 All right, I have a little bit after 10 o'clock, so we may have a few arrivals still straggling in, but let me go ahead and call our panel discussion to order. Thank you all for attending. Thanks to Chantal and Jess for organizing and promoting this event. As you all probably know, this is one of a continuing series of panel discussions hosted by the Science Circle with various topics. This session will be recorded and available on YouTube in a day or two, and you can also find an archive of our past panel discussions on the Science Circle YouTube channel or through the Science Circle website. Today, I'm kind of pleased to have a little bit more of a cheerful topic, I'm hoping, than last week, or should say last month, when we discussed the mass extinctions, which was pretty depressing. Today, we're going to look at recent breakthroughs in medical therapies or treatments or sort of previously intractable diseases. This idea was prompted by a report I heard on NPR a month or so ago, where Anthony Fauci actually was interviewed on NPR. It's kind of rare that a medical breakthrough is significant enough that he personally would promote it publicly, and this is a new therapy for cystic fibrosis, which is a rare ailment affecting where the lungs become filled with fibrous gunk and making it very difficult to breathe. It's a genetic disease and is usually condemns be afflicted to a short life. Maybe they're lucky to live into their mid-20s, I think, and my cousin's son has cystic fibrosis, so this announcement really popped out at me. So let me actually sort of start with a little discussion of this new breakthrough on cystic fibrosis. The Cystic Fibrosis Foundation has published a press release. Today marks a tremendous breakthrough and exciting news for people with cystic fibrosis. The U.S. Food and Drug Administration approved Trikafta for people with cystic fibrosis who have at least one copy of the F-58 Dell mutation. With the approval of Trikafta, more than 90% of people with CF could eventually have a highly effective therapy for the underlying cause of the disease. Until now, most people with a single copy of the mutation did not have an approved treatment for the underlying cause of CF. Clinical trials of Trikafta showed dramatic improvements and key measures of the disease. People with two copies of the mutation had a 10% increase in lung function compared to treatment with a modulator, and people with one copy had more than a 14% compared to placebo. Trikafta is apparently a kind of a cocktail drug of three other drugs, so this kind of reminds me a little bit of we're increasingly seeing these kinds of medications similar to what we have with the AIDS cocktail. I should mention that the drug comes with warnings related to elevated liver function test, drug-drug interactions, and liver enzyme complications, also risk of cataracts. That was the news that sort of prompted this topic. So I also wanted to, in order to kind of expand it out a little bit, I've invited a couple of our favorite medical and biology people to help me discuss these breakthroughs. I have with us a tagline, Dr. Robert Hendricks, who has presented here at the Science Circle. I think we're all familiar with Robert, and also Stephen Geyser, and they will each discuss different aspects of breakthroughs. I believe that Stephen is going to give us an update on CRISPR in clinical trials and other potentials for the use of CRISPR, and tagline wants to Dr. Hendricks wants to talk to us a little bit about interesting new technologies, medical technologies that are on there. Before we get started with that though, I also wanted to share a couple of other interesting just medical breakthroughs on other topics. Just bear with me here a little bit while I pull this up. I don't want to do that one yet. Here we go. So one other interesting topic is migraines. More than one in 10 Americans deal with migraines. There is now a new drug that may help. Food and Drug Administration recently approved RIVO, RIVO, to treat acute migraine. The drug is active for short-term migraine, isn't intended to prevent migraine. The drug treats migraine with or without a common sensory phenomenon or visual disturbance that can accompany migraines. It was tested in two randomized double-blind placebo-controlled clinical trials. It has been characterized as a significant breakthrough because it's a new class of medications known as di-tans. This kind of medication works similar to another type of medication called triptans, a class of medications to treat migraine that came out of the 1990s and helped with acute migraine. But triptans narrowed blood vessels, so they weren't a good choice for patients with cardiac or stroke risk factors. Common types of triptans include imetrix, omeg, and maxalt. Experts say that di-tans work similarly to triptans, but do not have the cardiovascular effects. This will allow us to use it for people with migraine who cannot take triptans due to concerns of stroke or heart attack. This class of drugs has been called a game changer because it works on different receptors than triptans. Also, many patients do not respond to triptans, so this will be an additional option. So I thought I wanted to bring that to your attention as well. And then also, I wanted to mention some breakthroughs in multiple sclerosis. There's been an important discovery. Now you may know that multiple sclerosis is a muscle degenerative disease that is chronic and progressive. It's an autoimmune disease, apparently similar to psoriasis or rheumatoid arthritis. Researchers at Trinity College in Dublin have identified a molecule known as IL-17, which is involved in priming cells that cause multiple sclerosis. Rather than being directly involved in damaging the nervous system, IL-17 kick starts the disease causing immune response that mediates the damage they believe. And they have recently published work suggesting there is significant potential for drugs that target the IL-17 molecule. MS is a debilitated disease that affects some two to three million people globally and over 9,000 people in Ireland for whatever that's worth. This is a report from Ireland, so it's associated with the infiltration of immune cells into the brain and spinal cord that cause damage to nerves leading to neurological disability. Oh, so I'm correct. It's not a muscle degenerative. So early clinical trials with antibody-based drugs that block IL-17 are showing promise in the treatment of relapsing, remitting MS and have already been licensed for treatment of psoriasis. So, yeah. Yes. Thank you, Sissi G. It is a neuro-disease. My bad on that one. But that sounds promising. And MS is a really devastating disease. And it's very interesting that they're able to identify some significant molecules that appear to trigger it. And then, in a typical strategy when you do that, is to then create antibodies against that molecule so that you can find up that molecule in your body so that it can't bind to its receptors and so forth. That's a very typical strategy. Yeah, I was a little bit surprised to read that it can infiltrate into the brain. That's kind of terrifying. So with that sort of introduction into what prompted me to present this topic, I'd like to now invite my guests to chime in. And I guess if it might be, Steven, if you're prepared to talk, why don't we get a little bit of an update on the status of CRISPR, which is always a sexy topic and we're always curious to know what updates are available for CRISPR. So please feel free to take the mic. All right, great. Thank you, Berrigan. Yeah, I think CRISPR is always sexy. And the reason it is is it really opens up new avenues for thinking about the molecular biology, how we understand diseases, as well as ways we can think about creatively to treat them in a way that's not just drugs or trying to blast a body with some sort of effect and hope that it preferentially affects the disease as compared to healthy tissues. And it really is something where you can think about permanent solutions for a person's disease, because you just change the DNA of cells in people in order to correct or to alleviate some sort of pathology. So when we were first talking about this, I just picked a subset of diseases that we had discussed and to illustrate really different ways in which CRISPR-Cas9 can be thought about as a way to study disease and as a therapeutic. And so I actually found three kind of interesting aspects or stages of development that scientists and companies are thinking about CRISPR-Cas9. So I do want to give just one brief two minute reintroduction to what CRISPR-Cas9 is. And this is essentially an enzyme that comes from bacteria, a lot of bacteria have them actually. And it has the basic feature on property that the protein when complexed with an RNA molecule, and RNA are the messenger types of molecules in the cell that come from DNA, that when complexed with this will actually find a corresponding specific sequence of DNA in the genome, and then it'll cut it. And that's what's being demonstrated in this picture here is the yellow is the RNA, the orange blob is the protein, and that yellow is specifically finding that blue sequence. And that blue sequence allows the orange to have these molecular scissors that cut the DNA. And I'm not going to talk, again, you can look at prior talks I've given about CRISPR or you can look at YouTube online to talk about or to kind of understand a little bit more all the things that can and can't do. But I'll talk about some of those specifics for the different diseases. But the key thing, the key thing that's amazing is that you can basically target any sequence in a cell you want and then try and affect different types of changes. And that's what's really amazing about the technology. Now bacteria use it as an immune system, a way to try and fend off DNA or RNA based viruses. And then there are some other like other ways that they fight each other respect here. But that being said, something I talked about in my, oh sorry, let me say in general, you can actually think about CRISPR-Cas9 as being involved in different stages of the development of how we understand a disease. And that, well, I think it's important to think about it as a therapeutic. It's actually, there are other stages of science in which this has become an incredibly powerful new tool. And again, oh sorry, I didn't mention that, you know, CRISPR-Cas9 as a technology has only been around since 2012. And in terms of it accelerating very quickly into the lab, and it's a therapeutics, it's actually a very amazing and fast and rapid development cycle. So, you know, in addition to thinking about CRISPR-Cas9 as a therapeutic, targeting cells, changing genes, doing things, how CRISPR-Cas9 is used in the lab is that you can actually start mimicking the types of mutations that we know cause disease in tissue culture, in cells you can study, or in whole animals or model organisms or even like subsets of tissues. And the ability to directly recreate mutations that we know lead to disease, and then to study those in the lab in these model systems is incredibly powerful. The other thing you can do with Cas9, again this is a somewhat similar technologies have existed before, is you can mutate or otherwise affect cells that you're working with in the lab to just discover how your disease gene interacts with other genes. And in some cases, and I'll talk about an example of this at the end, where you can find other genes that when you overexpress them, alleviate the toxicity of the pathology protein. And this is the type of idea where, again, if you didn't have the ability to really mask green and mutagenize lots of things at the same time, then, my clothes are dry by the way, then, you know, it's an incredibly powerful discovery tool. And then the other thing, and I just want to be, you know, this technology is accelerated very quickly. But the translation of it into an actual therapeutic is still a big hurdle that we have in the, in how we think about these as therapeutics. And so there are some limited applications that we have right now. I don't really want to go into that, that would be time for a better talk. But just one thing to keep in mind that for the last couple of decades, we've had recombinant DNA technology. And there's still this challenge of how do you get your packages into the right cells in the right amount, and then also not elicit the mean responses from the target tissues. So we're still trying to overcome some of those hurdles. But again, depending on the disease, like for example, there was a lot of early work that's being done in eye diseases. And the reason eye diseases are very nice to work with is that there's no immune system response in most cases when you deliver, you know, viruses. So it's actually one of those interesting aspects. The other very last exciting thing is that there's a new paper that came out that I talked about in my CRISPR year review. And the thing about it is that it actually creates a very different, more precise way that we can fix DNA and make changes in the targets. And so, you know, this is something that it's so new, people are still taking some time to really adapt it and how we might think about it in terms of therapeutics. But I think one thing is as I go through the talk, you'll see how if you could just imagine me a little bit more precise in how you change DNA, you can actually accomplish even more interesting things. So the first disease I'll talk about, and this is one of the ones where at its stage right now, it's actually in clinical trials. And so the disease here is something people, again, taking basic biology or you hear about it on the news is sickle cell anemia or beta thalassemia. And these are caused by defects in how red blood cells interact with DNA and travel through the body. And the key things about it is it's modifying hemoglobin. And hemoglobin is the actual protein complex that binds oxygen. And when that's defective, you have one poor oxygen delivery to tissues. But then specifically in the case of sickle cell anemia, it causes the red blood cells to not be very flexible and to get point pointy edges. And that can actually block up capillaries and lead to a lot of pain and other crises when you are in a low oxygen situation. Again, and without medical intervention, people that are homozygous recessive for sickle cell anemia usually die before the age of 10. And one thing that's important to recognize in this context in terms of how we, our bodies deal with oxygen is that if you are an embryo, a zygote growing inside your mother's womb, you need to be able to be better at grabbing oxygen from her bloodstream than her other tissues. And there's this, there's this modification of hemoglobin known as gamma hemoglobin. And this is essentially something that we only express as baby, because it's not as good as regular hemoglobin for oxygen delivery in an adult. But in terms of that situation being the womb, it's much, it's very good at capturing oxygen from, from the, from the mother. And what has been known from the literature for a long time is that there are people who have beta thalassemia. So they're defective in their ability to transport oxygen with a mature hemoglobin. But they have an overexpressed amount of the fetal hemoglobin, the gamma hemoglobin. And this is what the chart is showing here is that as you go towards the left, that's the symptoms on the x-axis. That is the amount of expression you have of gamma hemoglobin. And then the y-axis, the higher you go, the less, or that's the degree of symptoms that you have. And so as you go to the right, where you have more gamma hemoglobin, then you actually have less symptoms of beta thalassemia. And so the exciting thing about this is that, again, from the literature, and what I'm showing here in the lower, lower panel, is some work showing that there are variety of deletions that have been found in human populations that allow gamma hemoglobin to be expressed in adults. And what the therapeutics, coming from vertex and in a combination with CRISPR therapeutics, they actually are in phase one clinical trials of trying to recreate these deletions with Cas9. And doing this in patient's blood cells, express gamma hemoglobin, alleviate sickle cell anemia or beta thalassemia. And so one of the key things about this, this is very exciting, right? This is something, a nice body of science that tells us how a disease works, how we can alleviate the disease. And then CRISPR-Cas9 allows us to recreate that situation. Most of the somewhat limited type of effect in that CRISPR-Cas9 is coming in and actually trying to purposely delete DNA in the target cells. So we're not trying to do something very precise. We're not trying to do something that's, you know, this very subtle ways of affecting DNA. We're just boom, trying to chop out a piece that allows the expression to happen. And, you know, more details about how that works in particular, I think the emphasis I want to make is that CRISPR-Cas9 is something where if you have a situation where deleting fragments of DNA allows you to fix the disease, we can do that. And this is in clinical trials, not showing some effectiveness. So I'm glad I put this next slide in. I'm going to switch gears to a different disease, cystic fibrosis, which is something that Berrigan was mentioning at the beginning. And the basic problem with cystic fibrosis, and cystic fibrosis, I don't know, I don't know if there are any books where people have just focused on how that particular disease and gene and the genetics has helped us as a field understand, you know, genes and pathologies. But it's an amazing story. It's been around for a very, like decades. And what we know is that it has this failure to move chloride ions across membranes. And the reason it doesn't do this is one of two reasons is that the protein is either A, not present on the cell membrane, where it needs to do its action. If you're going to push something across the cell membrane, you need to be at the cell membrane. Or there are the catalytic parts that are binding other proteins or binding the chloride, and those just aren't working very well. Now, if you look at this chart, what we're actually looking at is the structure of the gene. It has a lot of exons, has lots of component parts. And then its actual protein has lots of different domains and things that are happening. And so, actually, yeah, let me CB ask a good question in local chat. Is that why is sickle cell anemia? Why is it such an issue? Is that if you have, if your heterozygous for the mutation that causes sickle cell anemia, it's been shown you have a little bit of resistance to malaria. And so malaria is a bigger issue in terms of survival than having rare numbers of people die from being homozygous recessive. So that's kind of the dynamics in terms of evolution, as well as interaction with parasites. Okay, but again, and cystic fibrosis is actually an interesting story too. Actually, that brings up a really good point. And I already mentioned the context of why cystic fibrosis is highly prevalent as mutation in Caucasian populations is that it's believed, the best theory right now is that it's protective against diarrhea. That one reason that things like cholera actually kill you is they make you push a lot of chloride ions from inside your body into your intestine. And that helps push more water into your intestines. And that's how you get diarrhea. And then the bacteria that are causing this to happen can then spread more easily to get all over the place. And so if you have in some degree of inefficiency, right, your heterozygous for the mutation, then you do that less efficiently, you retain more water and you can survive better against the disease. So again, coming back to the idea of evolution. Okay, but it's a complicated protein. And this is what's actually interesting about this in terms of therapeutics, is that it's when you have a very complicated gene that has lots of things that's doing, the ability to do genome editing is somewhat less effective, because it's going to be very hard to come up with one single way of dealing with those different mutations. Unless you can just go in and replace stuff, which is also very difficult with very big genes, you have to find very precise strategies. And so this review coming from Craig Hodges and Ron Lennon talks about how, as Berrigan mentioned, there's a very specific, highly prevalent mutation, which is actually deletion of a few genes, or sorry, a few amino acids in an important catalytic site. But then there's a lot of other mutations that are just one nucleotide change to another. And so, on the other category, there are several that cause splicing to be different, so that the arrangement of axons and you're missing whole chunks of the protein, it doesn't work very well. And these all require, in essence, slightly different strategies in terms of genome editing to fix it. Now, one of the important advances we've had with CRISPR-Cas9 technology is in contrast to trying to break DNA and then hope it fixes together in some way that is beneficial, there are these things called base editors. And this is where you come in with a deaminase that basically modifies DNA in a way that's just one base at a time, and then hopefully you just mutate it to a different one. And that's what I'm showing here under the picture on the right, is that we have the capacity right now with CRISPR-Cas9, and these what are called base editors against something developed by David Liu at Harvard, is to change a particular C to a T or an A to a G when we think about that top strand, or to change a G to an A or a T to a C in terms of just how we orient on that top strand. The other limitation, of course, also is that the spacing of this has to be correct when it comes to thinking about where Cas9 is binding. Remember, Cas9 can't bind any sequence in the genome. It's limited by what's called the PAM. And so you have to have a PAM in the right amount of distance to the base you're trying to edit for these things to actually be effective. And again, it doesn't always work precisely, and there can be background. So what was interesting is that the main limitation that people are excited in developing methods and showing in tissue culture models that they can fix cystic fibrosis. And I would say that the main limitation right now is trying to understand the best way to deliver this into tissue, because lung tissue, on the one hand, we can adapt adenoviruses, which are something that actually infect lungs. We modify their genomes. They're actually pretty good at getting into epithelial tissue. But those are the ones that also invoke strong immune responses. So it's an interesting topic. But I think the stage of this is that we have targets, and we can relatively efficiently modify them. But in terms of delivery, it's not quite there yet. All right. And then the last gene that I want to talk about is Parkinson's. So actually, sorry, there are two more I'm going to talk about. So Parkinson's, again, understanding the genetic causes of Parkinson's is something that's still not fully understood. So in term, in contrast to cystic fibrosis, where we can say, oh, here's the gene, here are the mutations, can we just fix these? We don't know that as well for Parkinson's disease. However, what has been shown in the pathology is that there's a protein known as alpha sinuclein that is associated with the pathology. And it's been shown in models that if you can help alleviate the aggregation of this protein, you can actually help alleviate or reduce the toxicity of the cause and effects of Parkinson's. And so here's the interesting paper that came out. Again, this is very early studies looking at tissue culture. This is actually done in yeast. This is the funny thing. But they call this method prism. And it stands for perturbing regulatory interactions by synthetic modulators. And what they're actually doing specifically is taking CRISPR-Cas9 and saying, okay, you're not something that's going to cut DNA. What you're going to do is land in your genes. And what you're going to do is turn the gene on. And so this, try to turn the gene on and then seeing how that affects what's happening in the rest of the cell, when you're specifically looking for, say, a toxicity phenotype, that's something we can do pretty well on yeast. And we can do this in a mass effect where, again, discovering what's out there. We don't know what we're going to get. We don't know if we'll get anything. But just see if some gene, by being overexpressed, can alleviate a toxicity. And so that's what's being shown here in this diagram from the lab. Again, this is only a couple of years old. But they are just randomly trying to turn on lots of different genes in yeast and see if you can alleviate the phenotype of the alpha synuclein causing the yeast cells to die. So you're just looking for cells that survive. And what I think is really powerful about this type of approach is if you can find things where just turning on the gene or a network that turns on a gene, that becomes your therapeutic target, right? You don't target the gene that's a pathology. You target something that interacts with it and helps alleviate it. And so this discovery work is pretty nice. And at least the stage at which this work was in 2017 was they showed that the genes that worked in yeast to alleviate the toxicity, also the corresponding genes in mammalian cells can alleviate toxicity in mammalian cells. So again, not in patients, not in animal models, but very early cellular work. So I think that's really cool. I mean, it really changes the approach you have to understanding how you can treat symptoms or disease. Okay. And then the last one I'll talk about, and this was when I was trying to look up CRISPR for multiple sclerosis, I couldn't find anything. And again, multiple sclerosis is one of these, I think, multifactorial things in most cases. There's not a simple disease gene target that you can always fix. But as I was doing that, there's actually this interesting related neurodegeneration. So it's something called progressive multifocal leukoencephalopathy. So PML, and I'm going to refer to it as PML from now on. And what this is, is the activation and expression of a virus that almost all of us have, basically nine of 10 of you that I'm looking at, are infected with this virus. Now, most people with normal immune systems, it's just lies dormant, doesn't affect us in terms of our biology. We don't even know it's there, right? Before I said this, you probably didn't even know this thing existed. And but what happens in people that are immune compromised, like people who have HIV and then undergo your later stages of that, but also people who are being treated for MS. So one thing is that when you think about multiple sclerosis, again, don't worry, Scissor G, I'm not going to cause you to have the disease. But one thing that you do with MS is MS is an autoimmune disease. And so the treatment for it is actually suppress your immune system. Well, the second you start suppressing your immune system, this is a secondary effect you can have, where this thing gets reactivated and actually starts causing the myelin demyelination of neurons. So it's almost a kind of sad kind of effect that you can have some cases. Now, what's really interesting about this, of course, is that the expression of this virus and cells doesn't benefit you at all. Sorry, it's not one of your genes. It's just a very easy target that as long as you can affect that this target viral genes and not have bystander effects of human genes, you can use CRISPR-Cas9 to target it. And that's essentially what Willabo at all was showing in this recent paper, is that in tissue culture systems, if you express Cas9, again, something that's able to cut DNA, and you target specifically only a viral replication protein, well, the gene that makes a protein, you can actually decrease the amount of infection you have in your tissue culture cells. And so what I think is very interesting about this is as we think about a lot of different types of pathologies, things like hepatitis B has people started working on it, herpes simplex virus, and there's another one that I'm now blanking on that they talked about. But the idea of trying to therapeutically treat viral infections to humans with CRISPR-Cas9, this is something that's also, I think, on the horizon and something relatively feasible, because as long as you're not accidentally making breaks in human genes at the same time, you can have a very specific target that otherwise doesn't affect the human host. So those are my examples. So again, this is very early, but it also invokes the idea of, you know, we're not targeting human genes, we're targeting pathology genes as a way of CRISPR-Cas9 to work. So any questions? That's fantastic. Steven, if we aren't targeting genetic diseases that have a protective effect for something else, what's the strategy for, you know, preserving the protective effect? I was thinking for sickle cell anemia, you know, one strategy would be, well, we'll cure the sickle cell anemia, and then we'll make the disease-carrying mosquitoes. Is that, is, well, what am I thinking of? What is the, I guess, sickle cell is just genetic. So, but, oh, but it does protect against malaria, so we could just make the disease-carrying, the malaria-carrying mosquitoes go extinct. That would solve the problem, but, you know, maybe that's a little bit facetious, but is there any thought given to, you know, how to treat these diseases while preserving the protective effect they grant? No, well, there are two things you could do. So one, you could try and fix the genes that are defective in the tissues where it affects you as a pathology, but then still leave it as protective for the types of cells that are important for resistant disease. And there's ways of thinking about tissues' specificity, but I will say the examples we're thinking about, right? I mean, the treatment for cystic fibrosis, I'm sorry, the treatment for, say, cholera infection. People have shown this, these were tests done by the Army on, I think, young recruits was just forced them to drink lots of water. If you drink lots of water, cholera cannot kill you. It's only a matter of dehydration. And so when we think about malaria, we have anti-malarial drugs, nets, nets are a great way of reducing infection rates, and we actually are also, the scientific community, are trying to find ways to, yeah, eradicate mosquito populations using CRISPR and gene drives. So, you know, a cystic fibrosis, again, the protective effect of that is protected against bacteria. Well, we have lots of ways of protecting against bacteria. You get diagnosed early, you take penicillin. You know, the majority of the things that these genes are protective against are things that we have much better ways to treat. We have other ways of thinking about how to manage those diseases. That's fascinating. My brother last year was diagnosed with a very rare form of leukemia, which is caused by a genetic mutation that does not kick in until you're in your 60s, which is kind of spooky in and of itself. It just lies dormant until you're, basically, until you're old. And it is, but it is a genetic, it is caused by a mutation. And so, of course, the first thing I thought about when we learned about this was, well, this sounds like a perfect target for CRISPR therapy. And he, in fact, he did talk to his doctor about that, but it's too often in the future. Although, maybe in five or six years, who knows. So, what they did do was a more, I guess, more quote-unquote conventional therapy, which still strikes me as unbelievably science fiction. He was treated at the M.D. Anderson Cancer Center in Houston and had a stem cell transplant. That worked. So, you know, so he had to undergo massive chemotherapy to completely kill his bone marrow. And then he was transfused with, so his stem cells also were matched through the, through a global registry. And his donor was some stranger from Greece. Can you believe that? So, actually, one of our family members did have a match, my older brother, but my older brother is in his 70s. And we felt was just too old to be a donor, basically. Ideally for these kind of things you want, you know, young, robust stem cells. Anyway, the stem cell transplant worked. And he re-grew his bone marrow with, which generated new blood cells and immune cells that did not have the mutation. Now, he does, so that was about almost a year ago now. And he does have a restored immune system, but it's weak. It probably will never be as robust as it was before the disease. But, you know, it's good enough. But this will probably keep him alive, maybe, until a CRISPR cure is available, maybe in five or 10 years. So, it's all quite fascinating to me. These kind of rare diseases, I think, are a great target for therapies. Primarily because they are rare, they're sort of, you know, these rare, they're sort of a, I guess, a treatment of last resort, I would, and that makes them, I think, valuable. And they're kind of like would be an orphan drug type. So, but the reason I mentioned this is just because that I remember when the notion of stem cells as therapeutic seemed unbelievably science-fictiony, like back in the 1980s, I think stem cells were almost hypothetical about whether they even existed. And now, here they are, stem cell transplants are practically routine. It's unbelievable. So, anyway, so I just wanted to share that story. I think stem cell transplants are really remarkable advance for these, especially for leukemias. And so, yeah, I'll just mention, let me just talk about that. Yeah, go ahead. Yeah, CRISPR. But these types of things where you can extract people's blood cells, circulating cells, grow them from the lab, do genetic manipulations, then re-implant them back into the same patient, that really is one of the best areas where you can start doing that type of work. And so, that's where there's a lot more advancing, I think, for CRISPR-Cas9, because of that ability to take stuff out, grow it up more, put it back in. Yeah, yeah, that's right. And it's also remarkable to me that they can isolate stem cells from a donor's blood. You know, the transplant is, it's basically just a blood transfusion. It's like, it's the actual procedure is simple. Once you can isolate the stem cells from the donor's blood and then grow up the stem cell population to a therapeutic amount. Okay, let's move on here a little bit. Before I yield to a tagline, I wanted to mention another interesting breakthrough. This is related to Parkinson's, which we have also discussed. I wanted to mention that recently the FDA granted breakthrough device designation for NQ Medical's neuroquarty technology. And the reason this is kind of as a segue to what a tagline is going to talk about says breakthrough device status is given to medical devices that have the potential to be an effective treatment or diagnostic tool for life-threatening or irreversibly debilitating diseases. That speeds up the review and assessment of the process so the devices can master. The neuroquarty software measures how fast a person is typing on a smart device and how much pressure they apply to each key. An artificial intelligence method called machine learning can detect small changes in the typing movements, which it can associate with different diseases such as Parkinson's. The software does not record the words that were typed only the patterns associated with the typing action. And then it goes on to quote one of the founders of the company. Everyone has a unique typing and touch screen signature. Research has revealed that the way we interact with computers and mobile devices can reveal with startling accuracy the presence of certain neuro motor, neurocognitive and neuro behavioral disorders. I just wanted to mention that because I find that fascinating that that are the way we interact with our devices as a signature. And with that I will use that as a segue for tagline to tell us a little bit about recent breakthroughs in medical technology. So take it away. A couple quick thoughts. Can you hear me? Yes. You're able to hear me? Yes, I hear you. Oh, okay, good. An immediate response to that is that if we can get a hold of data from POTUS's cell phone, because I doubt he can type on a keyboard, maybe we can figure out what's wrong with him neurologically. There's a couple of points. One that occurred to me in terms of cystic fibrosis. One of the consequences sometimes this is also known medically as mucovisidosis, which is sort of descriptive of the extremely viscous mucus that tends to cause obstructions and damage to lungs and all sorts of excretory systems, including pancreas and other organs. Polyps, nasal polyps are not unusual. If you see children with nasal polyposis, that's considered medically to be cystic fibrosis until proven otherwise. And there have been reports where the presence of nasal polyposis in children was felt associated with variants in some of the genes associated with and gene disturbances associated with cystic fibrosis. One of the other things that occurred to me was I was at University of Pennsylvania, I knew a fellow who was really brilliant named Dr. Dick Doty. He was an olfaction. He was one of the developers of one of the first olfactometers or ways of measuring olfactory function reliably, which is extremely difficult. At any rate, he used to talk about how so many of these degenerative neurological diseases likely entered the central nervous system via these little neuro olfactory endings from the olfactory bulb, which is just above the nasal vault and it sends down little roots through sleeves and you have some fairly direct access to the central nervous system by infectious agents and chemicals through that. But infectious agents may have access that way and cause all kinds of long-term effects. Now it's kind of not very much time left, so I'm going to do basically a flyover. I tend to think globally, I enjoy thinking globally, and I want to just say in terms of changes in medical technology that are striking, there's always been kind of a conflict at times or at least hopefully a balance between what are called lumpers and splitters. Lumpers are people that just kind of see things generally and often it has seemed to me that these are the people that say I trust my gut and that sort of thing. And the splitters, the people that look for more and more detail and sometimes get buried in it. But with some balance, I think one of the biggest achievements of modern medicine has been increased precision and most everything it does. That includes diagnostics and imaging for primary diagnosis and also for monitoring of disease and the effects of treatment. And another example of increased precision is the development of minimally invasive surgery. I wrote out some ideas here on a, you can't see it, but it's a napkin. And I did that because I was originally a mathematician. But one of the things I wanted to discuss quickly that I've seen develop in my career is cochlear implant surgery. You go back to the 30s and 40s, you had operating microscopes. I actually have one of the first operating microscopes ever used in the state of Ohio. It was being thrown out. It's on a big, heavy iron base and I've dragged it around with me for years. It's a field or basically a field microscope. But use of microscopy for seeing what you're doing when you're drilling out the ear. Originally, if people had subperiosteol, abscess or mastoiditis, acute mastoiditis from periolint or pus forming bacterium that got in the middle ear and caused osteitis like that, it could cause meningitis and they used to basically do incision and drainage. And sometimes they had facial nerve injuries and other things, but a lot of people had histories of mastoid operations, but they were basically pretty primitive. The whole thing progressed using high quality optics to do middle ear surgery and mastoid surgery and taking out the stapes, which is about five millimeters tall. I've done many stapedectomies in my years and it gets fixed in place. It's one of the three ossicles that transmit sound to the inner ear and who can remove it. Some people do this by lasering a hole into the foot plate of the stirrup bone, stapes. I just removed it mechanically and I always did well with that, with 10th of a millimeter right angle picks. This is kind of a small field. 10th of a millimeter? Holy moly. 10th of a millimeter, yes. The tools involved in this are just so tiny. It's amazing. The stapes are about five millimeters tall. The length of the cochlea is between eight and nine millimeters. The length of the inner ear, if you unrolled it, it's kind of in a two and a third roll of turns like a shell. But at any rate, that was sort of primitive compared to the interdisciplinary combination of technology that's used now in cochlear implant. That fixed a mechanical problem. Well, it became a sensory neural loss eventually because the process that caused the bone to get fixed in place, odospungiosis that evolves into odosplerosis became toxic to the inner ear and damaged the sensory neural apparatus. So eventually people would have inner ear type loss as well, but you could get people up to essentially normal hearing by doing this and it would last for decades. And as they got older, sometimes they had aging effects. Presbyacusis, it would worsen maybe more profoundly because of continued odospungiosis type changes. I mentioned in one of the science groups discussion that people had tried using fluoride treatments to arrest odospungiosis, but you can get fluoridosis of the bones and untoward changes like that. But I want to transition from that to talking about the cochlear implants. They began when I was early in my career and they were one channel implants, basically something to stimulate the auditory nerve. And it was a habitual to say sensory neural loss. It really made it sensible to discuss sensory loss versus neural loss. If you have neural loss, loss of fibers in the acoustic nerve, as you can get with acoustic neuroma, for instance, you have decrease in your ability to discriminate or unscramble complex sound and interpret what you hear. You might be aware of a sound, but you can't make any sense of it. If you just have hair cell loss in the under the tectoral membrane, you know, business end that transduces the vibrations into neural impulses, you lose those. You can have tinnitus and hearing loss, but if you can stimulate the auditory nerve directly, by putting an electrode into the scale of timpani, which is this, you have this oval window where the stapes bone fits and a round window, which is kind of like the hydraulic system, you can insert an electrode through that, or you can drill a little hole into this through the the audit capsule and to the scale of timpani and insert an electrode through there. That's come a long ways. It gave people who had nothing, at least the perception of sound. I'm not sure if I would have done it versus having a cat or dog that responds and you could see that dog respond, that noise. So, you know, that's pretty practical, expensive, and biological way of dealing with it. It's now up to 16 channels or 22 channel type electrodes where basically you implant under the skin of the scalp above the ear a receptor. You have a pickup, a microphone, and a processor that goes up behind the ear and over the skin of the implant and can send signals to it and send frequency specific signals to various channels. Now, it may not be tuned quite right. People, they actually do pretty well with speech considering, but music's not so great. And you think of music if they, and sometimes I've known people with perfect pitch, who are really bothered when people play off tune or tune their instruments without tuning it to standard tuning. But perception of music, recognizing if a frequency goes up or down, things like this are difficult for people with these cochlear implants, but they are really getting way better in just one generation. I think it's really remarkable. Really running out of time. Shall I go on? It's almost... Yeah, sure. I think it's okay if we go a little long. Is that okay, Shantal? I won't go 30 minutes. I'll try to hit a couple big points. Okay, I think it's okay. Okay, thank you. I always tend to go over, but at any rate, I also was, I wanted to mention this about the cochlear implants, and I'm not an ophthalmologist, and since 1960, ophthalmology and otolaryngology have been separate disciplines. But in ophthalmology, certainly, Lasik surgery is similar, in my thinking, to stapedectomy, except it's really quick. You can do it in eight minutes with a raise of a flap on the cornea and do a laser contouring of the underlying cornea and lay the flap back down. And then the next day, take off the bandages and people will have normal or nearly normal vision. It's really quite remarkable. And it's something that it's quite doable. At any rate, there's been all kinds of advances in various disciplines. I'm going to focus on otolaryngology, which was my field. Endoscopy or visualization because of fiber optics. You know, the Romans, I was reading about this. Romans used glass. They drew out in rods and noted that glass could transmit light. And like 1930s, Haile Shalom, L-A-M-M, did a bundle of fiber rods and used them for internal examinations, internal medical examinations. And his work was pretty much forgotten or maybe ahead of its time and probably World War II didn't help. This, of course, transmission of light into a lumen or into a field, surgical field by fiber optics was quite useful. One other aspect of this, having light sources, like high powered halogen light sources, that if you look directly at it, you will burn a hole in your retina. But that will allow you to have enough light transmitted through this tiny port, which is essentially what these fiber optic systems are, makes it possible to have really stunning visualization inside the nasal cavity and the pharynx and the esophagus throughout the GI tract. And this, I should point out also 1965 attenuation of the loss of light energy was made possible by doping the silica glass with titanium. A titanium is right after scantium, so that's atomic number 22. And we think of it as part of steel, but this kind of goes along with the development of the semiconductor industry. They doped glass with fluorine and various elements in the nitrogen group and gallium, of course, and other things. But another big advance, engineering-wise, that was stunning was for 1983, they could only produce two meters per second of an optical fiber. 1983, the engineering process was innovatively changed, so they could suddenly produce 50 meters per second fiber optic cable, or not cable, but fiber optic rod. And that became competitive and faster, really, than producing a copper wire. So that fiber optics became competitive in terms of communications with just conductors. Anyway, back to medicine, it was in the 1980s when the use of rigid endoscopes were really starting to be used for nasal cavity surgery, working on the maxillary sinus or the ethmoid sinus is a frontal sinus, even, which is really, it's the access to that, it's more difficult. And I could fix it so you could have 30 degrees, 45 degree angle looking up, and you had to really know your anatomy. And there, before this, they had people doing intranasal ethmoidectomies and having blindness as a postoperative complication was not particularly unusual. Anytime you have nasal cavity surgery, you can have injury to the eye and vision or injury to the skull base and have the brain injured or vascularity of the brain damaged or leak of cerebral spinal fluid. One of the things that's a combination of technology, they're now making it so that you can make high resolution CT scans and have markers so that the scope, the equipment knows where the tip of the scope is, and you can look at a monitor and see where your scope is with relationship to the orbit, which is where the eyeball is, or the skull base and the brain above. There's a horrendous historic picture and I don't know exactly who was to account for it and it may have been staged for all I know, but it was scary of endoscopic sinus surgery that the ideal was it was stopped in the middle of the surgery and a lateral x-ray was made of the head and the endoscope was up in the brain. When you've got a nasal cavity full of polyps and disease, it can be difficult to tell it like mush and it bleeds. That's all better controlled. The changes from making incisions in the face down along the nose or flipping a flap down off the forehead to bring down the end and cutting through the anterior table, the frontal sinuses, or going up under the lip like a cold wall luck procedure, lifting the lip up and stripping the periosteum and superficial tissues off the anterior table in the maxi sinus and knowing to stop before you hit the infororbital nerve so you wouldn't have numbness of the whole cheek and upper lip, and you would tap with a chisel and enter the sinus and scrape it out and with this endoscopy you could improve the drainage systems of these sinuses from within and leave the mucosa to recover and have its natural function. It's an example of minimally invasive surgery. Another example of that is like parathyroid surgery used to be I did a lot of thyroid surgery actually and I didn't do so much parathyroid I would for those elsewhere, but I did I had to deal with parathyrates because you try to identify them so that you don't remove them when you total thyroidectomy. That was one of the hardest things I had to do in my surgical practice identify these little clumps of brownish tissue there are four of them normally and sometimes they're embedded in the thyroid gland and thyroid glands are removing they have cancer in it. So if you do remove it you try to take it and mince it and you can implant it subcutaneously but there is a again a number of a combination of technologies and this goes back to Sieborg. Sieborg I think is had a element 106 named after him Sieborgium. He was a physicist in California was responsible for about a discovery of about 12 synthetic elements but he used a cyclotron Lawrence who has element 103 named after him invented the cyclotron and he used a cyclotron with molybdenum which has atomic number of 40 let's say 42 42 and bombarded that with protons and created technetium m99 the m means metastable it's a it's a nuclear isomer of technetium 99 and molybdenum it becomes to molybdenum 99 becomes technetium m99 molybdenum 99 has a half-life of about two and a half days 65 hours and it has I think a beta decay and becomes a in a beta decay the one of the neutrons becomes a proton and emits an electron and so it becomes the next heavier element technetium which has atomic weight of atomic number of 43 and the technetium 99 m has a half life of about six and a half hours so you can produce with a cyclotron molybdenum to 99 to technetium 99 m and transport that and then you combine it with uh in what's called uh technetium m99 sesamibis sesam means six and mibis stands for ethyl isobutyl isonitrite or nitrate in in these it's a ligands these six molecules associated with the element and uh yeah I think I was trying to say that syrugy that it it was a beta decay process but at any rate there's hardly any technetium in the soil of in the crust of the earth it was one of the gaps in mendelina's uh periodic table and it's easier to uh produce by nuclear synthesis so any rate the technetium m99 decays and forms technetium 99 which will later decay also a beta decay to the next heavier element um which is uh um rutherium uh are you um I don't know if it's 99 or not uh any rate um to rutherium um so the it's the most used uh radioisotope in medicine uh yeah the atomic uh number uh the atomic weight for rutherium I think is uh on average around 101 right and and it's a beta decay by with rutherium uh uh rutherium I guess r u is the symbol rutherium and is pronouncing it uh rutherium is produced by beta decay as well um it's atomic number 44 at any rate this uh technetium 99 m can be used to it's in it's useful in doing uh um beta scans for the heart um also some with breast uh disease but also for parathyroid excessive activity of parathyroid glands takes up this um uh technetium 99 m system eb and so you can have minimal uh minimally invasive surgery of thyroid instead of making a big long incision across the neck a collar incision you make several small incisions and you can use endoscopes and special um instruments to do your uh dissection and you have a gamma probe that is sterile used in the surgical field it has to be done within two hours of the injection um and the surgery can take one or two hours but uh it can be pretty fast and some places people go home the same day uh the isotope helps to visualize uh the steroid tissue now the m uh the technetium 99 m is a gamma emitter and um so you have a gamma probe and as you're dissecting and you can put your probe up in there and you can see if you're getting close to your parathyroids where they are difficult as hell to find uh half the time or more and so um it's turned uh uh kind of a beautiful surgery but it's a difficult surgery it can be botched up if you're not good at it um and uh it's one of those things you need to do a certain amount to be able to do well uh but it's improved the precision of uh doing this one other aspect about this doing minimally invasive surgery is robotics I've had to stand on my head and do all kinds of uh interesting incisions in the neck to be able to get to base of tongue the back third of the tongue and uh lateral pharynx or the hypothermics um you can do um um robotic surgery uh in the pharynx or in the uh on the larynx and I have people I have not I went for years I think that with the rise in obesity I had some people I just couldn't get direct line of sight with the standard traditional laryngoscopes to visualize the larynx to remove things from the larynx and the vocal cords and with these um uh robotics particularly you can get to anywhere just about uh there's one I go to tumor board regularly uh which is multidisciplinary and uh there's a urologist who does lots of um robotic surgery on uh um removing kidney uh lignancies and uh um even prostate tumors can be removed uh with robotic surgery so robotics is a big move forward also just employ lasers and being able to um ablate or destroy tissue that you want to get rid of right finally one real quick right last one anthology pat yeah last one now I'll shut up pathology is just it's marvelous what's happened you think back the organic dyes developed and develop of high quality microscopes and basic optics and you had Colk and others that were able to develop um uh a good quality scientific pathology to identify tissue that's where the problems in medicine is uh that that had for a long time it's they didn't know what they were dealing with and they really couldn't see it they didn't have a well-defined uh cell theory that anyway you got into identifying tissue and abnormal tissue or including tumors by um orthologic micro microscopic change um pathological examination under a microscope this evolved um and I'm just going to give this in a kind of a nutshell um immunohistochemistry or IHC IHC is the common term goes back to 1941 a guy named Albert Koons used um ways of the antigens particularly in cell surfaces but that can be inside the cells as well depending and you can have ways of making the antibodies that you use to detect the presence of certain antigens um to um light up uh or become visible in various um kinds of light and some variations on some of these things like flow satometry but at any rate immunohistochemistry was a big advance and that's gone beyond now so that you have a whole new field developing called molecular pathology which looks not so much at cell morphology but at molecules in a cell that define its behavior and that is so complex that I was talking to the pathologist uh at the tumor board yesterday morning uh there's a whole uh sister field to this that they're dependent on basically referred to as informatics which can't be very surprising the database for all this is so vast and it's changing so quickly that no one can keep up with it and by uh being able to input your problem with um a system artificial intelligence sort of system that yeah that's what I was thinking yeah you need AI for that yeah you can come up with great diagnoses and this is kind of uh graduating from what used to be traditional you'd have protocols for treatment of a certain disease presentation which would be multi-discipline or multi-institutional because no one had enough of patients that had hypoferential cancer of a certain type and you have like 10 major medical centers and you could have enough patients to be able to conclude if one treatment was better or not but this can go to a much vaster database and it can keep up much quicker and let's see I'm looking at my napkin here well nope I think we're out of time okay one comment about coronavirus I make a you know all right okay they it's an RNA virus I I'd mentioned before type four and when I presented on coronavirus and they generally for active disease you would use a reverse transcriptase PCR polymerase chain reaction test and the United States I I'm not sure why except everything is being politicized in the United States now and have all this America first America uber Alice kind of mentality so that instead of using WHO guidelines and well-developed tests they decided to develop their own and they didn't work and they in the 14th of February they announced they were going to do surveillance in New York Chicago LA San Francisco in Seattle that has not started yet and right now only the CDC and Illinois Idaho Tennessee California Nevada and Nebraska are able to do any tests and they've got so few of these test kits the test kits have about six or seven hundred tests that can be done with one um so yeah are the are the diagnostic tests still like RNA based I mean it seems like it would be a lot cheaper and faster if we could develop an antibody that's really useful what's the hold up with that well that's only useful after you have an immune response that's developed if you have naive patients who are infected but right right right that was a similar problem with AIDS where they it wasn't generating antibodies until it was too late yeah so you get acute and convalescent samples and you see a rise in antibodies and that's uh evidentiary proof of a recent infection of whatever you're looking at but at any rate this has really been handled poorly I'm afraid and uh this is a matter of life and death and that people should speak plainly about it yeah we I wasn't used that mentioned the other day that some of these kits sent out by the CDC had a defective component so they had to have sort of a recall well this seems to me like a symptom of the fact that the CDC budget was cut and they and they lost a lot you know fired a lot of the personnel and basically you know the agency was just caught flatfooted and just could not ramp up fast enough so they got sloppy that's true and uh yes they were they were saying that it was a faulty component I did all the search I could to find out what that faulty component is I can't find any information printed anywhere about it that probably was a lie well it it was probably a euphemistic right the test the test was not specific and uh it also um uh they had problems about the uh drug enforcement agency saying that it's gotta be more specific and accurate and a sign of thing as though it were something that were going to be marketed rather than something being used for an emergency oh brother uh the one of the problems is the team all the positions that handled the Ebola crisis uh in 2009 I think have been defunded because you know that was this terrible previous president so we don't want anything that he did so and we don't want to hear anything from scientists a great surge yeah a muscling scientist it's quite a dangerous thing so I hope people will speak out well on that cheerful note yeah okay it's very good uh I'm just going to throw in a couple of thoughts which is I uh I'm curious to see whether nanobots uh nanites will ever be developed for sort of micro robotic surgeries or interventions and also whether the use of I think already there's some things to this but whether virtual reality will play a role also in uh sort of medical devices and surgeries and visualizations and so forth I'm not quite sure what advantages virtual reality would bring um but it does seem like a way that perhaps you could uh uh maybe a finely control surgery a little tiny micro tools or something like that but I just wanted to mention nanobots and virtual reality um and I guess uh just we should just wrap this up quickly and I want to once again thank Chantal and Jess I want to thank my panelists um Robert and Steven for their preparation for this topic really appreciate the work you guys put into getting ready for these discussions and I also want to thank the science circle for hosting us and for of course all of our students who attend thank you all and have a great week thank you Bergen yeah thank you Steven and thanks for everyone for coming thank you Steven that was a very nice presentation I enjoyed it thank you