 Think Tech Hawaii, civil engagement lives here. Okay, there's 12 o'clock block here on March the 5th. And here we are, I just got back from vacation, I'm feeling good. Community matters with Andrea Flagg, an old friend of mine, we served together on the board of directors of the Hawaii Academy of Sciences. She went on to be the president or the chair, the chair of the board of Hawaii Academy of Sciences, and she's still on that board. And in fact, if you didn't know it, I want to tell you right now, okay, that runs, the Hawaii Academy of Science runs, not only the Science Cafe, I guess it still runs the Science Cafe, but much bigger than that, it runs the Hawaii State Science Fair, wow. Exactly. Fabulous. And we are affiliated with the International Science and Engineering Fair, where we send our winners from the Hawaii Science and Engineering Fair and they get to be exposed to all the students from all over the world, you know? And they realize, oh my goodness, I'm not the only nerd, there's other nerds everywhere else. Nerds are good people. I agree, I'm a nerd, I love myself. So how'd you get to be a nerd, Andrea? I think, I actually don't know, I was this little and I told my mom, I said, mom, how do I become a professor? And she told me, honey, I don't know, you have to find that out yourself. And I always had a knack for the natural sciences, you know, particularly biology, and I was just fascinated how life works and I guess that everything else is history, you know? So you are the assistant chief of biomedical research at the Queens Medical Center, right? What does that involve? So we're associate director for biomedical research at the Queens Medical Center and basically what we have done 20 years ago, the Queens Medical Center and the University of Hawaii really had a very good collaboration. They still collaborate very well, but 20 years ago they decided we want more biomedical researchers in Hawaii. And they recruited myself and my husband to come to Hawaii, Reinhold, Reinhold Penner, and said, hey, here, build something. All we want to see from you, what we want to see from you is papers and grants. And I'll tell you, those two words are the most powerful world because that's how you make it or break it, you know, with papers and great grants. And so that's how- Public shall perish, yeah. Public shall perish, exactly, yeah. So you, but you got at some point, you got into immune system research. Yes. And that's a specialty. That's pretty specialized, isn't it? So our basic premise from a scientific point of view is that we study cellular communication, you know, cells, how do they communicate with each other and how does, which proteins are involved? And basically, we all know if communication breaks down, boom, that's it, right? And so in disease, the same thing happens, cells cannot communicate properly with each other anymore and then disease happens, have you cancer or immune disease, whatever it is. And so we are coming from a basic research background in that we really wanted to understand, okay, which proteins are involved in that process? And so we're studying proteins in the plasma membrane of cells and they are so-called ion channels. And these, you can imagine, they're little gates. And these gates, they allow the flux of calcium, magnesium, potassium, chloride in and out of the cell in a controlled fashion. And so that was our background. Now, we always wanted to identify which proteins, which ion channels does the cell have? And, you know, the past 20 years have seen the genomics and all that. And so we identified maybe five or six proteins, ion channels. And so then we say, okay, once we understand these ion channels, which disease model do they fit? So we don't come from, we study autoimmune disease, we study cancer, we come from the ion channels that the targets, the molecular targets that we work with, where do they do their job? And if that job goes wrong, which disease happens? And so that is our approach. Okay, so the research you're doing, we want to clarify is with your company, you and Reinhold have a company called Cybera, is it? Cythera. Cythera. And Cythera is doing research on this kind of, let's call it communication, communication of cells, communication of ions and the like. It's not for Queens, not the Queens Medical Center, or is it? It is. So what we've done is basically our whole research has been based at the Queens Medical Center. It's our home institution. They've been wonderfully supportive all those years. But we create patents. And these patents, they belong to the Queens Medical Center. And so what we've done, we have founded a company to help patients with autoimmune disease based on one of those patents. So we have, as a company, have licensed the patent from Queens. So it's basically, we are not in the business, we are scientists. We're not in the business of building an empire or the next engine or so. We are really very focused on how can we apply our research and that is through the licensing and patenting process. So you're taking work that has already been patented and you're taking it further. You're refining the art, so to speak. Exactly. Because what we do is we work at a clinic, at a medical center. So every day we see patients, I mean, we don't treat patients. We are not physicians. You're a PhD. I'm a PhD in biochemistry. In biomedical sciences, specialty neurosciences. Okay, I want to get that straight. Yes, exactly. That's really something. And you took that a long time ago. Where? At the University of Hawaii. I did my PhD at Japson, John and A. Burns-Gullerys. Right, how about him? What does he got? He's got a PhD in pharmacology from Germany, University of Gießen. Perfect match. Very. Because one goes hand in glove with the other, doesn't it? Exactly, it does, yeah. And you still get along in this company together? We do. We are a 24-17. Don't ask me how that works. Oh, you can. I have a few answers for anybody. Yeah, we, I, we're okay. Now you have to have a laboratory. Do you have a laboratory in Queens or outside of Queens? So, basically the company that we founded is, if you wish, a virtual company in the sense that things that we don't know about, we outsource. So we basically, we know, we have built the business plan. We know exactly how to develop, like it's a, so what we did is we focused on FDA-approved drugs. We said, okay, we want to go fast to the market, right? And the idea was always, okay, we find a target that is in our research, then find a drug, we did drug screening. We started that 10 years ago at the Queens Medical Center, non-profit research, 10 years ago to help patients with autoimmune disease, because we knew how that works on a cellular level, on a cellular level. We were lucky. Together with John Lou from Johns Hopkins, we identified an alfazamine, which is actually an anti-leprosy drug. So it's an antibacterium, if you wish. And we found a human target, and that human target is specific for a certain type of immune cell. Now you have to understand, there's two types of immune system. There's the primary, which is responsible for invasions, of all sorts of fighting off yeast and bacteria and viruses and cancer cells and so on. And once that has been done, some cells survive and they remember. They're called memory T cells. They remember, oh, I've seen this bacteria before, boom, a taxid invasion is much faster. Now, autoimmune disease, what happens is the immune system is overactive, okay? And what's overactive is the secondary immune part, those memory T cells, and they underlie most of the autoimmune diseases. There's about 80 of them. And they attack different organs. They attack the whole system. For some reason, we don't understand. So the current, there's no cure for this. What happens is there's an increase in the disease, then there goes dormant, then there's an increase, then it goes dormant and so on. So when there's a spike, patients are treated. And then the current treatment suppresses the whole immune system. It suppresses the primary immune system and the secondary immune system. And that causes all sorts of long-term problems. Cancer, infections, you name it. Janine, you have your immune system working properly. Exactly. So with plafazamine, the drug, so what plafazamine does, it suppresses the secondary immune system, part of it, the memory T cells. It suppresses the ones that are actually causing the autoimmune disease. We don't know why the memory T cells do that, but we do know if we suppress those, we can help patients with this. So the tropazamine, can you spell it? Plafazamine, C, L, O, F, I. No, I'm a very bad spelling bee. Perfect. Trope, trope. C, L, O. Oh, it's on the screen. Here we go. There we go. Oh yeah, thank you, exactly. Yeah, okay. All right, so this will moderate the autoimmune system from going out of control, and that's a surprise, because that's not what it was originally developed for. Exactly. And that's the magic of what you're doing with Reinhardt, that you're finding drugs that were directed at one thing, and you're finding that they're useful in another capacity. Exactly. And tropazamine. Tropazamine is one of those drugs. Exactly. And so it has a way of moderating the autoimmune system so that the memory, the T cell memory cells, that might go out of control. Exactly. Does it make them lose their memory? Does it make them inert in some way? No, no, they don't. So for example, so we're tackling psoriasis first, which is an autoimmune disease of the skin. The skin is one of our largest organs that we have. And so it's only the cells that are under the patch. Psoriasis. Under the psoriasis patch, under the so-called plaque. Those cells under there, they are overactive and that causes the growth of skin cells and they build up and then they scale and then you have these open wounds if you wish. Which can lead to other things. Exactly, you know, infections and all that. So that's why we're developing a topical cream so that as soon as it starts up, you apply the cream containing clofazamine and the prediction is based on our research, our nonprofit research and our patent and the applications that we have that it should calm down that area. Yeah. So okay, so you've identified one target illness, target disease, namely psoriasis. Is that what you're working on these days, the psoriasis or do you have other autoimmune problems you're working on also? So the idea for the company now is that psoriasis will be used as proof of concept. Because once you have proof of concept, because other autoimmune diseases are caused by the same mechanism, you can then eat clofazamine as a pill, for example. You can develop that. It probably won't be us, but the idea is that you then spread out. So you look for other targets. We look for other targets. Once you find the mechanism by which it works. Yes. Have you found the mechanism by which it works? Yes, we have. What is the mechanism? It's a potassium ion channel called KV1.3. Of course, at home, my wife and I speak of little else at dinner, yeah. Exactly. 1.3 it was, yeah. Just give me a Chinese work, right? So it's a potassium, now the trick with potassium channels is we have a lot of different kinds of potassium channels. And the heart needs potassium channels, right? So if you suppress potassium channels in your heart, you basically die. So the FDA has said every single new compound that comes out to the market has to be tested for its acts on potassium channels in the heart. Now, this particular potassium channel, the KV1.3, Hachi, thank you very much, right? That one is particularly overexpressed. So it's massively upregulated in memory T cells. It's massively over, it expressed elsewhere also, but it's at so low levels that other potassium channels can do the job and it doesn't really matter. So that's why, because these memory T cells, they rely on this particular potassium channel that they're very sensitive to inhibition by any compound that is selective. My right to think, and I could be way off on this, my right to think, a potassium channel, it's a communicator. Yes. That's why in the heart it's important, that's why the FDA wants to know about it because it communicates the other cells. Exactly. So that's a profound discovery that if you change the way the potassium works, you're changing the way the messaging works to the autoimmune cells. Yeah. And that is based on hundreds of scientists' work. So that's not our work. We just, we're standing on the shoulders of giants. We just thought, okay, it was sort of indivudous because there's other mechanisms that regulate what this particular potassium ion channel regulate, but those, and that is the beauty of plafazimines. It's very specific. Many drugs are nonspecific. They are very good for one target, but then they also affect this one and that one and this one. And that's why this particular target and drug is a beautiful dance, if you wish. Yeah. Beautiful, it is. Science is beautiful. And research is beautiful. You can tell I'm getting all excited. And that's okay, I am too. So much so that we're gonna have to take a break because Andrea Flagg and she's the Associate Director of Biomedical Research in the Queens Medical Center and she's also a principal with her husband, Reinhold, in Scythera, which is a virtual research company that's working on autoimmune diseases and we're gonna find out more. In fact, we're gonna go back and look at that slide and you can explain it to us right after this very short break. This guy looks familiar. He calls himself the Ultra Fan, but that doesn't explain all this. Why? He planned this party, planned the snacks, even planned to coordinate colored shirts, but he didn't plan to have a good time. Now you wouldn't do this in your own house, so don't do it in your team's house. Know your limits and plan ahead so that everyone can have a good time. All up in the confusion, nothing is making sense. We're back and we're getting deeply into this subject with Andrea Flyg. She's a principal of Scythera, which deals with research on autoimmune systems and they stand on the shoulders of giants. That is, they find drugs that have already been approved and patented and all that and they take them another step, see if they can find another use for them and in this case, she's working on something which involves psoriasis and what's the chemical again? Chlorphazamine. No, chlorphazamine, but... Oh, the channel? The channel. KV1.3. Which is? A potassium ion channel. Potassium? Yeah, potassium. Potassium, you know, is good for you. Sometimes. It is. Too much is not good for you. It's more sodium that's not good for you. Okay, all right. Thank you. It's the balance, you know. So let's look at that slide now for a minute and see if we can get a full explanation of chlorphazamine and this is the mechanism that Andrea was talking about before. What does this slide tell us? So we have four different panels here and you want to look at the left upper panel where what you see is what's called a current-time relationship. Currents, basically what these currents are, tiny, tiny currents that we measure in a single cell. In this case, a single T lymphocyte that is a cell line so it's not, you know, we perpetuate it. It's coming out of a cancer, human cancer of lymphoma. And what we do is we use biophysical methods to measure currents in these cells and what you see of the blue line basically is the control. So we have 100% current over 200 seconds and nothing happens. Now if you apply increasing concentrations of chlorphazamine, you have the orange one I believe is 100 nanomolar. You see a little bit reduction in the current, this tiny current measured in one cell and then when you apply from the outside of the cell 10 micromolar chlorphazamine, you basically get 75% suppression of the current. Now how does that correlate to what the cell does? And that is shown on the right upper panel where you have what's called a dose response curve. So what we looked at is the release of T lymphocytes of a certain protein that's called IL-2. IL-2 is an important cytokine in the immune disease, in the immune process. And on the x-axis, you see the increasing concentration of chlorphazamine and what you can see is that if you increase the concentration of chlorphazamine, the less IL-2 will be secreted from the T cells. And the inhibitory half concentration, in this case it's 630 nanomolar. So you only have to have 630 nanomolar in your system to reduce the IL-2 production by 50%. Okay, now we know on the cellular level, now let's go into the animal level. The animal level is shown on the left lower panel. You see this huge mouse, mice are huge animals, I tell you, so we'll be very careful with them. We're very conservative, very aware of that we are working with mice and with animals. So what we did in this case, what you have to understand is that mice have a different immune system than humans and they don't use this potassium ion channel KV1.3. They don't need this ion channel to cause an immune response. And therefore, we could not use, we could not test lofazamine on a normal mouse. So we had to use what's called a humanized mouse and a humanized mouse is a mouse that has no T cells in this case and they have to be kept in very stale conditions because they cannot mount an immune response. So what we did is we injected human T cells into these mice, supplemented them with T cells and then what we did is we did an organ transplant. We took human skin and we transplanted that on those mice. And the control mice in the upper day, 0, 8 and 19, you can see that it kind of shrivels up. This skin, right, it becomes crown and flaky like when you heal, you get like a crust. That means that the organ, the skin was rejected. Why? Because lofazamine did not work. But if the mice who have the lofazamine given, the T cell activity is suppressed and the organ is not rejected, as you can see with this little nice brown patch a day 19 on the lower panel. So it works. It works. Has it gotten further, hasn't gotten to humans yet though? No, that's what we're currently fundraising for. So we are in the seed round fundraising and I cannot go into details, but for many reasons. But that is the next step. So create a topical cream and then do what's called animal toxicology to make sure that the cream itself doesn't cause like the skin to fall off, you know? Right, right, right. And then once, then with those data, we can file an IND investigation, your drug with the FDA. And after that, with this IND, we are allowed to go into human clinical trials. Okay, have you published anything about this? Yeah, so what the slide that you've seen has been published. That slide, it was an article actually. There's an article from 2008. Where was it published? It was published in plus one, which is quite a good journal actually. And together with Jun Lu from Johns Hopkins, his group and our group. Okay, so now you raise money to do clinical trials. My recollection is that usually clinical trials cost a fortune. Yes. So you have to raise a lot of money for this. We have to raise a lot of money. However, so the beauty of psoriasis is that it is a relatively. If there is a beauty in psoriasis. If there is a beauty. You're gonna hear about it now. The beauty, we should have named the show the beauty of psoriasis. The beauty of psoriasis. Oh my goodness, thank you, yes. However. So the advantage of when you look at a disease, you want to have something that is not lethal, right? You don't want to have the patients who suffer the most. You want to have something where you see relatively quick results. Multiple sclerosis, devastating disease also takes years to study, which is hard. But if you have proof of concept in something that you can study faster, then you can go into multiple sclerosis with the same concept. So it's relatively inexpensive to do a psoriasis clinical trial. You need fewer patients and you need, and it's a faster process. So refresh me on the patent law. If company A has designed this for, I forget the original use, what was it again? Leprosy. Leprosy, which is not pandemic or anything. Right, right. And now you're using it for psoriasis, same drug, same methodology again. You get your own patent, don't you? Correct. Based on that patent. So it's sort of a finer art, so to speak. So we don't have a novel compound. What our patent is called is a use patent. So we have a use patent where we basically use a known drug that is FDA approved, but for a different indication. And we repurpose it for a new indication and a new formulation. So that is the patent law. And it's also 20 years. You haven't yet? Yes, it's patented, it's... So now it's just a matter of showing that it works. Exactly. So it's a solution of the regulators. Exactly. Once it works, then it sounds to me like you're going to have a solution to psoriasis, which will be amazing because psoriasis, what do they say, the heartbreak? Yes. Not the beauty, but the heartbreak. The heartbreak, yes. And there isn't really a specific cure for it until now. It's not a cure, so it's a treatment. It would be a treatment where 90% sure it'll work. And then it will be a treatment, where you don't have to swallow anything. You know, you don't have to inject anything. You don't have to pay $40,000 a year to... Is that what it costs for some of this? Certain treatments are there. The biologics are very expensive. They work with the side effects of possibly cancer and possibly infections, but... So the clopazamine is going to be cheaper? Yes. Cheaper than $40,000 a year. So there are four different treatments out there right now. You have topical creams that many times don't work. They run around $1,000 a year. Then you have UV light that's about $4,000 a year. Then you have corticosteroids, $8,000 a year. And then you have the biologics around $40,000 a year. So if you look at that picture, if a cream really works, we probably can price it or whoever has the company or markets probably $2,000 to $3,000 a year. And it will be very likely, it's highly likely that it's going to be reimbursed by payers. Oh, this will be great. When you say pay, you mean insurance? Yes, insurance. Oh, that'll be just terrific. That'll be a real... It'll be a game changer. A game changer and you can feel really good about that. You advance science in that case. And the nice thing is, it doesn't exclude to use biologics, but if you start out, it's not like boom and I have a huge plaque. But if it starts to build up and if you start with the cream, every single patient is put on creams first before they go to the biologics when patients have a flare. So if you have a cream that works, well, you don't have to go to the biologics, have you? Yeah, no, just go right to the best treatment available. So where does this all take us? I mean, you're talking about some very sophisticated communication, potassium communication channels and all this. Talking about biochemistry really, at the root of it somehow, cellular communication, you know? Yeah. And it reminds me of some of the research at the medical school here, Japsum, over cancer. Yes. And I wonder, what's the parallel? What's the connection? Is there some resonance between what you're doing and cancer research? Absolutely, there's... Out there in the world, the link between the immune system and cancer is getting the big hype. I'm not particularly... I haven't made the connection yet myself, but I know that it's the big buzzword right now. So we are originally immune biologists, and we have moved into cancer from a different angle of research about six to seven years ago. And so we are also affiliated with the University of Hawaii Cancer Center. And so we're hoping that there's a synergy, of course, yes. Yeah, okay. So what's your next project? I know you've got plenty to work and do on this, but just leapfrogging over that for a moment. We are currently developing pet imaging tracers for positive emission tomography, where we want to see, okay, where do the drugs that we have developed, where do they go in the body, and can we use them to diagnose? So we're going into diagnostics with our basic, with our translational research now. Is there enough medical research going on in Hawaii? No. How do we achieve a greater amount of medical research here? We have wonderful researchers here at JABSM, at the Cancer Center, at HPU, and there's good collaborations going between chemists and biochemistry and cancer researchers. But we're too small. It would be nice to have more. With the woes of the NIH, I don't know how we can change that. Luckily, Hawaii is one of the idea states which is where traditionally underfunded states that are underfunded by the NIH, there's a federal requirement that they pay special attention to these states, and Hawaii is one of them. So we have the INBER-3, for example, which is a large research network encouraging. So you basically have to start with young people, right? You have to bring up graduate students and postdocs and give them actually a career perspective. Which is hard. And you have to give them jobs, too, I think. Exactly. That's the career's perspective. It's not like, okay, we give you money for the first five years of your career as a system professor, and then, hello, NIH runs out of money. But we have the possibility of doing it. Absolutely. We have the talent. We have the interest. We have certain institutions that will support it. Absolutely. So it's important that people watch this video and try to understand exactly. The methodology you were describing. And I'm a great advocate. That's why I came to Hawaii in the first place. I thought, you know, I did my PhD here at the University of Hawaii and at JAVS and Biomedical Specializing in Neuroscience. And I just felt that it's so important to come back and do my best, you know? And the other thing they can do is come around to the science fair and march and take a look at some of those posters. That's right. Who knows? There might be a poster about... Khufazimid. Khufazimid. Right. You'd be interested in seeing that, wouldn't you? I would go there in first comfort, you know? Yeah, that's right, yes. Thank you, Andrea. It's been great to talk with you. Same here. Thank you so much, Jay. Next time soon. Next time soon. Aloha.