E79: Painting a Picture of Hope to Treat PACS2

Piotr Kosla, founder of the PACS2 Research Foundation, joins us to discuss his personal motivation to develop the first treatment for Development and Epileptic Encephalopathy 66 (PACS2 Syndrome), how cell painting assays are being used to repurpose a treatment for this condition, what the future holds for research in this area, and how you can help contribute to his mission.

Show Notes

• PACS2 Research Foundation
• Drug Repurposing Through Cell Painting Could Treat Rare Disease
• ASO Screening Services
• Gene Therapy Services
• Art of Science: Cell Painting
• Free for Life: The Story of n-Lorem Foundation

• Podcast Transcript

  Piotr Kosla (00:03):
  Oh, drug discovery - to find a treatment for Lena and other PACS2 disorder. Because right now there is no treatment available. And because the syndrome is so rare with only a hundred patients right now diagnosed worldwide, if you look at it from the financial point of view, it's simply not enough patients to make that kind of financial business case because it's ultra ultra disease. So we've no treatment available and only this kind of occupational therapy being available for the kids. We try to find something from the drug discovery point of view. So that's the goal of the research foundation and this is where we are basically transferring 99.9% of our funds.

  Mary Parker (01:02):
  I am Mary Parker and welcome to this episode of Sounds of Science. I'm here today with Pieter Kla, founder of the PACS2 Research Foundation, and father to twin girls, Lena and Zuzanna. It's a pleasure to have you on our show.

  Piotr Kosla (01:17):
  Thank you for having me here. And also I'm happy that I have a chance to basically talk a little bit more about our journey.

  Mary Parker (01:23):
  Tell us about yourself and your family and your twin girls.

  Piotr Kosla (01:26):
  I have family of four, so there's me, Piotr, my wife, Malgorzata, and my twin girls, Lena and Susanna. So we are a family of four. We are based in Warsaw, Poland. And the thing that I like to share every time I talk about my family is that we are travelers. So we basically in our twenties and then early thirties, we've done a lot of traveling with the many countries. Right now, logistically it's a bit more of an issue, but still we try to be outside. We've met at business school, at the university with my wife and we're not scientists. So again, another thing I like to highlight that we are not scientists, but we try to conquer scientific world with the PACS2 Research Foundation and my girls are three years old.

  Mary Parker (02:15):
  And how would you describe Lena? What are some of the things that make her special?

  Piotr Kosla (02:20):
  Oh, I mean I could talk a lot about Lena, that's for sure. She's a warm and friendly kid who would love to discover the world and who tries to discover the world, but she has some barriers and obstacles to overcome from the very beginning. She does have kind of dual nature, so I guess most of the toddlers and newborns, sometimes she's like Jekyll and Hyde. So one moment she's the sweetest person walking on earth and you can't love her enough. A few months later she can change her temperament. I think one can say that she could have pretty short fuse, and I guess some of it's kind of also coming from the fact that from the symptoms she's having as person impacted by the PACS2 syndrome.

  Mary Parker (03:09):
  So can you tell me a little bit about the origins of how you found out that Lena has this PACS2 Syndrome? I know that the beginning when you first got diagnosed was kind of a whirlwind.

  Piotr Kosla (03:21):
  So basically my twin girls when they were born, everything seemed normal. So they got 10 out of 10 on the upscale score. There were some kind of things we did observe some things at the beginning more connected with hypotonia, but because they were twins, that's kind of normal. It happens that one twin has a bit lower tone, so that's it basically. So apart from that, both of them were developing quite normally and because they were a bit pre-born, they were like 36.6 weeks. So they were just two days away from being treated a bit differently. But because of that, they also had a lot of different examinations as well. So there was no concern at all. And then suddenly during the Christmas Eve back in 2021, Lena had her first seizure in the morning. So that was three years ago and this is where the whole situation, the whole story started.

  Mary Parker (04:21):
  So after that first seizure, what did the doctors recommend?

  Piotr Kosla (04:26):
  So what we've learned is that you don't diagnose straight away in very detail after first seizure. So what we found out from neurologists is that the moment you have the second seizure, this is the moment that you start to treat things seriously because sometimes you can have a seizure because of the very, very high fever in the newborns. What we found out is that 10% of the people they experience one seizure in their lifetime and 10% of them they experienced the second one. So you can say that around 1% of the population could have epilepsy and soon after the first seizure, the Latin experience back in Christmas, if in 2021, obviously we rush to the hospital after the first one, but because it was like Christmas time, maybe we were out, we're supposed to wait two days for the EEG to see what's going on.

  (05:22):
  And we were given an option, either we stay at hospital during Christmas time or we just come back in two days and the EEG will be performed anyway. So we decided to come home because we also had a second girl, Susanna at home. And we didn't manage to wait this two days because after day and a half, Lena explained the second seizure. So we again rushed the hospital and then this is where let's say her status epilep started. So she had more than 30 seizures in 48 hours. So we're trying to do everything we can to control them together with the doctors at the hospital.

  Mary Parker (06:04):
  How did the doctors progress in her diagnosis?

  Piotr Kosla (06:07):
  We were kind of lucky in the unlucky situation, I would say in a very unlucky situation because we were admitted to the hospital between Christmas Eve and the new year here in Warsaw. And this is time of day year that many people from the capital of the country, they go to the family and let's say the volume of amount of people in the hospital is a bit lower. So it does, I mean then normally the diagnosis is faster during that time. So it was easier and faster to get the MRI easier and faster to get the examination of the spinal fluid and so on. So we were treated very seriously and because of her's epileptics, they were trying to find out the reason why. But frankly speaking, we did all that was possible to be done in the hospital without genetic testing and everything seemed normal.

  (06:59):
  So we had no idea what is the cause of this. And the only thing that was left was to perform the genetic testing and this is what we did later on. And also we were initially a bit lucky in the unlock situation because very often when you do the gene panel testing, when you test for example X, Y, Z amount of genes that are connected with the seizures, you got to first collect doses of samples and then from doses of kits and you run the machine to look for the gene mutation in this kind of cohort of kids. So that was not the kind of situation because the institute running the diagnostic, they have 59 out of 60 samples needed to start the machine, and then I was never 60, so she was the last one to turn on the button and otherwise you would have to wait from the beginning to collect around 60 babies and the samples to run the machine and another cycle and which obviously gave us some time and speed up the whole diagnostic journey. But from the panel gene testing also there was no results. And back then I didn't know about things which is called whole exam sequencing. So back then when we done the panel gene testing and we basically checked around a hundred genes, everything against seemed to be normal. We just found out back then that Lena inherited some kind of mutation from me, but the mutation that is kind of not pathogenic and that's it. And then we managed to basically diagnose her finally through the whole exome sequencing.

  Mary Parker (08:43):
  PACS2 Syndrome is an ultra rare neurodevelopmental disorder with 100 diagnosed patients in the world. Can you tell our listeners a little bit more about this disease and what it means for Lena?

  Piotr Kosla (08:56):
  Yes, you're right. So right now in 2024, we know about roughly a hundred plus cases diagnosed. We do have the Facebook page when we have a lot of parents from all over the world. So Poland, obviously United States, uk, Germany, you name it, there's a lot of 'em. Back then when I was diagnosed, she was the second one in Poland to be diagnosed with PACS2 Syndrome with this specific mutation. And back then she was I think patient number 40 50 in the whole world. So that's kind of the first thing to mention. Second thing is to mention is that this syndrome was firstly described in the publication in 2018 by Heather Olson from Boston Children's Hospital. 2018 is like yesterday. So it was very, very fresh freshly described syndrome. And when you read the first publication from Dr. Heather Olson, you will see that most of the kids, they experience moderate to severe intellectual delay out spectrum.

  (10:03):
  Most of them, majority of them are nonverbal. They have issue hypotonia, they have issue with overall the growth and fine motor skills. So let's just say this is the description you don't want to read as a parent quickly after diagnosis. But this was a situation we were kind of faced with on 14th of February. So another, let's say we are not fully lucky to the dates in a way that when there's a special date, like Christmas time or Valentine's Day, this is where this kind of information were kind of hitting us and the ceiling was kind of bumping on our head with.

  Mary Parker (10:48):
  So what led you and your wife to decide to create the PAX two research foundation?

  Piotr Kosla (10:55):
  This was for sure the mutual decision, I would say. So from the very beginning together with my wife, we are like tandem and we make all decisions together. And obviously we knew that we won't be running, both of us won't be running the foundation at the same level because we have second daughter, we need to provide for the family and so on. And it took us some time to make a decision to reflect on it because it's not a small thing to decide to open the research foundation and start to look for the treat and discovery. It's not like two plus two is four, it's it's a huge project to run. But we've always been very entrepreneurial. We finished business school and we kind of treated this problem, this situation, this life situation as a project in a way that we've done many project working the multi national companies for many, many years and we were quite successful. And they were like, okay, so let's try to treat it as another project and let's try to see what we can do and add some, and maybe not some, but a lot of parental love and motivation into that and let's see where it can get us. So it took us couple of weeks to make a fun decision, and in May, 2022, we have decided to open the PACS2 Research Foundation.

  Mary Parker (12:27):
  And so far, what is the main goal of the research foundation?

  Piotr Kosla (12:32):
  Oh, drug discovery. To find a treatment for Lena and other PACS2 disorder, because right now there is no treatment available. And because the syndrome is so rare with only a hundred patients right now diagnosed worldwide, if you look at it from the financial point of view, it's simply not enough patients to make the kind of financial business case because it's ultra rare disease. So we've no treatment available and only this kind of occupational therapy being available for the kids, we try to find something from the drug discovery point of view. So that's the goal of the research foundation. And this is where we are basically transferring 99.9% of our funds.

  Mary Parker (13:21):
  I mean, that makes perfect sense. When you need something right away, the absolute easiest way is to try and find a drug that's already approved. It's already had all the safety done and see if it can be used for in a different way for this ultra rare disease. So you guys have a special situation since Lena is a twin and she has her sister, Susanna, how are you using Susanna's help? Susanna sells to help Lena?

  Piotr Kosla (13:47):
  Yeah, so maybe before I go to the Susanna cells, I can spend a couple of, let's say sentences about Zanna overall. And again, also in Polish language. Her official name is Susanna, but if you want to call her in more sweet way, and she's basically what I like to say, our 24 7 free coach for Lena. So I think that was the thing that kind of kept us above the water. I would say that we had second kid Suya and in a way we tend to say, and we say very often that she kind of saved us because we knew that there's another human being which is healthy, and she's supporting land development a lot. And we see that on an everyday basis. So obviously we tend to take Lena for many therapies. She has commercial therapies like rehabilitation, speech therapy and so on. But the fact that she has someone kind of developing, I mean someone at her age next to her 24 7, she has a benchmark.

  (15:01):
  So even though Lena is behind couple of months, it's not that far away that she cannot try to do things that Sujay is doing. So for instance, I said at the beginning that if you look at the description of the Pakistan syndrome in the first publication, most of the kids are nonverbal. Lena managed, I mean Lena, she's speaking. So she managed to develop the language, she managed to become verbal. And for example, the first 10 words she said was exactly words from suya with exact same mistakes in pronunciation. So that's kind of think on a daily basis. So she's had 24 7 free coach, and obviously you can see this twin love, but also a bit not always love because there's obviously sometimes some punching and biting included, but that's on a day-to-day basis on a scientific basis, the fact that she's twin, she obviously she's maternal, but the fact that she's twin, she's kind of the perfect control. So very often in the research space, having the control is extremely important obviously. And you try to make the control as close as possible to the disease cells. And in our case, in of Twin, that's the perfect situation to be in.

  (16:31):
  And this is something that we used from the very beginning when, for example, doing the cell pending, which I am pretty sure we're going to talk about later on. And I think that's something that also can create some interest among scientists and researchers and physicians because it's not a, let's say, very common situation to try to find the drug for the syndrome and have the twin on the side as well.

  Mary Parker (17:00):
  Do you get the impression that Susanna likes helping her sister?

  Piotr Kosla (17:04):
  I think she does. I think she does. Sometimes. She was even telling that she wants to join the therapies that Lena is joining. Sometimes she was even angry that she's not coming to the place that Lena is coming. So we started taking her together and she's there for Lena and she understands more and more that she's supporting her and the fact that she's basically playing with her, even just playing with Lena, it creates a lot of value for Lena's development.

  Mary Parker (17:44):
  Can you tell me a little bit about this cell painting that Charles River's helping out with and what it means since you have these twin girls, how can these drugs be repurposed to help Lena?

  Piotr Kosla (17:58):
  Sure. So cell painting is really painting cells. So initially when you hear about the cell painting, obviously again, we are not scientists, so we had to do a lot of research around it and read a lot. So what I like to say is that we started from no scientist level, and then we are slowly moving to the junior scientists and the more senior kind of scientists still kind of highlighting other, we have the business background. So the cell painting, just to say in a very using easy words, is basically painting cells, cells using different dice. So you use different dice to activate different area and different parts of the cell of both diseased and healthy. And then you compare it. So for example, you use the dye that is activating nucleus, for example, in the cell. So you use the dye that activates nucleus parts or make it, I don't know, blinking or make it visible on the image in the diseased cell and the healthy.

  (19:03):
  And then you compare morphology. But we are talking about images, we are talking about thousands and thousands of images. So if you would like to do it with your own human eye, it'll take forever. And also we also know that human eye will not spot everything. So that's why you got to use some computational solutions like machine learning for example, to make sure that you do within a, let's say, pretty good timing instead of doing it for several months or years. But all in all, the cell painting is about painting the cells using different dyes and comparing the morphology of both diseased and healthy cell. And here we're talking about obviously Lena and her control Zia.

  Mary Parker (19:54):
  Yeah, I've seen these pictures and it's really quite something. So you can use the dyes and say you can use a green dye and make it have something fluoresce and then you can compare the disease cell to the healthy cell and you can literally see that they are different shapes. I mean you don't even need to be a scientist to be able to look at these two images and get the idea that one is healthy and one is looks not like the healthy version. And so I can just imagine exposing those cells to different therapies and seeing then visually how they get closer to looking like the healthy cell means that drug might be a good candidate.

  Piotr Kosla (20:33):
  Yep, exactly. Exactly. And frankly speaking, when I was seeing the first images, let's say from the phenotyping stage, call it this way, and when we given some pictures to look at during the calls, like you said, you don't have to be scientists to see there's a difference, there's a clear difference between healthy and the disease. Obviously sometimes what you see again with the human eye is not really something that you are looking for because you need to analyze thousands and thousands of images and obviously before you go to the compound stage to try to see if there's any kind of compound, for example, already approved with some safety proven you first work only on the healthy and the disease without applying any kind of compound on them. So this is kind of the stage one called phenotyping and then you create the ass essay. So coming back to what you said some of the images were for us, yeah, I mean there's clearly the difference between helping the disease, but then you still need to add the compound and to see if there's any compound kind of changing the morphology of the disease one towards healthy.

  (21:46):
  So there are also different in other stages following the phenotyping and acid development

  Mary Parker (21:54):
  And like you said, machine learning and AI algorithms are, they're especially good at analyzing images. I am a little distrustful of AI in terms of writing or creating creative images, but in terms of taking a thousand images and pointing out the tiniest mins little details, it's something that it really excels at.

  Piotr Kosla (22:16):
  Yep, totally, totally. I mean, like I said, we are talking about thousands of images and yeah, it'll take forever. It'll take forever to analyze them in a manual way. So here the machine learning and the AI is the perfect solution for that to scale up to speed up and to find some efficiencies in the whole process. So totally.

  Mary Parker (22:41):
  So have these cell assays done by Charles River led to any potential good candidates

  Piotr Kosla (22:46):
  After the phenotyping and the essay development, we then performed another three stages of the project. So first we did the pilot screen, so we screen around 1400 different compounds to see if there's some of them changing the morphology. And then we did the primary screen when we've screened I think more than 5,000, more or less, I mean in overall I think we've screened close to 6,000 compounds, try to see if there's something changing the morphology from the disease to the healthy one. And yes, answering to your question, we did identified about 20 plus compounds that are changing to some extent morphology of the cell from the disease towards healthy. And then what you want to do is perform the last stage of the project that we've done is the potency screen to see if there is the dose response curve. But basically you're trying to see if there is some kind of correlation between the dosage and then the impact of the compound.

  (23:48):
  And so from this 20 plus compounds, we identified some couple of them that are also looking nicely on this dose response curve as well after doing the potency screen as the last stage of the project. And another thing is that obviously we would love to have a jackpot clear compound changing morphology from the disease to healthy 99.9% and open the champagne, that's for sure. But on the other, I mean that's kind of hitting the jackpot and that would be awesome. But also on the other side, you can think of doing some combination of the compounds and the drugs. So you can basically take one, two or even three compounds which are changing morphology to some extent, kind of mix them together as a kind of cocktail which is safe and then try to utilize the effect of all compounds together. But also even if you find a compound that is changing the morphology to some extent, and then you prove that it's not only changing morphology but it's actually working by using this compound in different research, it is a great thing to have because you are already impacting the phenotype of the disease.

  (25:06):
  So it's not always about finding something that will kind of move patients to completely healthy status. I mean, you can also find some shortened solution, midterm solution, long-term solution and drug repurposing could serve both. So you can either have a jackpot and then you find something that really is helping a lot for the patient, but also you can find something that helps a little bit, but it helps as well. It's better to have something but nothing, right, and in the meantime you can explore different options as well. And this is kind of approach we have at our foundation, so we focus on different projects. So we look at the PAX two from short through meat to long term.

  Mary Parker (25:54):
  Well, that actually gets into the next thing I wanted to ask you about before we get into the next section of the story. Is there anything else that the PACS2 Research Foundation is pursuing that you want to talk about?

  Piotr Kosla (26:06):
  Sure, for sure. So what we've done, I think the model we've created it, it's important to highlight because what we do here in Poland, it's something that we like to share with other people at the European or global level because we work internationally. That's thing to highlight that we work with the people from Leiden, the team from the Charles River. We also work with some scientists from academia, from Chicago, from Pittsburgh, also here we have strong team in Poland supporting us. So we really work internationally and we try to be as open and transparent as possible to allow information flow between the scientists to basically speed up wherever we can. And like I said, we focus on the short-term midterm and the long-term solutions. So drug screening is a more short-term thing that we want to find something to potentially use as a bridging in case we find something that is kind of curing the disease at its source.

  (27:17):
  For example, you could think of a SO therapy. So ENA is part of Enlo foundation for instance, and silencing the allele that dissipated could be the ultimate goal, but it won't happen overnight. So you want to find something that's kind of helping in the meantime as a bridging and supporting somehow her development. But what also I would like to say is that from the very beginning we tried to combine three important words. So the word of the basic research understanding what is going on with this disease because no one really knows what is the pathogenicity of the paxo surgeon, what is exactly happening and what is kind of causing this phenotype. And that's why you have basic research. Then translational research, which for example is what we are doing with Charles River. So this cell painting, and then also you want to look at the clinical side.

  (28:15):
  So from the very beginning we work with the neurologists trying to understand the phenotype, the clinical phenotype of the disease, focusing on the natural history study, understanding what is the evolution of the disease, whether at some point you expect to see some progression as well. So you want to, from the very beginning, we kind of coordinate these three words together to make sure we are kind of pushing everything as much as we can and also try to interconnect these three words. So on the other side, we allow researchers to talk with the physicians and with the patients, with the caregivers and see patients. You would be amazed that very often the scientists working on a specific disease. Very often they've never seen the patient in real world being impacted by this disease. And by being in center of it, we kind of created a space for that and the opportunity for that.

  Mary Parker (29:15):
  Yeah, I mean that kind of gets into our next issue. I assume that through this foundation you have reached out to other families that are dealing with the same disease as you. So how does collaborating with organizations like Enlo EM help make these treatments more accessible to patients worldwide?

  Piotr Kosla (29:36):
  Okay, so the question is how much time do I have? Because I can speak about for a lot of time, and I mean I will start by saying that loam gave us tremendous hope

  (29:50):
  Even before Lana got accepted because we found a place that is actually doing something for this nano and the alter disease, which means they're this patient are not left alone. Because initially when you hear that your daughter, she's impacted by the syndrome with only 40 patients diagnosed worldwide, you think, okay, this is game over, so done. I mean there's nothing you can do about it. And then you start to research, research, research, and then you find and learn and then you find out that there are people out there like Stan Andro crook who believe that every single patient should have a chance for normal life and the actions can prove that. So they already have few patients with few different diseases that are using the experimental A SL, and you see some nice results coming out of it. What anatomy is doing it hard described, it's so precious, but from the very beginning it gave us hope that even for the nano and the ery disease, there is a way to go. There are options to explore. So it's not like game over. Once you get the diagnosis, there are things you can do to try to explore if there are some chances for the kids. Yeah,

  Mary Parker (31:09):
  Well, by joining a rare disease community like this one, the patients will have more access to the cutting edge treatments because you're banding together as a group and a group is always more powerful than an individual family trying to run it alone. So have you noticed that there has been an increased awareness in rare diseases since the start of your foundation?

  Piotr Kosla (31:34):
  That's for sure. We did notice that that overall worldwide there are more and more conversations and discussions about the rare diseases including the older diseases. And I'm talking from every angle. I'm talking about academia, I'm talking about the business, biotech families, also organizations like rds, which were worldwide organizations. So there's some, let's say increasing number of discussions around the rare diseases. And also since we opened the foundation, there are more and more research foundations like ours being opened in the US initially, but we also see some traction in Europe as well. So back two years ago, I think it'll be fair to say that, I don't want to say we were the only one, but not for sure there are many of them, many different exist foundations across the Europe. But it wasn't that let's say, I don't want to say popular, but there was not such awareness that you can actually do something with the OT diseases like there was in the us.

  (32:50):
  So the US kind of started the whole thing and I started the movement and the Europe is kind of joining the party I would say. And I think that one of the example to show that is that for example, back in June this year, we were invited together with my wife to the APNA symposium in the UK about the NU Plate AC therapies was in our Ational symposium a couple of weeks ago. And we were invited as the family to share our experience and to show what could be the role of the patient caregiver driven research foundation in this whole journey. And so first of all, it was great that we had a chance as the families from Poland to share our experience with people from the uk. By the way, during this meeting we also met representation from S. So I finally managed to meet David Fisher in person and it is also showing that the rare disease are getting some interesting fraction, even the rare disease program in the uk, but also how right now the European Union is looking at red diseases, it's showing that this is getting more and more traction. So that's for sure.

  (34:12):
  And also I can probably say that we also inspire a couple of families in Poland as well to open the research foundation and try to follow our path because we show them that hey, there's actually something you can do. You don't have to just sit and wait, there's actually something you can do. And we try to basically also share our experience with as many people as we can. So for instance, this September we organized the conference in Warsaw. Initially we wanted to focus on PACS2 only, but then we decided to go beyond that. So it's called unlocking the hope for the water disease based on PACS2 example. So we also have and Andrea from Charles River, Andre Van Marla coming to talk about cell painting for instance. And we are going to invite different patient organizations again to share our knowledge, to share our experience, to be open and transparent, to inspire others as well. So I think that back two years ago when we were starting, there were two organization, us and another one trying to move, push the research. Now we're talking about probably like 10 10 plus. So things are changing.

  Mary Parker (35:32):
  Speaking of collaboration, when you're thinking about embarking on an area of research, what is the importance of finding a collaborator like Charles River or another contract research organization to help you achieve your research goals?

  Piotr Kosla (35:49):
  I mean, this is crucial. So I mean this is crucial to find someone that you feel treat you professionally from the very beginning, although we are not big biotech company, what I can say that from the very, very beginning I didn't feel like we have a small organization with small budget that is kind of looking at every dollar from all the kind of different sites. So what was amazing, since we started with collaboration, we felt professionalism from the very beginning and also kind of going for this extra mile for us because of the, we are the patient organization, we embark on a journey that is tough to accomplish. And like I said, we were treated super professionally, professionally from the very beginning. And I think at some point we also get a little bit to the kind of private connection in a way that during the whole collaboration it was so successful and so smooth. And it's also important to find a partner you can trust. Trust is also of the utmost importance. And again, the collaboration we had with Chas, but not only with the CHAS but the other people we're working with. We feel the trust from both sides. And I mean this is kind of the solution you're looking for.

  Mary Parker (37:26):
  What role does fundraising play for the PACS2 research foundation and where does the money go?

  Piotr Kosla (37:33):
  We wouldn't be able to move fast without fundraising. Sometimes I think that we could even move faster if we had access to more funds. But initially we've used some substantial amount of money from our private savings to get things started. But very important is the fundraising from friends families. And like I said, somewhere at the beginning, 99.9% of money goes to research only. So we work pro bono of my wife and we cover Lana expenses privately as well. And this is something that we want to highlight that we are a research foundation, so we do not kind of fundraise the money for LANA therapies or for other kids therapies. We focus only on the research and this is where all the money, all the money go basically.

  Mary Parker (38:26):
  Yeah, that's really important for a small organization to have a focused goal in mind. It keeps you on task and makes every dollar count as two when you have such a laser focus on one goal.

  Piotr Kosla (38:39):
  We try to negotiate as much as we can, that's for sure. But we've also met people along the way that are also trying to use the resources they have currently to support us somehow we also giving some small kind of exploratory grants hoping that the reception can apply for the bigger one. And in fact, we did have some successes in this area as well. So we basically trying different options I would say. But like you said, we look at every dollar from two sides, which make us obviously efficient, lean, and yeah, we try to show that you don't need to have, I dunno, few million dollars to start something, right? Obviously research expensive, but you don't need to already have, I dunno, 5 million to get started like generating IPSC line, which is induced potent stem cell line. It costs like 10 plus K and it's important for the research.

  (39:45):
  And when you approach the research researcher or scientists and then you tell him I already have IPC line for instance, then discussion goes in a totally different direction. The good direction I would say, versus I plan to have something or I think about something or I have nothing, but I think I will get that. But versus I already have the I fibroblasts, so fibro fibroblasts that were used during the cell painting, which is also another funny story around it because when we were submitting the samples to corridor institute at the very beginning, we had no idea what they're going to be useful, what are the fibroblasts. But we spoke with a couple of different research foundations in the US and they told us you got to have the reagents. So that's kind of the most important thing to do. The more and more I explore the scientific world and the rare diseases, it's such an inspiring place to be in and we are thinking what to do from the long-term perspective. So like I said, we're already doing the conference, we are inviting other families, we shared knowledge, we've learned a lot in the last two and a half years and we want to share this with as many people as we can. But then we are thinking, okay, what is the next step? Should we structure our knowledge in a way that we can do something more for the community, for the diseases overall? So we are in it like a hundred percent, I mean maybe even 200% I would say.

  Mary Parker (41:22):
  Well, that segues perfectly into what I was curious about next. So in your opinion, what does the future hold for rare disease drug discovery and development?

  Piotr Kosla (41:33):
  So like I said, it's getting more and more traction both in the US and the Europe, which is great to see. Like I said, that you have dozens of the organization like ours in the US in Europe, we were kind of the innovators together with a couple of different ones. But we see traction happening. I think the future is kind of optimistic, I would say. So even here in Poland, there are more and more discussions even on the governmental level about the rare diseases. We are also doing the kind of national plan for the rare diseases focus first more on the diagnostics because that's a crucial part. So for instance, there was a big diagnostic project in uk, which was I think in a way joined by David Cameron, the prime minister, like former prime minister in the uk. And they did a lot of holic and sequencing and they were discovering more and more syndromes causes and more and more patients from the nano disease, the NRE diseases that were suddenly becoming the alter diseases.

  (42:43):
  And like 50% of the epilepsies are of unknown origin. And then actually when you do the whole exome sequencing, most of them, or almost all of them have diagnosis, have cost, and it also it increase the pool of patients for the potential research. So like I said, back then there was only 40 patients with the PAX stool. Now a hundred maybe at some point, I mean for sure, I'm pretty sure there are probably a few thousands of patients like that. So the diagnostics is moving faster and faster to the whole exam, sequencing is getting cheaper and cheaper, which will lead to the way that this pool of patients will grow. And then suddenly they're going to also get more interest from all parties, including biotech as well. So I think that the future is bright and it was the proper lean approach to the drug discovery In the rare diseases today we have 5% of the rare disease with treatment, but I'm pretty sure we'll quickly get to 10% and then more and more and more.

  (44:01):
  So I think the future is quite good, but you need to have also, now I'm going to brag about it a little bit, but you need to think about parents like us that can show that actually there's something you can do for the nano and the OT era. You need to have people like Stan and Roseanne from Lauren again to show that you can use technology that we have even for the nano patient because the disease, I mean the science doesn't care. It's like one patient, 1000, 1 million. So you can apply the solutions that are available right now even for the nano diseases. But also what is important, sometimes you can find insights from the nano or the OT diseases or rare diseases overall to more common diseases, for instance. So one of the reason that the scientists was focusing that much on the PACS2 was that there might be some connection with the Alzheimer disease. I mean we don't know exactly today, but who knows what future brings. So what I'm trying to say sometimes with this, by focusing on this ultra rare diseases, you can have some groundbreaking observations and you can have this kind of observations that you can potentially apply to understand more common diseases like Alzheimer for instance.

  Mary Parker (45:27):
  That would be incredible. Is that what you would hope that your families and Lena's and Susanna's legacies might be, is to help even more people down the road?

  Piotr Kosla (45:37):
  What I hope is that the Lena case will have some kind of significant impact on the other syndromes, on the other diseases and will inspire others to try to do something around the drug development, around the drug discovery. You don't need to be scientists to start something like we did. Maybe at some point we'll become scientists like my wife in a couple of years from now. But when I think about my private situation, I dream of the situation where Lana is obviously independent and where Zia tells me 15, 20 years from now, Hey, mommy, daddy, what you've decided to pull off for Lana is amazing and inspired her to be better person, for example. So I would love to mean obviously, let's see if she's going to listen to this podcast in 15, 20 years from now. But obviously I would love to hear Zia telling me that what we decided to pull off and what we decided to try and the journey to embark on was like, yeah, that was great, and maybe it was inspired Zia and she'll become a famous scientist in 34 years from now, who knows?

  (46:46):
  But on the other side, I want my kids to have happy life and feel loved. And for me, Lena's independence is the most important. I mean, I don't care what kind of profession she'll be capable of doing because of the limitations, if any, to be honest. But I mean, as long as she's happy, as long as she enjoys her life, I'm fulfilled as a parent. And basically I would try to do whatever it takes to try to get her there. So I mean, I think that my kind of person situation also changed a little bit the way I look at the world and I see myself as a good person, but I think the situation may be even better person.

  Mary Parker (47:29):
  No, I think that it won't take too long, maybe only 10 years, maybe only 15 before your kids say that they're proud of their parents and what they've accomplished.

  Piotr Kosla (47:41):
  Hopefully.

  Mary Parker (47:42):
  Fingers crossed or that, I think so. Well, how can our listeners help the PACS2 Research Foundation?

  Piotr Kosla (47:49):
  Yeah, so I mean I will start with some maybe not obvious things, but if there are some scientists that are willing to dedicate some part of the private time, feel free to reach out to us. If there are some scientists that would like to get involved in some other disease projects, we are in connection with different families as well that are embarking and starting the journey like we did. And also we have some areas that are not addressed in our journey as well. So we are right now running 10 plus projects. We are doing some research using the mouse models. We are growing narrows in us. There are interesting things we're doing, but there are also things that are not yet addressed. Also, if there are some families that are willing to embark on the journey listening to this podcast, we are happy to share the knowledge, talk about our ups and downs, pros and cons, and what we've learned along the journey.

  (48:47):
  Because I believe that the more people like us are getting involved, everyone's getting benefit of it, you increase the awareness, you share the knowledge, you make sure that you're not kind of making the mistakes that different family did as well. So that's another thing that if there's someone willing to embark in the journey and doesn't know where to start, feel free to join. Because I believe that growing awareness around the rare disease is also helping us as well. But obviously money is important. I mean, that's for sure. So we keep fundraising money. I think that for the first two years we were basically sacrificing 70% of our time for the fundraising and 30% on doing the research. And I always like to say to people, imagine if we would have different ratio. So I think we're moving fast, but I have a feeling that we could have moved faster.

  (49:44):
  And there are different ways to support us at the www.PACS2research.org. And like I said during the interview today, 99.9% goes to the research we work for pro bono because I think that's the way it should be. But also this is something that is giving us an inspiration and it's a nice feeling. It's a nice feeling to have that you're actually kind of impacting the world in a positive way. Maybe, I don't want to say impacting the world, but in a way impacting the world because I think we're doing something that at some point ising different people and kind of helping them to make the decision to start doing something without a guarantee because there's no guarantee we can meet in five years from now. And I will tell you, we haven't found anything that is really helping the Lena and the other kids with the PAX stool. But on the other side, what I'll be able to say is that I've done everything I could to try to get there and I'll be person that without the problem will look in the mirror and will say, Hey, you've done everything you could, or we are going to hit a jackpot.

  Mary Parker (51:01):
  I sure hope so. But truthfully, any ounce of patient advocacy does benefit the whole world because even if you're the healthiest person ever, if you live long enough, you're going to be a patient. And it might not seem like it, but patient advocacy for Lena leads to outcomes that can benefit anybody in the long run, whether you have a rare disease or not. Patient advocacy is just that important.

  Piotr Kosla (51:27):
  True, totally. And we already know that, for example, based on the research we're doing with Lena Sells, even though the cell painting, it allowed also the Andrea and his team from Cha River to get some interesting insights that they already think of applying in the different projects with the other families as well. So let's just say I already hear from couple of people, so I have a couple of different examples that we actually actually kind of impacted in a positive way. Some processes, some projects also by raising this awareness, like we mentioned, making people take the decision to embark on this journey or show them what is needed to embark on this journey so they can fully, so that they can make a proper decision whether to go towards the direction or not. Because it's a tough project. I mean, don't get me wrong, it's a difficult project, but on the other side, very inspiring and very inspiring and backed and supported by this parental motivation and parental love. No one will be as motivated as a parent to try to move the research towards finding the drug or something to positively impact the clinical phenotype of their kids and the other ones suffering from the same disease.

  Mary Parker (52:52):
  Yes, absolutely. Well, thank you so much for joining us here today. It was extremely interesting to hear your story, and I wish you all the best of luck in your research.

  Piotr Kosla (53:02):
  Thank you. And like I said, it was great to be here and being able to basically to share my story, maybe inspire someone. If there's anyone that would like to reach out to us, to my wife, to get more details, ask some questions, support us. We are open, we are transparent, we are open. We are waiting for the contacts.

  Mary Parker (53:24):
  Piotr Kosla is the vice president of PACS2 Research Foundation. Stay tuned for the next episode of Sounds of Science. Until then, you can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Thanks for listening.