doubling down on our biomarker efforts this year, and I think over the next 3 years, I think we're going to learn a lot from some of our biomarker studies. And as you mentioned, I think that's going to have huge implications on how we kind of select patients for clinical trials, how we monitor outcomes of these trials, etc.

19:42 [Akshata] Yeah, no, that's exciting. And I guess, are there any big hurdles that you think exist in terms of, you know, a lot of the targets that have failed? I'm curious, you know, what might be, you know, there might be many reasons, obviously, but then it's really difficult when you do all the work, you're excited, you're hoping for a therapy, and then in clinical trials, they fail, or they don't really reproduce, and I guess how, in addition to the rigor, I'm just wondering are there any hurdles that you guys have encountered that potentially contribute to that.

20:18 [Shalini] I think this is a really important question, right? And I think it's one of the biggest challenges in the field, and I think it's especially for the neurodegeneration field, I would say. I think this whole kind of translation of biology into actual clinical candidates is pretty long for neurodegeneration. It's complex, and it has several, several hurdles. I would say, I think based on our perspective, I think it's really the biological complexity of Parkinson's itself. I think now we realize, you know, based on recent years of funding, that it's not one single disease, it's likely to be a collection of diseases that share symptoms, but may have different underlying causes, so trying to kind of dissect what that heterogeneity, you know, is really about is kind of top of mind for us. So, even when we identify, as you say, a compelling target in the lab, it's not always clear, you know, which patients will benefit most, or when in the disease, you know, should we be treating them, you know, with this mechanism. So that's one. I think it's just a very complex disease, and even two people with the same genetic cause, you know, don't look similar, so that kind of really complicates, you know, clinical trial design, recruitment, etc. I would also say, I think, picking the right models and tools, I think are also challenging, right, Akshata? I feel we've all worked in the lab, we all kind of use, you know, the cells in a dish, and we use these mice models, and rat models, and somehow these preclinical models don't fully capture, you know, the human disease, so it makes it really, really hard to predict how a therapy will really behave in people. And this is why I think we are investing so much in biomarker discovery work now, is to help build those bridges between the lab and the clinic, so that we can identify what those measurable signals of disease are, and what that, you know, effect of the drug would be. So that's, I would say, definitely a second hurdle, I think, which is hard, I think, to fix. Because I think it's hard to kind of make better models, because the disease is so complex, so we just want to make sure that we can move from those models to humans, you know, quickly, as long as we understand, you know, all of the other aspects of the disease in people. I would say, I mean, I've been able to appreciate this next hurdle a lot more, you know, in the more recent years, which is really risk and resources. Drug development is expensive, it's time-consuming, and I would say early-stage projects, especially those that are tackling new biology or novel technology, I think they often, you know, struggle to attract investment, and especially now, right? I mean, I think there's lots of resources and kind of more of a risk appetite for oncology, but that kind of appetite isn't there for neuroscience. And that's because we haven't seen, you know, a blockbuster, you know, drug or, you know, a major success in the recent past, and I think that's really needed, I would say, in order for us to kind of attract that sort of investment. So, that's where we as a foundation, I think, can play a catalytic role, because we can help, you know, fund those early programs, hopefully de-risk those, you know, the promising signs, again, with the hope that, you know, industry partners will come on and, you know, take that program forward. So I would say... I would say that those are the main hurdles, but again, we already chatted about the challenge of clinical trial design, which is we're still defining how to select the right patients, the right endpoints, the right time points to detect meaningful change, and I think all these are areas that we're working on, and I think we're starting to see a little progress in each of these areas. So I think that kind of is what gives us, you know, hope in the coming years.

24:19 [Akshata] Yeah, no, and it's a great point about resources and, you know, what... because I think that for new technology, as exciting as it is, I think that having faith in, like, okay, that's gonna work, or, you know, if something's new, testing that out, and that's certainly a huge risk for whether it's biotech, or it's pharma, or, you know, even work done in lab, I think that scaling that up and having then recruiting patients to go through that, right? I think that's definitely challenging. And... but I think that your point about the new tools and approaches is really a great one, because certainly, and I'm sure in the decade that you've been at MJFF, you've probably seen some of these tools, approaches kind of grow, and I'm curious, you know, how you think they have changed, and also, what is the... we are all obviously hearing a lot about AI, and, you know, how AI is changing, and we all need to kind of adopt AI, so I'm just curious at MJFF, or even in interaction with other partnerships, how it's evolved.

25:28 [Shalini] Yeah. I would say, I mean, from the time I started, or even before I started at the foundation, I would say genetics has come a long way, so I feel like the genetic technologies have really emerged, and I think you brought it up, I think, as we started chatting today, about, you know, kind of going global with genetics. So I would say in the past years, we've been very focused on, kind of, what does the genetics look like for Parkinson's in the U.S., or in Europe, and so we've focused a lot on the Caucasian population, but again, a recent study, this is the Global Parkinson's Genetic Study, also funded by ASAP, you know, has really gone global with their studies, so they're now trying to expand, you know, our understanding of Parkinson's genetics to the global population, right? What happens globally? Is it the same kind of risk, you know, in terms of genes and genetic causes in the Caucasian population as it is in the other population? So I think that's been, that is actually proving to be quite a game changer, because we think, you know, what we kind of attributed to as, you know, the genetic cause of Parkinson's, which is about 15% or 20%, I think that number may increase, you know, with such strategies, and we also think that this is going to tell us, you know, more about, you know, potentially new drug targets that we should be focusing on. So I think I would say genetics is something that has really evolved in the recent years. I mean, and then I would say the other big, I think, a big technological advance has been really in the multi-omics technologies. I often laugh when I talk about multi-omics, because by the time we get started with one technology, we say, oh, let's do proteomics. There's already single-cell proteomics, and there is spatial proteomics, so I feel those technologies are just kind of evolving at a rapid pace, and I feel it's important for us as a field to make some quick discoveries using those technologies. Because at this point, it just seems to be generating a lot of big data.

27:41 [Akshata] Yeah. I completely agree with you, because I feel like we have all these, you know, yeah, there's all kind of this genomics, there's proteomics, you know, there is all kinds of SEQ data that's out there, and now all of that data mining, it's like, what does that mean? And, and...

27:56 [Shalini] You're right.

27:59 [Akshata] I'm hoping that's what AI helps, you know, in bringing some of that, you know, but...

28:01 [Shalini] Yes.

28:01 [Akshata] It's really... it can also be overwhelming, because you're like, okay, how do we make sense of all of this? And if it would be amazing if it could look like a nice, cohesive picture, but it's gonna take a lot of effort, at least in my opinion, but yeah, I would love to hear from you.

28:17 [Shalini] Yeah, yeah, agree. I think we are still figuring out how to make sense of all of the data, you know, how do you integrate that with clinical data, and, you know, make sense of all of that data. So that's kind of yet, you know, to be seen, but we are doing, you know, all of those omics approaches in, you know, our Parkinson's progression markers initiative cohort. So, as you know, that PPMI cohort is a cohort that we have followed, you know, for 15 years. These are subjects who we see, you know, on an annual basis. And we collect, you know, imaging data, clinical data, you know, biological data. We collect bio samples, and we are now, you know, profiling them using all of these, you know, multi-omics technologies. So I think that'll be kind of a nice, you know, cohort that will generate some sort of pilot data to tell you whether these technologies are, you know, giving us more information than what we already had. So we're seeing that a lot in our space. AI, yes, we're hoping that AI comes and solves all of our, you know, data problems. Again, I think we're still in the nascent stages, I would say, in Parkinson's disease with AI, I think we're kind of partnering with some, you know, companies to deploy some of their AI tools, but we're realizing that, again, you know, just like all other spaces, it's very, very important that they collaborate with PD clinicians, because they need to understand, you know, what the clinical symptoms are telling you, and what that data looks like in order to kind of, you know, matchmake those two data sets, and make sense of the data, so... Yes, I would say those are the three kind of areas, and of course, you know, digital is something that's kind of picking up as well, you know, in the Parkinson's space. We have, as you know, not very good endpoints for the disease. It's really based on, you know, the clinical visit to your doctor's office, and so these digital kind of technologies are providing, you know, avenues to be able to detect, you know, change, you know, in a shorter time period, which would be pretty, could be a game changer for clinical trial design, in my opinion, as well.

30:24 [Akshata] Yeah, and I think some of this longitudinal data would really help, because certainly talking to, you know, both patients, but... and I know from my own, you know, father's example, I would say that some of these symptoms, you know, patients have had for years and years, and it would be really amazing to kind of catch it early on, and see, you know, what is that, as you had implicated, you know, what is that tying point of, okay, this is where we are going to enroll and, you know, might be that inflection point where earlier is better, obviously, so... yeah, those studies are going to be really exciting to help define some of that.

31:02 [Shalini] Yeah, absolutely.

31:03 [Akshata] Yeah, that's exciting. And I'm curious from your vantage point, you know, is there something that you're excited about right now in the Parkinson's research? In terms of target, or, you know, in general, the biology, also.

31:20 [Shalini] Yeah. I mean, so it's very easy to get me very excited about anything and everything, so, I think it's... I think it's how the science is all finally, I think, coming together in ways, I think, that, you know, are directly shaping, kind of, how we design and, you know, may want to deliver the treatments, right? So I am, given kind of where I sit at MJFF, I mean, I'm focused kind of more on the early pipeline program, so for me, I mean, the genetic targets are very, very exciting, and when you kind of map those genetic targets, they kind of point to, like, you know, four or five key mechanisms, you know, that may be playing a role in Parkinson's disease, so I think understanding, you know, when those mechanisms are key, you know, along that Parkinson's spectrum, is what, you know, my area of focus is, and we talk about mitochondrial health, and this is, you know, your energy-producing cells in your brain, and we know that there are so many drug targets now that, you know, center around mitochondria, for example. But we don't understand, you know, if we have a therapy, you know, whether we should go into all people, or do we need to find people who have, you know, deficits in their mitochondrial function? And then when in the disease spectrum does this really happen? Do we have to go early, you know, pre-symptoms? You know, so those are kind of the areas of focus now where we're starting to map out, you know, these mechanisms in people with Parkinson's disease, trying to understand how we can kind of, you know, match the right drug, you know, with the right patient at the right time of the disease. So I think that's what's most exciting to me, but of course, I mean, I always, I feel, am very humbled when patients, you know, kind of are always so engaged and ask, you know, wonderful questions about, you know, the treatment pipeline, and I think that really also motivates us to go back and re-look at our strategy and make sure that we're doing, you know, the right thing, and not just funding science, you know, for the sake of funding interesting science. So, I would say that's kind of what excites me the most these days.

33:27 [Akshata] So, just to clarify, do patients actually sit on some of the scientific initiatives? Like if there are forums or advocacy councils.

33:37 [Shalini] Yeah, so we have a very active patient council. So their members, I think, who contribute to advocacy work, mainly, I would say, but we also use them as kind of our community champions, so we make sure that they, you know, understand, you know, what our research strategy is, that they're able to communicate progress in the field, and they're amazing, you know, really, really, you know, engaged, and know much more about, you know, Parkinson's research than, you know, you or I sometimes, I feel, like, they've read so many, you know... Yeah, articles, and they ask such great questions that it's amazing to engage with them. I would say from a programmatic standpoint, I think it totally depends on the program that we're focusing on. So some of our clinical programs, that's really looking at meaningfulness, you know, when it comes to change in clinical symptoms. Some of our clinical programs that previously focused on MedTech devices, those are programs that included patient voices in their program, so they were part of the review panel, the review process, providing inputs on, you know, whether this is something that they would use, or, you know, what's kind of most bothersome. And then, of course, most of our, you know, cohort studies and studies that are focused on patient-reported outcomes, such as the Fox Insight Study, which is an online study, which tracks patients, you know, which kind of, you know, tracks patients over time. And this is an online study, so you're not going to a clinic, so you're really kind of providing, you know, your experience, your lived experience with Parkinson's. So we kind of use them, you know, to deploy surveys, to understand more about the lived experience, to understand about the most bothersome symptoms, you know, what's, you know, etc. So, I think there's many different ways in which we leverage our patient community, and it depends, really, you know, which program, you know, kind of needs it the most. But, like I said, I mean, our patient council are very knowledgeable, and they're aware of, you know, everything that we support, so they always come to us with lots of questions, sometimes, you know, in the preclinical phases, and I'm amazed, you know? And they'll sometimes look at graphs, and they'll ask me to explain, kind of, a particular curve on a graph, and so... so it's really nice, yeah.

36:00 [Akshata] Yeah, and I've definitely... I had the opportunity to attend the MJFF conference that you guys hold annually, research conference, in New York, and I had the opportunity to attend it, and yeah, I was amazed. Obviously, there were researchers, but there were clinicians, there were also some patients, advocacy groups and patients themselves, and it was amazing that they kind of, as you said, sat through that, and also asked questions and knew really the details of it. So, yeah. That's...

36:26 [Shalini] Yes, yeah, no, super engaged, yeah.

36:29 [Akshata] Yeah, no, that's really amazing. And I am curious in terms of the research as it's going on, certainly there have been new model development around stem cells and using human iPSCs, and there are, you know, obviously a lot of tools and reagents that are being developed, and in your opinion, and I guess as MJFF is funding, is there more funding also for encouraging those kind of model uses, in addition to animal models for testing, especially as genetics, you know, the genetics of Parkinson's evolves.

37:06 [Shalini] Yeah, definitely. I think I did not touch on that in the previous question that you asked, but yes, we are investing heavily in iPSC-based models, which are stem cell-based models. The nice thing about these stem cell-based models are that they're human models, right? And so, I think it's easier to kind of grow them, you know, before you go into... grow them and work with them before we go on to kind of more expensive experiments, you know, in mice or rats, or, you know, monkey models. So we have been actually, you know, generating a lot of those resources, some with, you know, genetic mutations that are common in Parkinson's disease. And then, of course, we have been differentiating them into different cell types in the brain, so we don't know whether it's your neurons or, you know, your immune cells in the brain that's, you know, probably playing a role, so we've been kind of investing a lot in trying to understand, not only generate these resources, but also trying to understand how these can be leveraged to understand, you know, kind of the more mechanistic basis of Parkinson's disease. So understanding how genetics, you know, plays a role, how different cell types play a role, can they be modeled, you know, in a dish to tell you if your therapy is having the intended effect. So we have been, I would say investing a lot in generating the models, characterizing the models, and making them available, actually, at CRO, so that, you know, both companies and academic labs can use those models.

38:43 [Akshata] That's wonderful. Yeah, no, that'll be a really great resource to kind of, I guess, test it, not just in animal models, but actually in human cells, and see if, you know, they're efficacious before the expensive clinical trial design that's, you know, the next step, I guess. Yeah, and I'm also curious, obviously genetics is a big role, and I'm curious with some of the new data that's coming around exposomes and other environmental factors that are emerging factors in Parkinson's. Is that something that MJFF is investing in, or, you know, that something is not the core focus as of now?

39:22 [Shalini] Yeah. I mean, we're keeping our eyes open for the exposome technologies. So, as you know, I mean, from... ideally, all of these things are best studied, you know, in patient cohorts, like PPMI, again, where you can kind of understand whether, you know, an environmental trigger is kind of increasing your risk for Parkinson's. Right? I mean, that's kind of the ideal, the ideal kind of way to study this. I would say, we're monitoring the technologies, we're not at a space yet where we can deploy those technologies in cohorts like PPMI, however, we're very, very interested in, kind of, the environmental triggers of Parkinson's disease. So, again, I think through our collaboration with ASAP, in our most recent kind of funding round, we've specifically called out, you know, that we want to study environmental triggers of Parkinson's disease. And we want to entertain proposals where there is a strong kind of human arm, so we can kind of understand, you know, the epidemiology, and then take that, you know, understanding into kind of, you know, cell models in a dish, or rodent models, to kind of start to kind of dot connect across those systems. So yes, very, very interested, but very, very hard, I would say, Akshata, again, I think to take those findings and apply it to, I would say, a clinical trial.

40:50 [Akshata] Yeah, no. And I think, to your point, you know, sometimes you... as the field evolves, and as new data comes, you obviously want to incorporate those into models, but there's also a challenge of how fast can you move with the targets that you have in hand and reach clinic, so... It's certainly a race against time, you know, coming up with these targets, yeah.

41:10 [Shalini] Yeah, and I would say, I mean, we talk about environment, and I think many times when we model the environment in a dish or, you know, an animal, I think we focus on one toxin, right? But in reality, I think people are exposed to so many different things, we really don't understand what those triggers are. So I think that makes it, you know, more complicated, but of course, I mean, from a scientific, you know, perspective, I think it's important that we're trying to understand whether there is, you know, that environmental... there are some key environmental triggers that we can, you know, potentially prevent, and how they interact with, you know, genetic causes to increase someone's, you know, risk or penetrance for Parkinson's disease, so that's kind of the areas of focus, yeah.

41:53 [Akshata] Yeah, no, that's exciting, and curious how for some of the young scientists that are entering the field, you know, obviously neurodegeneration is generally a very hard field, right? Like, for us, from personal experience, nothing's as easy, and there's just... the complexity of it certainly makes it hard, but I'm just curious if anybody is excited to be part of Parkinson's research, especially, you know, some of the things that MJFF is doing is really, I think, giving tools with which is important, I think, right now, at this time in, you know, I think that it's important to have other funding sources, and, you know, feel supported, so I think that this is a really great initiative where, you know, you yourself are an example of having received funding from MJFF. Yeah, wondering, you know, what's the advice you would give to your young self, or the young scientists out there.

42:48 [Shalini] Yeah. I think for all the young scientists out there, I would say you just need to be a little patient. I feel... I mean, I see this with my kids, I feel, you know, we're living in a world, you know, of instant gratification where everything needs to happen, you know, right now, today. So I would say, you know, stay passionate, but be patient. As you said, I think neurodegenerative disease research is really, really tough, because things move very slowly, and I think there are days when I think the data just don't cooperate, right? So, I think you just need to stay curious and keep, you know, just keep sight of why you started, you know, this particular experiment, and, you know, just be persistent. I think that patience is something I think, that's key for today's new scientists. I would also say don't stay in your silo. I think we spoke a lot about collaboration, and I think sometimes mentors are really, really good at collaboration, and, you know, and they kind of enforce that in the lab, but I think if they don't, I think it's important, I think, for these scientists to understand that the most exciting discoveries are actually happening at the intersection of biology, data science, you know, imaging, genetics, and even engineering, I feel, these days. So, I would say definitely talk to people outside your immediate field. I think they would be really surprised by how much, you know, they learn. I would also say, I mean, when I started working in the lab, Akshata, I think I hadn't seen a person with Parkinson's for a long time. And I think it was, honestly, I think seeing and talking to a few people with Parkinson's that really made me switch my career from the bench to what I do now. So, I would say... I would also encourage all of the young scientists to talk to, you know, people with Parkinson's, or talk to people, you know, in whatever disease area you're focused on, you know, kind of make sure that you understand, you know, what you're working towards, because then I think you kind of, you know, don't just think about, you know, cells or pathways, and you can think about, kind of, what, you know, you're really doing to have an impact. So, I would say that's, yeah.

45:05 [Akshata] Absolutely, yeah, the motivation... yeah, I guess from meeting someone who's going through that and living through that every day, certainly, yeah, I can imagine that might... that can be a really big motivation.

45:16 [Shalini] Yeah. Definitely, yeah. And I've heard this from so many people. They say, oh my god, I met this person, and that's really changed the way I want to do my project in the lab. So, I would say definitely that, and I think finally for me, what really worked is finding, you know, good mentors. So I feel like it's important to build your network early on, and I think it's hard, because sometimes you're new, you know, you're shy, and I feel, but just finding somebody, you know, finding mentors and peers who just lift you up is, I think, important. Because I think, one, they can guide you, I think, as you have questions, you know, along... as you kind of, you know, go along your career path. But I think it's also, I think, you know, sometimes it's just hard. I think science is hard, and I think it's humbling as well, and I think having those people who kind of encourage you, and, you know, help you celebrate the small wins, I think, can make a world of a difference. So, yeah, finding your group, I think is important as well.

46:15 [Akshata] That's... yeah, thank you, that's really wonderful advice for all the young scientists listening to this podcast. And I guess, finally, I'm... I want to hear what... if you have anything to say to our listeners who are affected by Parkinson's, or, you know, even patient families. Any message you would like to leave for them.

46:35 [Shalini] Yeah. I mean, for them, I mean, I feel for everybody either living, you know, with Parkinson's or families and care partners, I think it's important to know that, you know, they're not alone, right? I mean, I think there is this global community behind them, scientists, clinicians, foundations, other people with Parkinson's. And I think it's important that they understand and know that we're all really working together urgently, you know, towards, you know, better treatments for all of them. So I would just say, you know, stay hopeful, stay engaged, participate in research, you know, read up on research, and just know that we are all in this together, right? So, I always say every study, you know, every data point, I think, every story kind of helps in kind of building, you know, that map, or kind of putting the pieces of the jigsaw puzzle together. So, yeah, I mean, I'm always appreciative of the patient community.

47:34 [Akshata] Yeah, no, thank you so much, and... Well, to close, we, if you're up for it, we can do a quick rapid-fire round, or it doesn't have to be rapid-fire, but a quick round of some fun questions.

47:46 [Shalini] Okay.

47:47 [Akshata] So a book or movie that's inspired you lately?

47:52 [Shalini] I think what's relevant to today's conversation, you know, I would say the Michael J. Fox documentary still, which I think was recently released. The foundation actually got to go see it, and I was actually thinking that, oh my god, I'm going to be really emotional, but it was so funny, because I think Michael J. Fox is just very humble and just is so optimistic that I kind of left that, you know, left the theater with a big smile on my face. So that was... yeah, so I would definitely...

48:23 [Akshata] That's awesome. Is the movie out there, and can we, I guess, watch it as well, or... Is this something...

48:29 [Shalini] It's out there, I don't know whether it's... whether you pay for it, or whether it's free, yeah.

48:33 [Akshata] Yeah, yeah, yeah, no, but if it's out in the movie, in the theaters...

48:36 [Shalini] It is out, yeah, it is out, yeah.

48:37 [Akshata] That's awesome! Oh, something definitely check out. Yes, definitely. And second question, one thing that brings you joy every day?

48:49 [Shalini] For me, of course, work-wise, I think it's the people that I work with and the mission of the foundation. I think really working with, you know, very passionate colleagues, people who really care about, you know, what you do, and what the Foundation does, and a community that never gives up is, you know, what brings me joy every day in my work.

49:12 [Akshata] That's awesome. And lastly, a mantra or phrase you live by.

49:16 [Shalini] Yes, for me, I need to live each day, you know, to the fullest, and I want to have no regrets when I look back, so I always do what I want to do each day, and I think my colleagues always laugh at me because I go from one vacation to another, so... I'm already planning my next vacation, and that's what I kind of want... I also look forward to, so in between my work, I'm always kind of looking at where I can travel and, you know, where kind of work takes me and how I can make my work, you know, more fun.

49:47 [Akshata] Absolutely, yeah. No, that's something to look forward to, right? Like, yeah, that's... That's great. Awesome. So, Shalini, it was such a pleasure having you. Thank you so much for your time today, and certainly I've enjoyed, you know, sharing this conversation with you.

50:02 [Shalini] Of course, thanks, Akshata, for having me.