Podcasts about vlp

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David Liu is an gifted molecular biologist and chemist who has pioneered major refinements in how we are and will be doing genome editing in the future, validating the methods in multiple experimental models, and establishing multiple companies to accelerate their progress.The interview that follows here highlights why those refinements beyond the CRISPR Cas9 nuclease (used for sickle cell disease) are vital, how we can achieve better delivery of editing packages into cells, ethical dilemmas, and a future of somatic (body) cell genome editing that is in some ways is up to our imagination, because of its breadth, over the many years ahead. Recorded 29 November 2023 (knowing the FDA approval for sickle cell disease was imminent)Annotated with figures, external links to promote understanding, highlights in bold or italics, along with audio links (underlined)Eric Topol (00:11):Hello, this is Eric Topol with Ground Truths and I'm so thrilled to have David Liu with me today from the Broad Institute, Harvard, and an HHMI Investigator. David was here visiting at Scripps Research in the spring, gave an incredible talk which I'll put a link to. We're not going to try to go over all that stuff today, but what a time to be able to get to talk with you about what's happening, David. So welcome.David Liu (00:36):Thank you, and I'm honored to be here.Eric Topol (00:39):Well, the recent UK approval (November 16, 2023) of the first genome editing after all the years that you put into this, along with many other colleagues around the world, is pretty extraordinary. Maybe you can just give us a sense of that threshold that's crossed with the sickle cell and beta thalassemia also imminently [FDA approval granted for sickle-cell on 8 December 2023] likely to be getting that same approval here in the U.S.David Liu (01:05):Right? I mean, it is a huge moment for the field, for science, for medicine. And just to be clear and to give credit where credit is due, I had nothing to do with the discovery or development of CRISPR Cas9 as a therapeutic, which is what this initial gene editing CRISPR drug is. But of course, the field has built on the work of many scientists with respect to CRISPR Cas9, including Emmanuel Charpentier and Jennifer Doudna and George Church and Feng Zhang and many, many others. But it is, I think surprisingly rapid milestone in a long decade's old effort to begin to take some control over our genetic features by changing DNA sequences of our choosing into sequences that we believe will offer some therapeutic benefit. So this initial drug is the CRISPR Therapeutics /Vertex drug. Now we can say it's actually a drug approved drug, which is a Crispr Cas9 nuclease programmed to cut a DNA sequence that is involved in silencing fetal hemoglobin genes. And as you know, when you cut DNA, you primarily disrupt the sequence that you cut. And so if you disrupt the DNA sequence that is required for silencing your backup fetal hemoglobin genes, then they can reawaken and serve as a way to compensate for adult hemoglobin genes like the defective sickle cell alleles that sickle cell anemia patients have. And so that's the scientific basis of this initial drug.Eric Topol (03:12):So as you aptly put— frame this—this is an outgrowth of about a decade's work and it was using a somewhat constrained, rudimentary form of editing. And your work has taken this field considerably further with base and prime editing whereby you're not just making a double strand cut, you're doing nicks, and maybe you can help us understand this next phase where you have more ways you can intervene in the genome than was possible through the original Cas9 nucleases.David Liu (03:53):Right? So gene editing is actually a several decades old field. It just didn't quite become as popular as it is now until the discovery of CRISPR nucleases, which are just much easier to reprogram than the previous programmable zinc finger or tail nucleases, for example. So the first class of gene editing agents are all nuclease enzymes, meaning enzymes that take a piece of DNA chromosome and literally cut it breaking the DNA double helix and cutting the chromosome into two pieces. So when the cell sees that double strand DNA break, it responds by trying to get the broken ends of the chromosome back together. And we think that most of the time, maybe 90% of the time that end joining is perfect, it just regenerates the starting sequence. But if it regenerates the starting sequence perfectly and the nuclease is still around, then it can just cut the rejoin sequence again.(04:56):So this cycle of cutting and rejoining and cutting and rejoining continues over and over until the rejoining makes the mistake that changes the DNA sequence at the cut site because when those mistakes accumulate to a point that the nuclease no longer recognizes the altered sequence, then it's a dead end product. That's how you end up with these disrupted genes that result from cutting a target DNA sequence with a nuclease like Crispr Cas9. So Crispr Cas9 and other nucleases are very useful for disrupting genes, but one of their biggest downsides is in the cells that are most relevant to medicine, to human therapy like the cells that are in your body right now, you can't really control the sequence of DNA that comes out of this process when you cut a DNA double helix inside of a human cell and allow this cutting and rejoining process to take place over and over again until you get these mistakes.(06:03):Those mistakes are generally mixtures of insertions and deletions that we can't control. They are usually disruptive to a gene. So that can be very useful when you're trying to disrupt the function of a gene like the genes that are involved in silencing fetal hemoglobin. But if you want to precisely fix a mutation that causes a genetic disease and convert it, for example, back into a healthy DNA sequence, that's very hard to do in a patient using DNA cutting scissors because the scissors themselves of course don't include any information that allows you to control what sequence comes out of that repair process. You can add a DNA template to this cutting process in a process called HDR or Homology Directed Repair (figure below from the Wang and Doudna 10-year Science review), and sometimes that template will end up replacing the DNA sequence around the cut site. But unfortunately, we now know that that HDR process is very inefficient in most of the types of cells that are relevant for human therapy.(07:12):And that explains why if you look at the 50 plus nuclease gene editing clinical trials that are underway or have taken place, all but one use nucleases for gene disruption rather than for gene correction. And so that's really what inspired us to develop base editing in 2016 and then prime editing in 2019. These are methods that allow you to change a DNA sequence of your choosing into a different sequence of your choosing, where you get to specify the sequence that comes out of the editing process. And that means you can, for the first time in a general way, programmable change a DNA sequence, a mutation that causes a genetic disease, for example, into a healthy sequence back into the normal, the so-called wild type sequence, for example. So base editors work by actually performing chemistry on an individual DNA base, rearranging the atoms of that base to become a different base.(08:22):So base editors can efficiently and robustly change A's into G's G's, into A's T's into C's or C's into T's. Those four changes. And those four changes for interesting biochemical reasons turn out to be four of the most common ways that our DNA mutates to cause disease. So base editors can be used and have been used in animals and now in six clinical trials to treat a wide variety of diseases, high cholesterol and sickle cell disease, and T-cell leukemia for example. And then in prime editors we developed a few years later to try to address the types of changes in our genomes that caused genetic disease that can't be fixed with a base editor, for example. You can't use a base editor to efficiently and selectively change an A into a T. You can't use a base editor to perform an insertion of missing DNA letters like the three missing letters, CTT, that's the most common cause of cystic fibrosis accounting for maybe 70% of cystic fibrosis patients.(09:42):You can't use a base editor to insert missing DNA letters like the missing TATC. That is the most common cause of Tay-Sachs disease. So we develop prime editors as a third gene editing technology to complement nucleases and base editors. And prime editors work by yet another mechanism. They don't, again, they don't cut the DNA double helix, at least they don't cause that as the required mechanism of editing. They don't perform chemistry on an individual base. Instead, prime editors take a target DNA sequence and then write a new DNA sequence onto the end of one of the DNA strands and then sort of help the cell navigate the DNA repair processes to have that newly written DNA sequence replace the original DNA sequence. And in the process it's sort of true search and replace gene editing. So you can basically take any DNA sequence of up to now hundreds of base pairs and replace it with any other sequence of your choosing of up to hundreds of base pairs. And if you integrate prime editing with other enzymes like recombinase, you can actually perform whole gene integration of five or 10,000 base pairs, for example, this way. So prime editing's hallmark is really its versatility. And even though it's the newest of the three ways that have been robustly used to edit mammalian cells and rescue animal models of genetic disease, it is arguably the most versatile by far,Eric Topol (11:24):Right? Well, in fact, if you just go back to the sickle cell story as you laid out the Cas9 nuclease, that's now going into commercial approval in the UK and the US, it's more of a blunt instrument of disruption. It's indirect. It's not getting to the actual genomic defect, whereas you can do that now with these more refined tools, these new, and I think that's a very important step forward. And that is one part of some major contributions you've made. Of course, there are many. One of the things, of course, that's been a challenge in the field is delivery whereby we'd like to get this editing done in many parts of the body. And of course it's easy, perhaps I put that in quotes, easy when you're taking blood out and you're going to edit those cells and them put it back in. But when you want to edit the liver or the heart or the brain, it gets more challenging. Now, you did touch on one recent report, and this is of course the people with severe familial hypercholesterolemia. The carriers that have LDL cholesterol several hundred and often don't respond to even everything we have on the shelf today. And there were 10 people with this condition that was reported just a few weeks ago. So that's a big step forward.David Liu (13:09):That was also a very exciting milestone. So that clinical trial was led by scientists at Verve Therapeutics and Beam Therapeutics, and it was the first clinical readout of an in vivo base editing clinical trial. There was previously at the end of 2022, the first clinical readout of an ex vivo base editing clinical trial using CAR T cells, ex vivo  base edited to treat T-cell leukemia in pediatric patients in the UK. Ffigure from that NEJM paper below). But as you point out, there are only a small fraction of the full range of diseases that we'd like to treat with gene editing and the types of cells we'd like to edit that can be edited outside of the body and then transplanted back into the body. So-called ex vivo editing. Basically, you can do this with cells of some kind of blood lineage, hematopoietic stem cells, T-cells, and really not much else in terms of editing outside the body and then putting back into the body as you point out.(14:17):No one's going to do that with the brain or the heart anytime soon. So what was very exciting about the Verve Beam clinical trial is that Verve sought to disrupt the function of PCSK9 storied, gene validated by human genetics, because there are humans that naturally have mutations in PCSK9, and they tend to have much lower incidences of heart disease because their LDL, so-called bad cholesterol, is much lower than it would otherwise be without those mutations. So Verve set out to simply disrupt PCSK9 through gene editing. They didn't care whether they used a nuclease or a base editor. So they compared side-by-side the results of disrupting PCSK9 with Cas9 nuclease versus disrupting it by installing a precise single letter base edit using an adenine base editor. And they actually concluded that the base editor gave them higher efficacy and fewer unwanted consequences.(15:28):And so they went with the base editor. So the clinical trial that just read out were patients treated in New Zealand, in which they were given a lipid nanoparticle mRNA complex of an adenine base editor programmed with a guide RNA to install a specific A to G mutation in a splice site in PCSK9 that inactivates the gene so that it can no longer make functional PCSK9 protein. And the exciting result that read out was that in patients that receive this base editor, a single intravenous injection of the base editor lipid nanoparticle complex, as you know, lipid nanoparticles very efficiently go to the liver. In most cases, PCSK9 was edited in the liver and the result was substantial reduction in LDL cholesterol levels in these patients. And the hope and the anticipation is that that one-time treatment should be durable, should be more or less permanent in these patients. And I think while the patients who are at highest risk of coronary artery disease because of their genetics that give them absurdly high LDL cholesterol levels, that makes the most sense to go after those patients first because they are at extremely high risk of heart attacks and strokes. If the treatment proves to be efficacious and safe, then I think it's tempting to speculate that a larger and larger population of people who would benefit from having lower LDL cholesterol levels, which is probably most people, that they would also be candidates for this kind of therapy.Eric Topol (17:22):Yeah, no, it's actually pretty striking how that could be achieved. And I know in the primates that were done prior to the people in New Zealand, there was a very durable effect that went on well over I think a year or even two years. So yeah, that's right. Really promising. So now that gets us to a couple of things. One of them is the potential for off-target effects. As you've gotten more and more with these tools to be so precise, is the concern that you could have off-target effects just completely, of course inadvertent, but potential for other downstream in time known unknowns, if you will. What are your thoughts about that?David Liu (18:15):Yeah, I have many thoughts on this issue. It's very important the FDA and regulatory bodies are right to be very conservative about off-target editing because we anticipate those off targets will be permanent, those off-target edits will be permanent. And so we definitely have a responsibility to minimize adding to the mutational burden that all humans have as a function of existing on this planet, eating what we eat, being bombarded by cosmic rays and sunlight and everything else. But I think it's also important to put off-target editing into some context. One context is I think virtually every substance we've ever put into a person, including just about every medicine we've ever put into a person, has off-target effects, meaning modulates the function of biological molecules other than the intended target. Of course, the stakes are higher when those are gene editing agents because those modifications can be permanent.(19:18):I think most off-target edits are very likely to have no consequence because most of our genome, if you mutate in the kinds of small ways like making an individual base pair change for a base editor are likely to have no consequence. We sort of already know this because we can measure the mutational burden that we all face as a function of living and it's measurable, it's low, but measurable. I've read some papers that estimate that of the roughly 27 trillion [should be ~37] cells in an adult person, that there are billions and possibly hundreds of billions of mutations that accumulate every day in those 27 [37] trillion cells. So our genomes are not quite the static vaults that we'd like to think that they are. And of course, we have already purposefully given life extending medicines to patients that work primarily by randomly mutating their genomes. These are chemotherapeutic agents that we give to cancer patients.(20:24):So I think that history of giving chemotherapeutic agents, even though we know those agents will mess up the genomes of these patients and potentially cause cancer far later down the road, demonstrates that there are risk benefit situations where the calculus favors treatment, even if you know you are causing mutations in the genome, if the condition that the patient faces and their prognosis is sufficiently grave. All that said, as I mentioned, we don't want to add to the mutational burden of these patients in any clinically relevant way. So I think it is appropriate that the early gene editing clinical candidates that are in trials or approved now are undergoing lots and lots of scrutiny. Of course, doing an off-target analysis in an animal is of limited value because the animal's genome is quite different than the human genome. So the off targets won't align, but doing off-target analysis in human cells and then following up these patients for a long time to confirm hopefully that there isn't clinical evidence of quality of life or lifespan deterioration caused by off-target editing, that's all very, very important.(21:55):I also think that people may not fully appreciate that on target editing consequences also need to be examined and arguably examined with even more urgency than off-target edits. Because when you are cutting a chromosome at a target site with a nucleus, for example, you generate a complex mixture of different products of different DNA sequences that come out, and the more sequences you sequence, the more different products you realize are generated. And I don't think it's become routine to try to force the companies, the clinical groups that are running these trials to characterize the top 1000 on target products for their biological consequence. That would be sort of impractical to do and would probably slow down greatly the benefit of these early nuclease clinical trials for patients. But those are actually the products that are generated with much higher frequency typically than the off-target edits. And that's part of why I think it makes more sense from a clinical safety perspective to use more precise gene editing methods like base editing and prime editing where we know the products that are generated are mostly the products that we want are not uncontrolled mixtures of different deletion and insertion products.(23:27):So I think paying special attention to the on-target products, which are generated typically 70 to 100% of the time as opposed to the off targets which may be generated at a 0.1 to 1% level and usually not that many at that level once it reaches a clinical candidate. I think that's all important to do.Eric Topol (23:51):You've made a lot of great points there and thanks for putting that in perspective. Well, let's go on to the delivery issue. You mentioned nanoparticles, viral vectors, and then you've come up with small virus-like neutered viruses if you will. I think a company Nvelop that you've created to push on that potential. What are your thoughts about where we stand since you've become a force for coming up with much better editing, how about much better and more diverse delivery throughout the body? What are your thoughts about that?David Liu (24:37):Yeah, great. Great question. I think one of the legacies of gene editing is and will be that it inspired many more scientists to work hard on macromolecular delivery technologies. All of these gene editing agents are macromolecules, meaning they're proteins and or nucleic acids. None of them are small molecules that you can just pop a pill and swallow. So they all require special technologies to transfer the gene editing agent from outside of the cell into the cell. And the fact that taking control of our genetic features has become such a popular aspiration of medicine means that there's a lot of scientists as measured, most importantly by the young scientists, by the graduate students and the postdocs and the young professors of which I'm no longer one sadly, who have decided that they're going to devote a big part of their program to delivery. So you summarized many of the clinically relevant, clinically validated delivery technologies already, somewhat sadly, because if there were a hundred of these technologies, you probably wouldn't need to ask this question. But we have lipid nanoparticles that are particularly good at delivering messenger RNA, that was used to deliver the covid vaccine into billions of people. Now also used to deliver, for example, the adenine base editor mRNA into the livers of those hypercholesterolemia patients in the Verve/Beam clinical trial.(26:20):So those lipid nanoparticles are very well matched for gene editing delivery as long as it's liver. And they also are particularly well matched because their effect is transient. They cause a burst of gene editing agents to be produced in the liver and then they go away. The gene editing agents can't persist, they can't integrate into the genome despite what some conspiracy theorists might worry about. Not that you've had any encounter with any of those people. I'm sure that's actually what you want for a gene editing agent. You ideally want a delivery method that exposes the cell only for the shortest amount of time needed to make the on-target edit at the desired level. And then you want the gene editing agent to disappear and never come back because it shouldn't need to. DNA edits to our genome for durable cells should be permanent. So that's one method.(27:25):And then there are a variety of other methods that researchers have used to deliver to other cells, but they each carry some trade-offs. So if you're trying to edit hematopoietic stem cells, you can take them out of the body. Once they're out of the body, you have many more methods you can use to deliver efficiently into them. You can electroporated messenger, RNA or even ribonuclear proteins. You can treat with lipids or viruses, you can edit and then put them back into the body. But as you already mentioned, that's sort of a unique feature of blood cells that isn't applicable to the heart or the brain, for example, or the eyes. So then that brings us to viral vectors. There are a variety of clinically validated viral methods for delivery. AAV— adeno associated virus— is probably the most diverse, most relevant, and one of the best tolerated viral delivery methods. The beauty of AAV is that it can deliver to a variety of tissues. AAV can deliver into spinal cord neurons, for example, into retinal cells, into the heart, into the liver, into a few other tissues as well.(28:48):And that diversity of being able to choose AAV capsids that are known to get into the types of tissues that you're trying to target is a great strength of that approach. One of the downsides of AAV for gene editing agents is that their delivery tends to be fairly durable. You can engineer AAVs into next generation capsids that sort of get rid of themselves or the gene editing agents get rid of themselves. But classic AAV tends to stay around in patients for a long time, at least months, for example, and possibly years. And we also don't yet have a good way, clinically validated way of re-dosing AAV. And once you administer high doses of AAV in a patient that tends to provoke high-titer, neutralizing antibodies against those AAVs making it difficult to then come back six months or a year later and dose again with an AAV.(29:57):So researchers are on the bright side, have become very good at engineering and evolving in the laboratory next generation AAVs that can go to greater diversity issues that can be more potent. Potency is important because if you can back off the dose, maybe you can get around some of these immunogenicity issues. And I think we will see a renaissance with AAV that will further broaden its clinical scope. Even though I appreciate that the decisions by a couple large pharma companies to sort of pull out of using AAV for gene therapy seemed to cause people to, I think prematurely conclude that AAV has fallen out of favor. I think for gene therapy, it's quite different than gene editing. Gene therapy, meaning you are delivering a healthy copy of the gene, and you need to keep that healthy copy of the gene in the patient for the rest of the patient's life.(30:59):That's quite different than gene editing where you just need the edit to take place over days to weeks, and then you want the editing agent to actually go away and you never want to come back. I think AAV will used to deliver gene editing agents will avoid some of the clinical challenges like how do we redose? Because you shouldn't need to redose if the gene editing clinical trial proceeds as you hope. And then you mentioned these virus-like particles. So we became interested in virus-like particles as other labs have because they offer some of the best strengths of non-viral and viral approaches like non-viral approaches such as LMPs. They deliver the transient form of a gene editing agent. In fact, they can deliver the fully assembled protein RNA complex of a base editor or a prime editor or a CRISPR nuclease. So in its final form, and that means the exposure of the cell to the editing agent is minimized.(32:15):You can treat with these virus-like particles, deliver the protein form of these gene editing agents, allow the on-target site to get edited. And then since the half-life of these proteins tends to be very small, roughly 24 hours for example, by a week later, there should be very little of the material left in the animal or prospectively in the patient virus-like particles, as you call them, neutered viruses, they lack viral DNA or RNA. They don't have the ability to integrate a virus's genome into the human genome, which can cause some undesired consequences. They don't randomly introduce DNA into our genomes, therefore, and they disappear more transiently than viruses like AAV or adenoviruses or other kinds of lentiviruses that have been used in the clinic. So these virus-like particles or VLP offer really some of the best strengths on paper at least of both viral and non-viral delivery.(33:30):Their limitation thus far has been that there really haven't been examples of potent in vivo delivery of cargoes like gene editing agents using virus-like particles. And so we recently set out to figure out why, and we identified several bottlenecks, molecular bottlenecks that seemed to be standing in the way of virus-like particles, doing a much more efficient job at delivering inside of an animal. (Figure from that paper below.) And we engineered solutions to each of these first three molecular bottlenecks, and we've identified a couple more since. And that resulted in what we call VLPs engineered virus-like particles. And as you pointed out, Keith Joung and myself, co-founded a company called Nvelop to try to bring these technologies and other kinds of molecular delivery technologies, next generation delivery technologies to patients.Eric Topol (34:28):Well, that gets me to the near wrapping up, and that is the almost imagination you could use about where all this can go in the future. Recently, I spoke to a mutual friend Fyodor Urnov, who talked about wouldn't it be amazing if for people with chronic pain you could just genome edit neurons their spinal cord? As you already touched on recently, Jennifer Doudna, who we both know talked about editing to prevent Alzheimer's disease. Well, that may be a little far off in time, but at least people are talking about these things that is not, we're not talking about germline editing, we're just talking about somatic cell and being able to approach conditions that have previously been either unapproachable or of limited success and potential of curing. So this field continues to evolve and you and all your colleagues are a big part of how this has evolved as quickly as it has. What are your thoughts about, are there any bounds to the potential in the longer term for genome editing? Right.David Liu (35:42):It's a great question because all of the early uses of gene editing in people are appropriately focused on people who are at dire risk of having shorter lives or very poor quality of life as it should be for a new kind of therapeutic because the risks are high until we continue to validate the clinical benefit of these gene editing treatments. And therefore we want to choose patients the highest that face the poorest prognosis where the risk benefit ratio favors treatment as strongly as possible. But your question, I think very accurately highlights that our genome and changes to it determine far more than whether you have a serious genetic disorder like Sickle Cell Disease or Progeria or Cystic Fibrosis or Familial Hypercholesterolemia or Tay-Sachs disease. And being able to not just correct mutations that are associated with devastating genetic disorders, but perhaps take control of our genomes in more sophisticated way that you pointed out two examples that I think are very thought provoking to treat chronic pain permanently to lower the risk of horrible diseases that affect so many families devastating to economies worldwide as well, like Alzheimer's disease, Parkinson's disease, the genetic risk factors that are the strongest genetic determinants of diseases like Alzheimer's disease are actually, there are several that are known already.(37:36):And an interesting possibility for the future, it isn't going to happen in the next few years, but it might happen within the next 10 or 20 years, might be to use gene editing to precisely change some of those most grievous alleles that are risk factors for Alzheimer's disease like a apoE4, to change them to the genetic forms that have normal or even reduced risk for Alzheimer's disease. That's a very tough clinical trial to run, but I'd say not any tougher than the dozens of most predominantly failed Alzheimer's clinical trials that have probably collectively accounted for hundreds of billions of dollars of investmentEric Topol (38:28):Easily.David Liu (38:31):And all of that speaks to the fact that Alzheimer's disease, for example, is enormous burden on society by every measure. So it's worth investing and major resources and taking major risks to try to create perhaps preventative treatments that just lower our risk globally. Getting there will require that these pioneering early clinical trials for gene editing are smashing successes. I'm optimistic that they will be, there will be bumps in the road because there always are bumps in the road. There will be patients who have downturns in their health and everyone will wonder whether those patients had a downturn because of a gene editing treatment they received. And ascertaining whether that's the case will be very important. But as these trials continue to progress, and as they continue hopefully on this quite positive trajectory to date, it's tempting to imagine a future where we can use precise gene editing methods. For example, you can install a variety using prime editing, a variety of alleles that naturally occur in people that reduce the risk of Alzheimer's disease or Parkinson's disease like the mutation that 0.1% of Icelandic people and almost nobody else has in amyloid precursor protein changing alanine 673 to threonine (A673T).(40:09):It is very thought provoking, and I don't think society is ready now to take that step, but I think if things continue to proceed on this promising trajectory, it's inevitable because arguably, the defining trait of our species is that we use every ounce of our talents and our gifts and our resources and our creativity to try to improve our lives and those of our children. And I don't think if we have ways of treating genetic diseases or even of reducing grievous genetic disease risk, that we will be able to sit on our hands and not take steps towards that kind of future solon as those technologies continue to be validated in the clinic as being safe and efficacious. It's, I teach a gene editing class and I walk them through a slippery slope at the end of five ethics cases, starting with progeria, where most people would say having a single C of T mutation in one gene that you, by definition didn't inherit from mom or dad.(41:17):It just happened spontaneously. That gives you an average lifespan of 14 and a half years and strongly affects other aspects of the quality of your life and your family's life that if you can change as we did in animals that T back into a C and correct the disease and rescue many of the phenotypes and extend lifespan, that that's an ethical use of gene editing. Treating genetic deafness is the second case. It's a little bit more complicated because many people in the deaf community don't view deafness as a disability. It's at least a more subjective situation than progeria. But then there are other cases like changing apoE4 to apoE3 or even apoE2 with the lower than normal risk of Alzheimer's disease, or installing that Icelandic mutation and amyloid precursor protein that substantially lowers risk of Alzheimer's disease. And then finally, you can, I always provoke a healthy debate in the class at the end by pointing out that in the 1960s, one of the long distance cross country alpine skiing records was set by a man who had a naturally occurring mutation in his EPO receptor, his erythropoietin receptor, so that his body always thought he was on EPO as if he were dosing on EPO, although that was of course before the era of EPO dosing was really possible, but it was just a naturally occurring mutation in this case, in his family.(42:48):And when I first started teaching this class, most students could accept using gene editing to treat progeria, but very few were willing to go even past that, even to genetic deafness, certainly not to changing a ApoE risk factors for Alzheimer's. Nowadays, I'd say the 50% vote point is somewhere between case three and case four, most people are actually say, yeah, especially since they have family members who've been through Alzheimer's disease. If they are a apoE4, some of them are a apoE4/apoE4 [homozygotes], why not change that to a apoE3 or even an ApoE2 or as one student challenged the class this year, if you were born with a apoE2, would you want to change it to a ApoE3 so you could be more normal? Most people would say, no, there's no way I would do that.(43:49):And for the first time this year, there were one or two students who actually even defended the idea of putting in a mutation in erythropoietin receptor to increased increase their endurance under low oxygen conditions. Of course, it's also presumably useful if you ever, God forbid, are treated with a cancer chemotherapeutic. Normally you get erythropoietin to try to restore some, treat some of the anemia that can result, and this student was making a case, well, why wouldn't we? If this is a naturally occurring mutation that's been shown to benefit certain people doing certain things. I don't think that's a general societal view. And I am a little bit skeptical we'll ever get widespread acceptance of case number five. But I think all of it is healthy stimulates a healthy discussion around the surprisingly gentle continuum between disease treatment, disease prevention, and what some would call human improvement.And it used to be that even the word human improvement was sort of an anathema. I think now at least the students in my class are starting to rethink what does that really mean? We improving ourselves a number of ways genetically and otherwise by virtue of our lifestyles, by virtue of who we choose to procreate with. So it's a really interesting debate, and I think the rapid development and now clinical progression and now approval, regulatory approval of gene editing drugs will play a central role in this discussion.Eric Topol (45:38):No question. I mean, also just to touch on the switch from a apoE4 to apoE2, you would get a potential 2-fer of lesser risk for Alzheimer's and a longer lifespan. So I mean, there's a lot of things here. The thing that got me years ago, I mean, this is many years ago at a meeting with George Church and he says, we're going to just edit 60 genes and then we can do all sorts of xeno-pig transplants and forget the problem of donors. And it's happening now.David Liu (46:11):Yeah, I mean, he used a base editor to edit hundreds of genes at once, if not thousands ofEric Topol (46:16):That's why it's just, yeah, no, it's just extraordinary. And I think people need to be aware that opportunities here, as you say, with potential bumps along the way, unquestionably, is almost limitless. So this has been a masterclass thanks to you, David, in where we are, where we're headed in genome editing at a very extraordinary time where we've really seeing things click. And I just want to also add that you're going to be here with a conference in La Jolla in January, I think, on base and prime editing. Is that right? So for those who are listeners who are into this topic, maybe they can also hear the latest, I'm sure there'll be more between now and next. Well, several weeks from now at your, it's aDavid Liu (47:12):Conference on, it's the fifth international conference on base and prime editing and associated enzymes, the somewhat baroque name. And I will at least be giving a virtual talk there. It actually overlaps with the talk I'm giving at Rockefeller that time. Ah, okay, cool. But I'm speaking at the conference either in person or virtually.Eric Topol (47:34):Yeah. Well, anytime we get to hear from you and the field, of course it's enlightening. So thanks so much for joining. Thank youDavid Liu (47:42):For having me. And thank you also for all of your, I think, really important public service in connecting appropriately the ground truths about science and vaccines and other things to people. I think that's very much appreciated by scientists like myself.Eric Topol (48:00):Oh, thanks David.Thanks for listening, reading, and subscribing to Ground Truths. To be clear, this is a hybrid format, roughly alternating between analytical newsletters/essays and podcasts with exceptional people, attempting to achieve about 2 posts per week. It's all related to cutting-edge advances in life science, medicine, and information tech (A.I.)All content is free. If you wish to become a paid subscriber know that all proceeds go to Scripps Research. Get full access to Ground Truths at erictopol.substack.com/subscribe

After the training, attendees will walk away with a general understanding of the eviction process in Massachusetts and specifically what defenses and resources are available to tenants to prevent or win an eviction case. Program participants will gain enough knowledge to begin volunteering with VLP's housing unit.    Questions? Inquiries about program materials? Contact Trenon Browne at tbrowne@bostonbar.org

This live webinar training will provide a basic overview of how to assist and represent low-income, owner-occupant landlords, many of whom have been financially impacted by the pandemic. It will provide information on why this underserved population needs assistance and how to help by volunteering with Volunteer Lawyer's Project's Landlord Advocacy Program. Law students and attorneys are encouraged to attend this training and volunteer with VLP.   Why we advocate for low-income landlords: To keep legal system even-handed, low-income landlords need access to free legal advice too Advocating for small, low-income landlords helps keep the rental market affordable and stable Mom-and-pop landlord demographic is vulnerable – typically elderly, non-native English speakers who survive on pensions and moderately priced rental income to pay bills, maintain properties, and keep mortgages up to date Owner-occupant landlords live in the property they rent out, so their tenants are also their neighbors; these circumstances can create unique challenges Questions? Inquiries about program materials? Contact Trenon Browne at tbrowne@bostonbar.org  

Watch here - https://youtu.be/kHQsH-LFkLkThe Legendary Mike Pachan is back for a visit!Mike is a long time friend, and has been a guest on this show since the beginning!The boys sit down and discuss, the current state of the world, climate change, self reliance, farming, VLP's, modern medicine, owning it, and tons more!!!!Strap in for an awesome discussion!Support the show

Lucky Girl Syndrome? How about CONSCIOUSLY LUCKY WOMAN?!Welcome to 2023 Self-Help Songwriter season, I'm kicking things off with a new series!! Breaking down what I learn from the Self-Help books I'm reading and/or listening to. "Conscious Luck" by Gay Hendricks and Carol Kline lays out "8 secrets to intentionally change your fortune." They are:Commit to being a VLP (very lucky person)Release your personal barriers Become a magnet for abundance Have luck worthy goalsTake consistent, bold action.Find your lucky tribeLearn the right place and the right time. Practice radical gratitudeLET'S DISCUSS!!Support the showMy WebsiteSpotify & other SpotifyInstagramMusic YoutubeFacebookWork with meSongwriting coachingCelebration Songs Free ResourcesCome to my next free monthly Zoom concert!Get my Free songwriting Worksheet!

Hoy en Elprimerfichaje de CLM Activa hablamos del MUNDIAL QATAR 2022 con Javi Ruiz siguiendo con la Segunda División con nuestro Albacete Balompié S.A.D con Luis Navarro , 1° y 2° Real Federación Española de Fútbol con el director Jesús Vlp , la #SUPERTERCERAG18 con Javi Ruiz y Futbol Juvenil de la Federación de Fútbol de Castilla-La Mancha con Luis Miguel Vicario Sánchez

In celebration of National Veterans & Military Families Month, Comcast has awarded $75,000 in grants and 100 laptops to Veterans Leadership Program. VLP is a non-profit that assists veterans with housing, career development, wellness and supportive services. Carol Eggert, Senior Vice President of Military and Veteran Affairs at Comcast NBCUniversal, steps up to the One Mic Stand to detail the importance of helping veterans through this program. Eggert leads a team that works collaboratively across Comcast NBCUniversal to provide strategic leadership to all aspects of programs and outreach engaging the military and veteran community, including recruiting, hiring and building talent at all levels of the organization. VLP clients may be eligible for the federal government's Affordable Connectivity Program (ACP), which provides eligible low-income households with a credit up to $30 per month toward their Internet and/or mobile service. Thanks to ACP, eligible Comcast customers can get home Internet through Comcast's Internet Essentials or Internet Essentials Plus at no cost once the federal credit is applied.

Hoy en Elprimerfichaje de CLM Activa hablamos de todas las crónicas de la jornada en LaLiga siguiendo con la Segunda División con nuestro Albacete Balompié S.A.D con Luis Navarro , 1° y 2° Real Federación Española de Fútbol con el director Jesús Vlp , la #SUPERTERCERAG18 con Javi Ruiz y Futbol Juvenil de la Federación de Fútbol de Castilla-La Mancha con Luis Miguel Vicario Sánchez

Más de 80 gestores de voluntarios y voluntarias de más de 60 países se reúnen en El Tiemblo (Ávila) para asistir al Programa de Aprendizaje sobre el Voluntariado. En ‘Ahora' queremos conocer sus experiencias. Hay aproximadamente 17 millones de voluntarios y voluntarias as en todo el mundo en Cruz Roja y la Media Luna Roja. En Cruz Roja Española son más de 250.000 voluntarios y voluntarias.

Hoy en el Elprimerfichaje de CLM Activa hablamos de la previa del Albacete Balompié S.A.D con Luis Navarro de la previa de 1° y 2° Real Federación Española de Fútbol CON EL director Jesús Vlp de la #SUPERTERCERAG18 de la Federación de Fútbol de Castilla-La Mancha con Javi Ruiz , de la selección de Futbol Sala y Futsal femenino con Munitis Parras Sanchez , del fútbol Juvenil con Luis Miguel Vicario Sánchez y la previa de LaLiga Presenta Fran Javier Petit Rodriguez Galvez

Hoy en el Elprimerfichaje de CLM Activa hablamos de la previa del Albacete Balompié S.A.D con Luis Navarro de la previa de 1° y 2° Real Federación Española de Fútbol CON EL director Jesús Vlp de la #SUPERTERCERAG18 de la Federación de Fútbol de Castilla-La Mancha con Javi Ruiz , de la selección de Futbol Sala y Futsal femenino con Munitis Parras Sanchez , del fútbol Juvenil con Luis Miguel Vicario Sánchez y la previa de LaLiga Presenta Fran Javier Petit Rodriguez Galvez

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.19.512957v1?rss=1 Authors: Jiu, Y., Zhang, Y., Zhang, X., Li, Z., Yang, H., Tang, D., Zhao, S., Zhang, Q., Li, B., Lappalainen, P., Cui, Z., Liu, H., Li, H., Zhao, W. Abstract: Emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a great threat to human health and economics. Although SARS-CoV-2 entry mechanism has been explored, little is known about how SARS-CoV-2 regulates the host cell remodeling to facilitate virus invasion process. Here we unveil that SARS-CoV-2 boosts and repurposes filopodia for entry to the target cells. Using SARS-CoV-2 virus-like particle (VLP), real-time live-cell imaging and simulation of active gel model, we reveal that VLP-induced Cdc42 activation leads to the formation of filopodia, which reinforce the viral entry to host cells. By single-particle tracking and sparse deconvolution algorithm, we uncover that VLP particles utilize filopodia to reach the entry site in two patterns, surfing and grabbing, which are more efficient and faster than entry via flat plasma membrane regions. Furthermore, the entry process via filopodia is dependent on the actin cytoskeleton and actin-associated proteins fascin, formin, and Arp2/3. Importantly, either inhibition the actin cross-linking protein fascin or the active level of Cdc42 could significantly hinders both the VLP and the authentic SARS-CoV-2 entry. Together, our results highlight that the spatial-temporal regulation of the actin cytoskeleton by SARS-CoV-2 infection makes filopodia as a highway for virus entry, which emerges as an antiviral target. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Hoy en el Elprimerfichaje de CLM Activa hablamos de la previa del Albacete Balompié S.A.D con Luis Navarro de la previa de 1° y 2° Real Federación Española de Fútbol CON EL director Jesús Vlp de la #SUPERTERCERAG18 de la Federación de Fútbol de Castilla-La Mancha con Javi Ruiz , de la selección de Futbol Sala y Futsal femenino con Munitis Parras Sanchez , del fútbol Juvenil con Luis Miguel Vicario Sánchez y la previa de LaLiga Presenta Fran Javier Petit Rodriguez Galvez

durée : 00:35:00 - Les Nuits de France Culture - par : Philippe Garbit - "Entre chien et loup, les graffitistes", une série de quatre émissions pour comprendre l'origine, le sens, les techniques, les risques et les joies de l'Art urbain, au fond des catacombes ou sur les bords du canal de l'Ourcq. Premier volet avec Didier Moulin, Jérôme Mesnager et le collectif VLP. - invités : Jérôme Mesnager peintre, artiste de rue, ébéniste

Vision-Language Pre-training (VLP) has advanced the performance for many vision-language tasks. However, most existing pre-trained models only excel in either understanding-based tasks or generation-based tasks. Furthermore, performance improvement has been largely achieved by scaling up the dataset with noisy image-text pairs collected from the web, which is a suboptimal source of supervision. In this paper, we propose BLIP, a new VLP framework which transfers flexibly to both vision-language understanding and generation tasks. 2022: Junnan Li, Dongxu Li, Caiming Xiong, S. Hoi Ranked #1 on Image Captioning on nocaps-val-out-domain https://arxiv.org/pdf/2201.12086v2.pdf

#blip #review #ai Cross-modal pre-training has been all the rage lately in deep learning, especially training vision and language models together. However, there are a number of issues, such as low quality datasets that limit the performance of any model trained on it, and also the fact that pure contrastive pre-training cannot be easily fine-tuned for most downstream tasks. BLIP unifies different tasks and objectives in a single pre-training run and achieves a much more versatile model, which the paper immediately uses to create, filter, clean and thus bootstrap its own dataset to improve performance even more! Sponsor: Zeta Alpha https://zeta-alpha.com Use code YANNIC for 20% off! OUTLINE: 0:00 - Intro 0:50 - Sponsor: Zeta Alpha 3:40 - Paper Overview 6:40 - Vision-Language Pre-Training 11:15 - Contributions of the paper 14:30 - Model architecture: many parts for many tasks 19:50 - How data flows in the model 26:50 - Parameter sharing between the modules 29:45 - Captioning & Filtering bootstrapping 41:10 - Fine-tuning the model for downstream tasks Paper: https://arxiv.org/abs/2201.12086 Code: https://github.com/salesforce/BLIP Demo: https://huggingface.co/spaces/Salesfo... Abstract: Vision-Language Pre-training (VLP) has advanced the performance for many vision-language tasks. However, most existing pre-trained models only excel in either understanding-based tasks or generation-based tasks. Furthermore, performance improvement has been largely achieved by scaling up the dataset with noisy image-text pairs collected from the web, which is a suboptimal source of supervision. In this paper, we propose BLIP, a new VLP framework which transfers flexibly to both vision-language understanding and generation tasks. BLIP effectively utilizes the noisy web data by bootstrapping the captions, where a captioner generates synthetic captions and a filter removes the noisy ones. We achieve state-of-the-art results on a wide range of vision-language tasks, such as image-text retrieval (+2.7% in average recall@1), image captioning (+2.8% in CIDEr), and VQA (+1.6% in VQA score). BLIP also demonstrates strong generalization ability when directly transferred to video-language tasks in a zero-shot manner. Code, models, and datasets are released at this https URL. Authors: Junnan Li, Dongxu Li, Caiming Xiong, Steven Hoi Links: TabNine Code Completion (Referral): http://bit.ly/tabnine-yannick YouTube: https://www.youtube.com/c/yannickilcher Twitter: https://twitter.com/ykilcher Discord: https://discord.gg/4H8xxDF BitChute: https://www.bitchute.com/channel/yann... LinkedIn: https://www.linkedin.com/in/ykilcher BiliBili: https://space.bilibili.com/2017636191 If you want to support me, the best thing to do is to share out the content :) If you want to support me financially (completely optional and voluntary, but a lot of people have asked for this): SubscribeStar: https://www.subscribestar.com/yannick... Patreon: https://www.patreon.com/yannickilcher Bitcoin (BTC): bc1q49lsw3q325tr58ygf8sudx2dqfguclvngvy2cq Ethereum (ETH): 0x7ad3513E3B8f66799f507Aa7874b1B0eBC7F85e2 Litecoin (LTC): LQW2TRyKYetVC8WjFkhpPhtpbDM4Vw7r9m Monero (XMR): 4ACL8AGrEo5hAir8A9CeVrW8pEauWvnp1WnSDZxW7tziCDLhZAGsgzhRQABDnFy8yuM9fWJDviJPHKRjV4FWt19CJZN9D4n

#blip #interview #salesforce Paper Review Video: https://youtu.be/X2k7n4FuI7c Sponsor: Assembly AI https://www.assemblyai.com/?utm_sourc... This is an interview with Junnan Li and Dongxu Li, authors of BLIP and members of Salesforce research. Cross-modal pre-training has been all the rage lately in deep learning, especially training vision and language models together. However, there are a number of issues, such as low quality datasets that limit the performance of any model trained on it, and also the fact that pure contrastive pre-training cannot be easily fine-tuned for most downstream tasks. BLIP unifies different tasks and objectives in a single pre-training run and achieves a much more versatile model, which the paper immediately uses to create, filter, clean and thus bootstrap its own dataset to improve performance even more! OUTLINE: 0:00 - Intro 0:40 - Sponsor: Assembly AI 1:30 - Start of Interview 2:30 - What's the pitch? 4:40 - How did data bootstrapping come into the project? 7:10 - How big of a problem is data quality? 11:10 - Are the captioning & filtering models biased towards COCO data? 14:40 - Could the data bootstrapping be done multiple times? 16:20 - What was the evolution of the BLIP architecture? 21:15 - Are there additional benefits to adding language modelling? 23:50 - Can we imagine a modular future for pre-training? 29:45 - Diving into the experimental results 42:40 - What did and did not work out during the research? 45:00 - How is research life at Salesforce? 46:45 - Where do we go from here? Paper: https://arxiv.org/abs/2201.12086 Code: https://github.com/salesforce/BLIP Demo: https://huggingface.co/spaces/Salesfo... Abstract: Vision-Language Pre-training (VLP) has advanced the performance for many vision-language tasks. However, most existing pre-trained models only excel in either understanding-based tasks or generation-based tasks. Furthermore, performance improvement has been largely achieved by scaling up the dataset with noisy image-text pairs collected from the web, which is a suboptimal source of supervision. In this paper, we propose BLIP, a new VLP framework which transfers flexibly to both vision-language understanding and generation tasks. BLIP effectively utilizes the noisy web data by bootstrapping the captions, where a captioner generates synthetic captions and a filter removes the noisy ones. We achieve state-of-the-art results on a wide range of vision-language tasks, such as image-text retrieval (+2.7% in average recall@1), image captioning (+2.8% in CIDEr), and VQA (+1.6% in VQA score). BLIP also demonstrates strong generalization ability when directly transferred to video-language tasks in a zero-shot manner. Code, models, and datasets are released at this https URL. Authors: Junnan Li, Dongxu Li, Caiming Xiong, Steven Hoi Links: TabNine Code Completion (Referral): http://bit.ly/tabnine-yannick YouTube: https://www.youtube.com/c/yannickilcher Twitter: https://twitter.com/ykilcher Discord: https://discord.gg/4H8xxDF BitChute: https://www.bitchute.com/channel/yann... LinkedIn: https://www.linkedin.com/in/ykilcher BiliBili: https://space.bilibili.com/2017636191 If you want to support me, the best thing to do is to share out the content :) If you want to support me financially (completely optional and voluntary, but a lot of people have asked for this): SubscribeStar: https://www.subscribestar.com/yannick... Patreon: https://www.patreon.com/yannickilcher Bitcoin (BTC): bc1q49lsw3q325tr58ygf8sudx2dqfguclvngvy2cq Ethereum (ETH): 0x7ad3513E3B8f66799f507Aa7874b1B0eBC7F85e2

Javier Vázquez, especialista en desarrollo sostenible y cambio climático, con Nico Yacoy en VLP! 17/FEB/2022

Facundo Del Gaiso, diputado por la Ciudad de Buenos Aires, con Nico Yacoy en VLP! 17/FEB/2022

Javier Aguirre, corresponsal en Corrientes, con Nico Yacoy en VLP! 15/FEB/2022

Agustín Suárez , Subsecretario de Ciudad Inteligente en CABA, con Nico Yacoy en VLP! 15/FEB/2022

Miguel Ponce, coordinador de la Comisión de Economía - Convención Nacional UCR, con Nico Yacoy en VLP! 08/FEB/2022

Juan Battaleme, secretario Académico del CARIy profesor RRII ,con Nico Yacoy en VLP! 04/FEB/2022

En este SEGUNDO episodio de HISTORIA DEL RAP MEXICANO hablamos del crecimiento y popularización del rap en México en los años 90, de grupos como Speed Fire, VLP, Molotov y por su puesto Control Machete.

Claudio Izaguirre, presidente de Asociación Antidroga, con Nico Yacoy en VLP! 04/FEB/2022

Marta Cohen, patóloga, con Nico Yacoy en VLP! 04/FEB/2022

Patricio Giusto, consultor político, con Nico Yacoy en VLP! 03/FEB/2022

Sandra Pitta, Ex-Candidata a Diputada Nacional, Farmacéutica/Biotecnóloga, con Nico Yacoy en VLP! 03/FEB/2022

Ezequiel Kopel, experto en Medio Oriente y Autor de "Medio Oriente, Lugar Común”, con Nico Yacoy en VLP! 03/FEB/2022

Alejandro Fargosi, ex consejero de la Magistratura, en VLP! con Nico Yacoy 31/ENE/2021

José Dapena, economista, en VLP! con Nico Yacoy 31/ENE/2021

In this episode, Sam talks with Leif Karlstrom about his work combining geophysical signals (from geysers and volcanoes) with visualization and sonification, inspired by his background as a musician. Who knew that the Earth made such amazing music?! Dr. Leif Karlstrom (he/him), University of Oregon, is an associate professor in the Department of Earth Sciences. He studies fluid motions in and on volcanoes, landscape evolution, glaciology, and geodynamics. Leif also has an active professional music career as a classically trained violinist. Personal website: https://pages.uoregon.edu/leif/ , VLP site: https://volcanolisteningproject.org/ , twitter handle: @VolcanoListener

Fabián Balazs, periodista de El Bolsón, con Nico Yacoy en VLP! 31/DIC/2021

Ignacio Carballo, economista especialista en Fintech y bancos digitales, con Nico Yacoy en VLP! 31/DIC/2021

Arnaldo Casiró, jefe de infectología del hospital Álvarez, con Nico Yacoy en VLP! 30/DIC/2021

David Miazzo, economista jefe de FADA, con Nico Yacoy en VLP! 30/DIC/2021

Diego Reynoso, director de la encuesta de satisfacción política y opinión pública de la Universidad de San Andres, con Nico Yacoy en VLP! 30/DIC/2021

Ramiro Marra, legislador porteño, con Nico Yacoy en VLP! 30/DIC/2021

Ramiro Heredia, médico del Hospital de Clínicas, con Nico Yacoy en VLP! 31/DIC/2021

José Rozados, presidente de Reporte Inmobiliario, con Nico Yacoy en VLP! 31/DIC/2021

Carlos Di Pietrantonio, ex director del Hospital Posadas, con Nico Yacoy en VLP! 29/DIC/2021

Silvana Alonso, abogada especialista en derecho del consumidor, con Nico Yacoy en VLP! 29/DIC/2021

Maricel Etchecoin, diputada de la provincia de Buenos Aires por Juntos, con Nico Yacoy en VLP! 29/DIC/2021

Learn 5  Business Growth StrategiesScale By Numbers PodcastOn our kickoff episode of the ‘Scale by Numbers' podcast, David discusses common founder issues and the legal complexities of becoming a scaling and successful business founder. He tells the story of how he has grown as a corporate attorney in San Francisco and why he loves going to bat for his clients.  VLP Law Group specializes in helping businesses close deals and getting investors to invest in companies. Without a clean back story, “you will make it easier for investors to say no.”  He shares tips on a few common founder questions and always recommends that founders gain support from a corporate attorney rather than turning to google for help! WHO IS OUR GUEST: David Goldenberg is a corporate attorney and founding partner of VLP law groupHOW TO REACH DAVID : Website |  LinkedInHOW CAN A CORPROATE ATTORNEY HELP YOU SCALE: David has built a practice at VLP which allows him to represent clients using a team approach where clients receive his direct attention on critical matters while still maintaining an efficient service for more everyday items.  VLP Law Group is a founder-friendly group whose main goal “is to parachute in, to learn very quickly what it is that that's your priority.” David says. He gives clients the personalized insight they need to make crucial decisions, and advocate for them to achieve their goals.  David's twenty-plus years of working with 500 companies have taught him to pinpoint the risks instantly and protect his clients from those risks.  “You don't know what you don't know,” and Clients don't see the 20 years of filter that he has when putting together contracts, term sheets, and stock option agreements. People choose David for his team with billion-dollar deal experience and focus on practical legal solutions.WHAT'S VLP's SPECIALITY: VLP law group helps companies of all sizes raise capital and general business matters.  They also assist with exit transactions, whether that's a merger or acquisition. They work on things like setting up a new company, joint ventures, equity investments, website, privacy policy, terms of service, significant customer agreements and selling your company at the end.SHOULD YOU GO IT ALONE:  If you are not good with paperwork and don't like detail, it's best to hire an attorney to do it for you.  When you are trying to raise money, investors will say no to you if they don't understand the backstory.  It's easier to start from the back and move forward than the other way around.  ATTORNEYS ARE NOT MIND READERS: David states it's vital to set clear goals and objectives for your corporate attorney so they can focus on adding value in the right ways.  Always remember, as a founder, it's your company, not the attorney's company.  Your attorney will do what you need based on the priorities.  Like any service provider, attorneys are not mind readers–you have to set clear expectations about your main priorities and concerns.  IS GOOGLE A GOOD SOURCE FOR HELP: There's a lot of information out there, and David understands that people with zero legal background and smaller budgets need help. It's okay to look for help, but If you don't know what you are looking for or are running into problems, that is when you need to call for legal backup.  Remember, the sooner you get help for an issue, or new business decision  the less money you must spend in the future fixing it.  It is best to keep your business free of skeletons.

It’s been a year since we last spoke with our vaccine expert, Dr. Peter Khoury. We discuss the different types of vaccines available, if there is a best one to take, if there are side effects or dangers to be worried about, and whether or not Covid 19 will be here for the long run. Dr. Peter Khoury, is the President and CEO of Ology Bioservices Inc. He is an expert on vaccines and biologics and during his 30-year career, he has worked for the Bill & Melinda Gates Foundation, Merck, and Baxter International. Dr. Khoury has involved in international forums on vaccines, pandemic planning, and biodefense preparation, including working with the Olympic Committee. TRANSCRIPT: Intro: 0:01 Inventors and their inventions. Welcome to Radio Cade and podcast from the Cade Museum for Creativity and Invention in Gainesville, Florida, the museum is named after James Robert Cade, who invented Gatorade in 1965. My name is Richard Miles. We’ll introduce you to inventors and the things that motivate them, we’ll learn about their personal stories, how their inventions work and how their ideas get from the laboratory to the marketplace. James Di Virgilio: 0:39 Welcome to Radio Cade . I’m your host, James Di Virgilio. And today we are bringing you a special episode. It is part two of the, everything you need to know about vaccinations and COVID-19, it’s been almost a year since I last spoke with Dr. Peter Khoury, you can catch that episode anywhere you listen to this podcast. Dr. Peter Khoury is the president and CEO of Ology, Bioservices, he’s an expert on vaccines and biologics. And during his 30 year career, he’s worked for the Bill and Melinda Gates foundation, Merck and Baxter International. Dr. Khoury has been involved in international forums on vaccines, pandemic planning, biodefense prep, including working with the Olympic Committee. Dr. Khoury, welcome back to the show. Dr. Peter Khoury: 1:20 Thank you, James. And it’s unfortunate. We can’t do it in person. Certainly. I’m sure you, myself and others are so used to doing teleconferences and Zoom calls. So we’ll see how this goes. And hopefully you can hear me well. James Di Virgilio: 1:35 Yes, we can. We’ll make this work last time. In our first episode, of course we were together. We were in a large room sitting far apart, but it is always great to have, of course, the person you’re talking with in front of you, like all of the listeners know and understand as well. So since the last time we spoke, a lot of things have changed, but really a lot of things that you had talked about on the first episode have essentially come to pass. You mentioned there’d be a potential small wave of infections followed later on by a much larger wave of illness that certainly happened. And then we got into the discussion, which is really going to be the crux of our discussion today of essentially game theory and viruses, which again, viruses are smart. They react, they change, they have different strands. I think a lot of the public across the world has learned about these things. And how do you deal with them? How do you stay one step ahead. So let’s open up now with that in the background and ask you sort of this big question, looking back now, what happened that maybe you didn’t foresee the first time we spoke? Dr. Peter Khoury: 2:29 There’s a couple of things and they, I guess aren’t really biology related, but they really did make an impression on me and were something I did not foresee. The first really was the amount of compassion and caring that people show when they’re in uncertain circumstances. It did once again, show me that compassion is an inherent trait and caring helps ease the burden. A pandemic can cause think about the long hours and risks that healthcare workers put themselves in, especially at the beginning of COVID-19. And there was so much unknown in so many people being infected and to be an emergency room nurse or physician at that time, and having to put in those long hours and put yourself at risk and your family at risk and not really sure if one mask or two mask or a shield or what exactly was going to really protect you, but they came in for work day after day, policemen, firemen, emergency workers, all of them. It’s amazing for them to really take care of those who had severe cases of COVID-19. So I think that’s the first thing that I didn’t really foresee that there would be that kind of positive response. And so many people that really took up caring for others. The other thing that I didn’t foresee was the ability of people who may otherwise be intelligent to actively ignore the science and the data. And instead believe what I thought were ridiculous, conspiracy theories and false information generated by self-proclaimed experts whose credentials are measured by the number of people who follow them on social media. So I was surprised by that, that otherwise people that I thought were pretty intelligent would trust that for their information instead of the experts in the field. Actually, there is another thing, a third thing that I didn’t really foresee a year ago, and that’s really how different people’s tolerance for being inconvenienced and then their mental calculation of the risk and reward removing something that is inconvenient. So simply stated their reasoning for justifying doing something that increases their risk . I happen to live out towards one of the most populated Springs in the area. And it was amazing during the weekends of this past summer, the hundreds, if not thousands of people that would go to these Springs and no mask, no nothing, whole family. And they would put themselves at risk. And it’s hard for me because I wouldn’t do that to actually see that. And now here we have, I think at least two States, Texas, and Mississippi that are basically taking down everything, no mask, full restaurants, everything back to normal, and I’m afraid. We’re just going to see another huge wave from this. So people need to understand, yes, you’re going to be in convenience for awhile , but that’s the only way to stop spreading a virus like this. Or of course, get everyone vaccinated and protected at least to a number where you get protection of the movement of the virus amongst a population. James Di Virgilio: 6:05 Yeah you mentioned an interesting narrative there with listening to experts and in my own field of investing, I like to tell people all the time, if you ask me questions about investing, I can speak as an expert in the past. This is why this strategy worked here are the data sizes and samples. Here’s the research done here. So we know it’s worked in the past. Here’s, what’s likely to work in the future, but if someone asked me six months from now, what exactly is going to happen in this market or this investment? The only right answer is, I don’t know, and neither does anyone else. And there seems to be some confusion between experts that know how to speak on things that have occurred, that they’ve witnessed and people making prognostications, using whatever kind of modeling, either simple, or as you mentioned, an opinion that comes from your mind and gets put onto social media, prognostications are difficult, but the hard data, the data we’ve observed, the data we know to be true of course tells a different story. And that I think is what you’re looking for. Obviously in a free society for people to begin to clean to what is the truth are things that we’ve observed before. So let’s set the stage for vaccinations. In general, last time you had mentioned, there’s essentially five main ways that you can create a vaccine to overly simplify and with Corona virus with COVID, we have essentially not used all five of them. If you could kind of walk through the landscape right now for the vaccines, we have the ones that may be worked on, and then we’re going to walk through them because I know that’s a huge question area for most people. Should I get an mRNA vaccine? Should I wait? What’s the difference? Is it risky? So if you could set that landscape again, what these vaccines are, and then we’ll dive into each one and give everyone out there a good chance to grasp what the differences are. Dr. Peter Khoury: 7:41 Sure. And I have to admit, I didn’t listen before this, to what I had said a year ago, but there are tried and true methods for making a vaccine, whether it’s a live attenuated vaccine, where they take either a virus or bacteria and they make it. So you have, what’s called a subclinical infection where you don’t really get sick from it, but your body responds as if you did. So you produce antibodies and an immune response to this modified bacteria or virus that’s been attenuated, or sometimes you just kill it and put it in hall in the person. An example is at the early days of vaccines, the very first one was a smallpox vaccine made with Cowpox. And they realize that milkmaids were not getting serious cases of smallpox it’s because they were infected with cowpox, which was a milder version. And that’s sort of like an attenuation in a sense. And so then they were able to take that and literally just bake it or whatever you want to do to kill the bacteria and use that. Then as a virus itself, you can also put it in a mixer and slice it up and you have a bunch of small pieces of a virus or a bacteria. And I say a mixer. It’s nothing like that, but you get the idea of slicing it up and in your body sees that as foreign. And it can develop an immune response to that. But the vaccines that are now on the market actually use newer technology, which really is ingenious. And unfortunately people fear mRNA’s or DNA and they think, Oh, this is genetic engineering. And they’re putting something into me and it’s integrating into my chromosomes. And I don’t know, the government can track me because of that. And it’s nothing like that. Really. If you look at it in the science behind cell biology is just amazing what each of your cells can actually do. And it’s really using that mechanism as a small factory in itself. So I think most people realize there’s a third vaccine that was just approved by the FDA, by a company. You know, them as Johnson and Johnson, they have a subsidiary called the Anson, which is out of the Netherlands, their vaccine portion of the company. And so this new vaccine just came on the market. It’s given us a single dose and the other two, which had been around now for a few months, the Pfizer in Moderna vaccines, those are really two dose vaccines. And so the Pfizer Moderna vaccine utilizes this manufacturing platform that you mentioned, which is mRNA or messenger RNA. What they do is they have this piece of genetic material that in a sense codes, it’s the recipe, for what’s called the spike protein or part of the spike protein, which is part of the Corona virus. And they encapsulate it in like this fatty particle. So it’s called a VLP. And so inside this, let’s say glob of fat, little glob of fat is this little piece of genetic code. Well you’re cells need energy. And so when they see that they use that for energy, this gets injected in your arm and your cells in your arm , see that those fatty particles and they start sort of sucking them in for energy use. And as they suck them in. And the middle is this little piece of genetic material, which is the messenger RNA once inside the cell . Well , your body has all the mechanisms to take that recipe, which is in a sense listed on this piece of messenger RNA and start producing the protein it’s encoded in it, which is that spike protein. So that spike protein is then released from yourselves and other cells. See, it may say, Hmm , that’s not part of our body that’s foreign to us. And so it generates immune response by your other cells, by your immune cells. In those remember seeing that particle after it eats it up or whatever. So it sees this spike, protein decides it’s foreign to your body. The immune cell then ingests that, but it remembers seeing it. So if you’re ever infected with a virus, your body immediately elicits an immune response. You don’t even know you were infected because antibodies instantly take up the Corona virus that you’ve been infected with. And that’s how you’re protected by that type of vaccine. Johnson and Johnson vaccine actually uses a different type of technology. They use what’s called a viral vector in what that is. It’s a virus, the one they use is called adenovirus, 26. It’s basically a virus that’s similar to what the common cold viruses is. They genetically engineer that. So it can infect cells, but it won’t replicate inside the cells. So it can’t spread throughout your body and give you any kind of infection or whatever, but it does have inside of it , the genetic instructions like that recipe again, to make that spike protein that is used to elicit an immune response. So instead of being carried in these little fat or lipid balls, the genetic instructions are injected by that weakened virus into the arm cells. And then they make that particle, which is the spike protein of the Corona virus. And that again is identified by your other cells as being foreign in your body. And it elicits the immune response. So that’s sort of the mechanisms for the three different viruses. Again, hearing that people consider that genetic engineering, you know , I just want to set the record straight. There is no modification of your genetics or of the virus genetics. So what is happening is, as I said, it’s truly amazing. If you think about that, the cells in your body, which have all the machinery to make any kind of protein, it has the recipe for that’s what’s included on your chromosomes are all these recipes for proteins that make your eyes a certain color and your hair, a certain color, et cetera, all it’s doing is simply introducing a new recipe, which either is delivered by a harmless virus that won’t replicate or that’s provided in like this little energy bar, these little lipid fat balls, and that recipe delivered uses the cell machinery to make the part of the spike protein that causes the immune response. Sorry, that’s a long-winded answer, James. James Di Virgilio: 14:41 No, it’s a good start. So mRNA founded in 1990 or so essentially by a Hungarian scientist, she had this novel idea and then all the way up until COVID-19 was never used or approved. Should there be concern that it now for the first time is being used in a vaccination that is going to be used worldwide. If it’s never been used in the real world before. Dr. Peter Khoury: 15:04 Now, it really should not be in the reason as is it does not modify your genetics at all. It literally is just, as I said, use the mechanism of your cell to produce a protein. I’m trying to think if there’s any other comparable in either veterinary medicine and nothing’s coming right to mind. But as I said, it’s not genetic engineering by any means. It’s literally putting a small piece of messenger RNA, which is normally in your body. So your chromosomes, which are DNA are transcribed into messenger RNA, which is read to make the proteins, this just skips the DNA part and goes right to the messenger RNA. James Di Virgilio: 15:47 So we don’t have to worry as the public, as far as we can tell scientifically that this is going to turn into something that’s going to alter body chemistry cause sickness down the road have any longterm effects. As far as anyone can tell. There’s nothing about these MRNs current vaccines that we should be afraid of. Dr. Peter Khoury: 16:03 Right. And it’s new technology. You really can’t tell the future. All indications are that it’s very safe in very efficacious. The amount of clinical studies that go behind products like this before they’re released is truly tremendous. I think that there would have been clear indications as they were either studying this technology early on or as it gets further on and goes through the phase one phase two and finally phase three clinical studies that there would have been warning signs that there were problems, but certainly none have arisen yet with this technology. And if you think about it, theoretically, there really is very little, if anything that could rise from having this done, but you never know until time’s passed. James Di Virgilio: 16:55 Right? The famous French economist in the 1840s, Frederick [inaudible] would talk a lot about unintended consequences of whatever you put in place in society. There are always unintended consequences that you cannot foresee, but scientifically it is good to note like you’re mentioning as far as anyone can tell scientifically this is not injecting a large risk into your own body. It is not altering genetic code, as you mentioned. Um , and that that’s , that’s something to hang on. So now let’s talk about something more nuanced. So we have two mRNA vaccinations that are available. Obviously big advantages are it’s much faster to bring them to market logistically before we get into the other ones. Are there any hurdles with an mRNA vaccination logistically with regards to freezing or refrigeration or transport that maybe would give a more traditional vaccination at advantage and delivery and rollout ? Dr. Peter Khoury: 17:41 Yeah, actually there is. I know with the mRNA vaccines, as far as the fats surrounding it, the VLP structured itself needs to be kept at low temperatures. So would that Moderna and Pfizer vaccines, the storage in shipping was between minus 80 centigrade minus 60 centigrade. So that’s minus 112 degrees Fahrenheit to minus one 76 Fahrenheit. So that caused a lot of trouble at first for States or for injections sites and clinics because they didn’t have those special freezers. We have them because of the work we do here, but they’re just not readily available. People don’t keep these in physician offices , et cetera. But what they did do is immediately started looking at temperature changes and how long the vaccine in a sense could survive at regular refrigeration temperature or in a freezer, regular freezer. So the FDA did ease up on those requirements, but even now that vaccine still only can be held in a refrigerator for five days and then must be used within six hours of being thawed and diluted. So there is a small window, and it’s because of those VLP that ball of fatty acid , that carries, that, that makes it. So you have to have careful handling per both the Johnson and Johnson vaccine, which uses the adenovirus actually can be kept at refrigerator temperatures for up to three months. So it’s far easier to store and ship because of that. Another difference between these one, as I mentioned is a one dose vaccine and that’s the Johnson and Johnson vaccine in the Pfizer and Moderna, the vaccines are both given as a two dose series. Obviously giving one dose is much easier since there’s no follow-up visits, which involves making sure the person in the vaccine are there at the right time for dose number two. So coordinating all of that goes away, where if you do have to come back for a second dose with the Pfizer/Moderna vaccine, you obviously have to coordinate it. So the person and the doses they’re at the appropriate time to administer at , but there are clinical studies were done a little differently. So when you look at the efficacy of Pfizer and Moderna, those vaccines had a rate of effectiveness during the clinical trials of 94 to 95%. So that means that they vaccinated people and they looked for antibodies production. In those people. It makes sense . Every hundred people that we vaccinated basically 95% over, I think it was four weeks had developed immunity by , in contrast with the Johnson and Johnson or the Yansen vaccine, they said it was 85% effective against severe disease and a 100% effective at preventing death. So during their clinical trials, not one person who got the vaccine. And I think there were 44,000 died from COVID-19. And I think 100% didn’t even go to a hospital. There were some people that did have severe disease about 15%, and there were people that had what they call moderate to severe illness. So that would be in a sense they were home, not feeling well, et cetera. So it’s hard to compare apples to oranges. In this case, since one was a two dose vaccine looking purely at efficacy and production of antibodies in the other was a one dose looking at severity of illness. So getting either vaccine is a great thing to do. If you get the one dose vaccine, you don’t have to go back for a second dose, but there is some chance that if you’re exposed to COVID, you may get a mild illness from COVID. And in fact, there’s a lower chance of only 15% that you could have a severe illness from that. We don’t know if you’ll die from it, but for the 44,000 people they had in their clinical studies, I think it was 44,000. None of them died from illness. So I think those really are the main differences. There’s a little difference as far as how quickly you’re protected that Johnson and Johnson vaccine works about two weeks after people get vaccinated with Madonna and Pfizer people don’t get full protection until about two weeks after the second dose. And the second dose is usually three to four weeks after the first dose. So from the very first dose, you’re talking five to six weeks after the first dose and you’re fully protected. James Di Virgilio: 22:53 Let’s bring this down to the granular level now and get to a decision point. So let’s assume, and I’m going to throw a fourth one in here with Novavax, which may or may not come through, but it’s another different type vaccine just to give us the thought experiment of being, let’s say late August, you haven’t had a vaccination yet. And you have this choice in front of you. You essentially have the mRNA, which you’ve mentioned is Moderna and Pfizer. You have Johnson and Johnson, and then you have Novavax, which is going to be one of the most traditional and time-tested vaccinations. If it makes it again, we’re speculating here, just to give an idea of what this may look like, and you have a choice. Does it matter Dr. Khoury, which one you choose? Is it simply saying, you know, it doesn’t really matter. Take either one of these for convenience or one you can follow through on, or is there a more educated decision that needs to be made if you’re facing a choice between these let’s call them three different vaccine deployments, Dr. Peter Khoury: 23:44 Right? Of course, a choice like that is personal on whether people want it to be vaccinated or not. I would say that the first hurdle is get vaccinated. There is no doubt that vaccination protects you when it comes to the choice. And there are so many people in videos, out of people, literally on their death bed, dying of COVID by themselves, in a hospital saying, I wish I had not gone to that party. I wish I had done this or that. You may think you’re otherwise healthy, but you’re playing Russian roulette with something that impacts people in very different ways. Even though they think that I’ve never been sick in my life, this couldn’t impact me. You would be surprised at the number of younger people and other people that get this disease and either suffer long-term consequences from that, or truly die within a few weeks of contracting the virus. The question is if you had the choice of vaccines, which one based on the technology used would be better. I always tell everyone if it’s been reviewed by the FDA in the United States or the other one is the Korean FDA. Korea has an incredibly competent FDA based really off the US FDA and both are very, very good at looking at the risk and rewards of every vaccine, European union, also very particular and conscientious about looking at the impact of vaccines. So I would say that if it’s been approved by the FDA in the United States, it’s a safe and effective product . So if Novavax does get approval, I would not hold back at all on getting that vaccine versus either Moderna Pfizer or the J&J products. All of them are winners. If you get at , if you’re needle shy, obviously you may want the one dose versus the two dose. So there may be some advantages mentally for you there. If you want to make sure the odds of being protected the best look at efficacy after two doses, it’s much higher than it would be after one dose. But again, all of them are safe, effective vaccines, and the technology makes very little difference in this case. James Di Virgilio: 26:12 So the take home there is assuming that they all have FDA approval and you have that choice. The reality is you don’t need to spend a ton of time researching which one to get, because the odds are, all of them, of course are going to work for you. And there’s just different sort of personal mechanisms. Like you mentioned one dose or two things like that. But right now there’s not a significant difference that should have you necessarily favoring one over the other. If you’re looking to get a vaccine. Dr. Peter Khoury: 26:37 Right. Just based on the last sentence you mentioned, I’m not sure what the composition is of the vaccine that may come out later on this year, but I know the Moderna, the Pfizer, the J&J vaccines do not have adjutants in them. So in they’re not produced like an egg. So if you have an allergy to eggs or egg protein, it’s no issue with these vaccines. If you have been issue , there’s what are called adjuvants, they help boost the immune system with certain vaccines. None of these have this. So they’re pretty pure vaccines. Some of the older technology you’ve had to use either a chicken, eggs, or hens eggs to produce the product. I think the one you had mentioned is a Viro cell product . So it is not produced in, in hens eggs, but some of that older technology does use adjutants and other things, which is that chemical treatment. So some people have had reactions to that in the past. James Di Virgilio: 27:39 To look for individual things that maybe you yourself have an allergy to, or , or some reaction to, but all in all, if it gets FDA approval at this stage, it’s gone through the rigors. And if you want to get a vaccination again, no need to sparse out exactly which one to get. The differences are not going to be, as you mentioned significant, despite the fact that they are in fact different delivery mechanisms. Now let’s talk about different variants. This has obviously gotten a lot of news play here. When we first talked, we talked about how stable COVID-19 was. Uh , we also talked about, of course, the fact that virus has changed and that we could expect COVID-19 to change. We just didn’t know how yet, given what you’ve seen with the variants . And we know we’ve seen numbers, Johnson and Johnson is almost 70% effective against variants. Each one of these is a different number. What is this variant landscape look like to you? And I know you don’t see the future, but as of right now, if I get a vaccine tomorrow, do I have decent protection against the variants we’re aware of right now? Dr. Peter Khoury: 28:32 Yeah . It’s important that people get vaccinated as quickly as possible because the quicker we can shut down the circulation of this, the chances of it mutating in doing what I had talked about is drifting and shifting gets eliminated. So through replication, that genetics change is virus adapt to their surroundings, just like humans do. If you look back at Neanderthals and us you realize that certain people are born with traits that allow them to survive better. In certain circumstances, that’s true with virus and bacteria. It just happens thousands and thousands of times faster than we replicate. So literally in 24 hours, virus have gone through 10,000 fold replications where humans takes nine months to birth out a baby. And it literally happens so fast that these genetic changes in that adaptation to your surrounding can happen very quickly. And as long as those changes have little impact on the spike protein, that’s a protein has been utilized by all manufacturers that I can think of as the target for the immune response, then really vaccinating now should protect you against most of the variants. The variants, it wouldn’t protect against would be ones that have totally shifted away from that current spike protein configuration. So if there’s a little drifting away that protection will go down a little bit. Some people won’t be protected as well, but if there’s a major shift, it doesn’t provide any protection. Now you don’t know if that’s going to happen. I talked to other people that are experts in the field, and some believe what’ll happen is this’ll become like the yearly flu vaccine that will be able to see the shifting happening in other parts of the world. And people will just change the messenger RNA or whatever it is that’s coding for the latest variant that’s circulating around the world. And then a few years later, if it changes again, you need to get another dose of vaccine against that. I’m hoping we don’t have to do that. I’m hoping that we’re able to shut this down as quickly as possible and make it just a one-time pandemic event and basically eliminate it from the world soon. James Di Virgilio: 31:03 And that’s a great point. And that’s something again, that wisdom would say, no one knows the answer to that question, but certainly we hope that COVID is not here to stay like influenza or influenza has some mutation strains that become very famous, like the Hong Kong flu in the sixties, for example, right. That’s influenza just a different strand. It’s still here today. Obviously it’s just not that significant bumps. So that’s a , we’re all hoping for, as you mentioned, and of course, like you said, one of the best ways to make sure that happens is if everyone does get vaccinated faster than you’re going to give this virus less of a chance to make these game theory changes, to look at what humans are doing and respond and say, okay, well, I’ll do this to try to keep myself alive. Essentially you’re reducing its options. And if you’re doing this options further enough, it may just totally be gone. Of course, that is over simplification . So here’s a question for you. What happened to the flu in this flu season? The CDC records indicate that the flu is essentially non-existent despite about a million tests. You’ve had very few positive results at all. Hospital admissions are down to levels, never seen before. What does influenza and COVID have to do with each other? What does this mean for the future? Any thoughts on that? Dr. Peter Khoury: 32:10 What we may be seeing is just impacted by the distance. People keep from each other and making sure they’re washing their hands, wearing masks, all of that impact flu also the transmission of flu. So I think flu is still here. There are cases, but people have become very conscientious about spreading viral diseases during this time. I think once the unmasking happens and people are back to what we consider a normal life, I think you’ll see dlu come back to the levels that it was before. James Di Virgilio: 32:50 Yeah. It’s an interesting thing to follow, obviously, because one of the major fears was, you know, what if you had COVID and influenza stacked on top of each other, and we don’t know yet how much these things co-mingle. Do you get one and not the other, can you get both in States like Florida, which had been largely open, you still have extremely low or non-existent really statistically influenza cases. There’s just a lot that we will unpack obviously in the future. All right . Let’s ask you this big question before we talk about what you were working on to close up today’s episode. So let’s put you in hindsight mode a year ago. If you knowing what you know now had the power to implement one change to impact the outcome of what we’ve gone through in the past year or so, what would that change have been? Dr. Peter Khoury: 33:30 Hmm , I think if truly there was a chance of getting all governments in the world together. I mean, that would potentially never happen. But I think in hindsight, if they were able to take a year and take a look at where we are now and the impact that it’s had on people’s lives. So the morbidity, the mortality, the impact on economics, all of that. And you could take all the decision-makers to this time and look back. I think all of them would agree that if we literally shut the world down for a week, made everyone stay home, put in very, very serious measures, whether it was a week or even two weeks that we could have stopped this right at the beginning, it literally wouldn’t have been able to become what it did. And if you look back at countries going to use Korea as an example where they did exactly that, or China or India, here’s a country with over a billion people and boy did an impact the number of cases they had much less than we have, but it’s an inconvenience obviously to do it. And if we had done something like that worldwide for a week or two, of course, people would have been inconvenience without knowing in the future of the impact or what that could prevent from happening. So looking back and having that hindsight now it’s nothing I could have done alone or whatever, but that would have been my advice to get as many people to stay home and watch Netflix or whatever you want to do for two weeks. Just get ready, implemented day that it starts in the day and the day it ends and enforce it . James Di Virgilio: 35:10 Yeah. It’s so interesting that the topic for a whole different podcast, like you mentioned, the hindsight hindsight analysis is always undefeated because you have information you don’t have. And as you mentioned, the question then becomes, how many days is it? How long is it? What if it doesn’t work the way we think it works? So then what happens is there’s a lot of decision points, but that’s why it’s a hindsight question is knowing what we now know that it did spread, it was highly contagious. It was going to go all over the world. Of course, as with any virus, if you can isolate you reduce the spread, right? It’s like playing tag as a kid. If you’re too fast and they can’t touch you and tag you, then you’re not going to be it. And so , uh , that’s an oversimplification, but that’s a good point about potentially the future. What do you do the next time this happens and what happens if it does fade away and its own. Okay. Will you said we lost 14 days, 14 days, certainly a lot better than a year. So lots of interesting thoughts there, let’s bring this right back down to what you and your company are working on. Tell us a little bit about an update. Last time we spoke, you are working on something COVID related. Tell us what’s going on with that. Dr. Peter Khoury: 36:07 Yeah, so we work with the US government on a couple projects, specifically with the department of defense to help protect military personnel and war fighters. And so we manufacture a vaccine for COVID-19 and we manufacture what are called monoclonal antibodies, which are also utilized to protect and treat, actually treat COVID infections. Both of these are in clinical studies. Currently we are expanding here in the Gainesville area. We’re in Alachua, we’re doubling our capacity . So the construction is underway for this. And I think it’s a great opportunity for this region because of University of Florida, some of the great research that goes on at that university in gene therapy and cell therapy, and in vaccines, it makes a lot of sense for us to make an investment, expand our workforce. So we’ve almost doubled our workforce. Since I last spoke to you, we’re over 300 employees during 2021, we expect to expand by over a hundred more employees. So there’s a lot happening here. All of that, very cutting edge science and all use to provide protection against infectious diseases. James Di Virgilio: 37:34 And let me bridge a gap here, because this could be maybe the best way to end this podcast. You obviously are an established expert in this field. You’re an expert on viruses on vaccinations, on deliveries. You’ve done it for your whole career. If you saw something that you thought was risky or reckless or not good for society or the population I’m imagining you would be standing on the rooftop, shouting this out, don’t take this vaccination, don’t do this. This is not safe. That would be correct. Dr. Peter Khoury: 38:01 It’s funny, James, because those that know me well, including our employees here, know that I speak the truth, I have great courage of conviction about what I say. My father was a United Methodist minister. My mom was a nurse that took care of some of the riskiest patients and both were just devoted people to what they did. And I think one of the most important things for any human being is their own dignity and not being able to stand up for what you think is right. And when you see something that, especially if you’re a professional and you know, information, not raising your hand saying that there’s an issue in something’s wrong is not good at all. So it’s not part of my being to ever cover anything up or whatever. And that’s a philosophy actually of our business here. I attend every one of our new employee orientations. And I tell them that everyone has the right to stop the process. If you see something being wrong done, or you’ve done something wrong immediately, we will stop. We’ll look at it, figure a fix and find a way of putting a parameter around it. So it never happens again. That’s all I care about. No one’s getting fired. You’re not going to be yelled at. We’re going to find a way. So it doesn’t happen again and fix what happened. That’s all there is to it. James Di Virgilio: 39:27 Yeah. That’s such a great commitment. And I think that perhaps is something that’s really gotten lost during this pandemic, is that not everyone is on two sides of offense fighting with each other and not every expert one way or the other is out there just trying to run a political agenda. It’s safe to say that many people are doing exactly what you said. Hey, if I think this science looks good or this looks good, I’m going to say this is safe. And if it’s not, I would say the opposite. And perhaps that bridge, as we mentioned, is something to move forward as a free society in the future. We’re looking for truth via evidence and data. And recognizing, as you mentioned, there’s a lot of people with that, very commitment. You’re simply trying to follow the evidence and say, Hey, look, I think this is what’s best for you and your family. You’re my neighbor. I love you. I care for you. And this is why I’m saying that. So a wonderful stuff as always, thank you for being with us. He is Dr. Peter Khoury, the president and CEO of Ology, Bioservices. You can find them on the web with a quick Google search. And of course, as we mentioned before, your illustrious bio, an expert on vaccines and biologics, and certainly one of our favorite guests here on the Radio Cade podcast. Thank you for spending a considerable amount of time with us today, Dr. Khoury. Dr. Peter Khoury: 40:29 Always my pleasure, James, thank you. James Di Virgilio: 40:31 And for Radio Cade I’m James Di Virgilio. Outro: 40:35 Radio Cade is produced by the Cade Museum for Creativity and Invention located in Gainesville FL. This podcast episodes host was James Di Virgilio and Ellie Thom coordinates, inventor interviews, podcasts are recorded at Heardwood Soundstage, and edited and mixed by Bob McPeak. The Radio Cade theme song was produced and performed by Tracy Collins and features violinists , Jacob Lawson.

疫情防控 16日，中央应对新冠肺炎疫情工作领导小组指出，制定方案，组织滞留在鄂在汉外地人员及滞留在外湖北籍人员返乡，有序组织援鄂医务人员分批撤离。 截止3月15日24时，湖北省全省低风险市县有71个，中风险市县有4个，高风险市县有1个（武汉）。 3月16日，上海市科委主任张全介绍疫苗研发进展：mRNA疫苗领域，已启动灵长类动物毒理和药效预实验，预计4月中旬临床试验；病毒样颗粒（VLP）疫苗领域，小鼠免疫实验已产生特异性抗体。 宏观经济疫情冲击下，前2个月消费、投资降幅超20%，失业率有所上升。【经济成绩单：1-2月宏观经济指标速览】3月16日，国家统计局发布报告显示，1~2月全国商品房销售额8203亿元，下降35.9%；全国房地产开发投资10115亿元，同比下降16.3%。1-2月份，社会消费品零售总额52130亿元，同比名义下降20.5%；全国固定资产投资（不含农户）33323亿元，同比下降24.5%，其中，民间固定资产投资18938亿元，同比下降26.4%。1-2月份，全国城镇新增就业108万人。2月份，全国城镇调查失业率为6.2%，31个大城市城镇调查失业率为5.7%。其中，全国主要就业人员群体25-59岁人口调查失业率为5.6%，就业形势仍比较严峻，就业总量压力和结构性矛盾依然存在。 熟悉的配方，美联储一次性打光子弹。【美联储降息接近零水平，启动7000亿美元量化宽松计划，中国央行未跟进】当地时间3月15日，美联储宣布下调联邦基金利率100个基点至0-0.25%，同时还宣布推出7000亿美元量化宽松计划，其中购买美国国债5000亿美元，购买抵押贷款支持证券（MBS）2000亿美元。在此背景下，中国人民银行并未调整政策利率，开展1年期MLF（中期借贷便利）操作1000亿元，操作利率3.15%，与此前持平，当日不开展逆回购操作。专家表示，这为以后储备政策子弹和空间，中美货币政策后续一定程度上会脱钩。产业纵深【3月17日国内汽柴油价每吨下调或超900元】随着国际油价大幅下挫，原油变化率负向幅度不断加深，3月13日一揽子原油平均价格变化率为-24.93%。据此测算，预计3月17日国内汽、柴油价将迎来大幅下调，每吨下调或超过900元，这也将成为2013年新的成品油定价机制出台以来的最大下调幅度。（全景财经） 【十大白手起家女富豪中国占九席】16日，胡润研究院发布2020胡润全球白手起家女富豪榜，前十名中9位来自中国。翰森制药59岁的钟慧娟，财富上涨至去年4倍多，以1060亿财富成为全球最成功女企业家；去年的全球白手起家女首富，龙湖集团56岁的吴亚军财富增长44%，以990亿财富位列第二；蓝思科技50岁的周群飞以660亿财富位列第三。 【乘联会：预计全国狭义乘用车市场全年零售总量损失约200万辆】乘联会发文称，综合估计，如4月疫情得到良好控制，汽车市场在下半年全面回暖，预计全国狭义乘用车市场全年批发总量影响约270万辆，零售总量损失约200万辆。如疫情出现反复，则经济损失、居民收入、供应链中断等风险之大难以估算，预计批发和零售销量将面临两位数负增长。 企业动态 【中兴通讯开盘跌停，公司回应：未收到美政府通知】3月16日开盘，5G概念股大跌，其中，中兴通讯持续走在跌停和打开跌停之间徘徊，盘中跌幅一度超过20%。据海外媒体援引知情人士报道称，美国司法部将对中兴通讯进行新的调查。中兴通讯特此澄清，公司未收到美国政府相关部门就此事项的通知，公司目前生产经营活动一切正常。 【浪潮集团旗下浪潮云今年计划科创板IPO】浪潮集团旗下浪潮云计划2020年登陆科创板。目前，浪潮云处于Pre-IPO阶段，完成C轮融资，估值突破100亿元。（科创板日报） 中概股赴港二次上市潮因疫情押后。【港媒：京东或将赴港二次上市，已与投行接洽探讨】3月16日，据香港信报报道，京东已与包括瑞银及美银在内的投行接洽探讨在香港资本市场第二上市。对此，京东方面暂未进行公开置评。京东在2014年5月于美国纳斯达克上市，目前市值约582亿美元。 【温氏股份调整公司组织架构，将成立水禽事业部养鸭】3月16日，温氏股份发布公告称，决定成立水禽事业部，为公司内部管理型机构，以确保公司持续高效发展。水禽事业部主要为养鸭业务，此次组织架构调整后，水禽事业部将与温氏股份养禽、养猪以及大华农事业部等并列。 字我都认识，题我就。。。【阿里巴巴数学竞赛圆周率日开赛，71个国家和地区的5万多名选手报名】16日，第二届阿里巴巴全球数学竞赛预选赛第一轮比赛完结。在经历了48小时竞逐之后，全球5万多报名者共有超过1.5万人提交答卷。本届大赛选定3.14圆周率日（πday）开赛，以此“致敬数学”。目前，第一轮赛题已经曝光。 【格力跨界申请专利：弹奏钢琴的机器人】近日，格力电器公布了一项新申请的专利——机器人弹奏钢琴的控制方法、装置、存储介质和机器人。该专利可解决现有技术中人为手动进行点位示教面临的工作量大、步骤繁琐以及准确率低的问题。 国际视野【全球奢侈品牌集体转产：LV牌洗手液、劳斯莱斯呼吸机…】国外疫情加剧，奢侈品牌开始转产。3月15日LV母公司路威酩轩集团宣布，准备使用旗下品牌迪奥、纪梵希和娇兰的香水和化妆品工厂来生产酒精洗手凝胶，并向法国卫生部门和医院免费提供。另外劳斯莱斯老板表示可以帮英国造数千台呼吸机，意大利高级时装公司也转型生产口罩。 你的车可能要等等了。【兰博基尼法拉利暂停生产】3月14日，法拉利宣布即日起至3月27日，暂停位于意大利马拉内洛全球总部工厂和摩德纳工厂的生产。该公司称目前正面临严重的供应链问题，已不允许企业继续生产。此前，同样位于意大利的豪车兰博基尼也宣布暂停生产。 航空业频频亮起红灯。【北欧航空扛不住了：裁员九成，涉及约万人】疫情影响，航班减少，总部位于瑞典的北欧航空开始“断臂”自救。北欧航空公司（SAS）首席执行官称，SAS被迫解雇大约10000名员工，约占员工总数的90％。（毎经） 苹果已决定进行上诉。【苹果被罚款11亿欧元，此前曾因降频被罚】据彭博报道，苹果公司被法国反垄断机构罚款11亿欧元，理由是后者在分销网络中违反了反垄断规定。今年在2月，法国宣布对苹果进行2700万美元的罚款，理由是苹果以防止意外关机，在电池管理功能上降低了旧款iPhone的性能 中国企业或成为飞利浦家电业务的潜在买家。【飞利浦拟30亿美元出售其家电业务】荷兰皇家飞利浦公司宣布出售家电业务，主要包括挂烫机/电熨斗、吸尘器、咖啡机/空气炸锅等为代表的厨房小家电系列以及空气净化器等产品。售价可能超过30亿美元（约合209亿人民币）。飞利浦称，家用电器业务近年来表现显著改善，但和飞利浦作为健康科技领导者的战略不匹配，因此考虑出售。

'Sabbath Bloody Sabbath' de Black Sabbath. Cuando el rock se vuelve místico ¡Bienvenidos a los Vinilos de Barbarella! El podcast donde sólo se escucha música en formato de vinilo. Este el programa número 43. Hoy ofrecemos la segunda y última parte de la grabación que realizamos en su día dedicada al disco 'Sabbath Bloody Sabbath' del grupo británico de heavy Black Sabbath. Hoy nos acompañan en el Podcast algunos de los colaboradores habituales: Eduardo Antón (@eduancast @ en Twitter) y José Maria Arellano 'Chema' (@JoseMariaARE en Twitter). A los controles tenemos a Carlos Buendía (@LopezCarloslop en Twitter). Por último, un servidor, Antonio Buendía (@abuendiab en Twitter). Los datos de dicha edición son: Título: Sabbath Bloody Sabbath Artista: Black Sabbath Sello Discográfico: Discos Victoria Label Code: C-30.467 (VLP-103) Año: 1984 País: España Los temas que reseñamos hoy son: 'Fluff', ‘Who Are You?', ‘Spiral Architect','Killing Yourself To Live' y 'Sabbra Cadabra'.. Los enlaces que aparecen en el Podcast son los siguientes: Web de Black Sabbath: www.blacksabbath.com Web de Toni Iommy: http://www.iommi.com Web de Ozzy Osbourne: http://www.ozzy.com/es/ Web de Ronnie James Dio: https://web.archive.org/web/20100513014925/http://www.ronniejamesdio.com/ Web de Asociación Podcast: http://www.asociacionpodcast.es No olvides dejar tu comentarios y puntuaciones en iTunes, para nosotros son muy importantes. Ponte en contacto con nosotros: Web: http://www.vinilosbarbarella.com Facebook: http://facebook.com/barbarellavinyls2 Twitter: @barbarellavinyl Instagram: https://www.instagram.com/barbarellavinyls/ Flickr: https://www.flickr.com/photos/116847885@N05/show/

'Sabbath Bloody Sabbath' de Black Sabbath. Cuando el rock se vuelve místico ¡Bienvenidos a los Vinilos de Barbarella! El podcast donde sólo se escucha música en formato de vinilo. Este el programa número 41, primer programa del año, dedicado al grupo británico de heavy Black Sabbath. Hoy nos acompañan en el Podcast algunos de los colaboradores habituales: Eduardo Antón (@eduancast @ en Twitter) y José Maria Arellano 'Chema' (@JoseMariaARE en Twitter). A los controles tenemos aC arlos Buendía (@LopezCarloslop en Twitter) y colaborando también a Eduardo Antón Junior. Por último, un servidor, Antonio Buendía (@abuendiab en Twitter). Hoy dedicamos el programa al disco 'Sabbath Bloody Sabbath' en una reedición española de 1984. Será el primero de dos entregas que realizaremos sobre dicho vinilo. Los datos de dicha edición son: Título: Sabbath Bloody Sabbath Artista: Black Sabbath Sello Discográfico: Discos Victoria Label Code: C-30.467 (VLP-103) Año: 1984 País: España Los temas que reseñamos hoy son: ‘Sabbath Bloody Sabbath', ‘A National Acrobat' y 'Who Are You?'.. Los enlaces que aparecen en el Podcast son los siguientes: Web de Black Sabbath: www.blacksabbath.com Web de Toni Iommy: http://www.iommi.com Web de Ozzy Osbourne: http://www.ozzy.com/es/ Web de Ronnie James Dio: https://web.archive.org/web/20100513014925/http://www.ronniejamesdio.com/ Web de Asociación Podcast: http://www.asociacionpodcast.es No olvides dejar tu comentarios y puntuaciones en iTunes, para nosotros son muy importantes. Ponte en contacto con nosotros: Web: http://www.vinilosbarbarella.com Facebook: http://facebook.com/barbarellavinyls2 Twitter: @barbarellavinyl Instagram: https://www.instagram.com/barbarellavinyls/ Flickr: https://www.flickr.com/photos/116847885@N05/show/

Michael Eastham founding principal of Fellowship Financial Group in Altamonte Springs, Florida.He served as Chairman of the Leadership Seminole Board of Directors and Treasurer of the Seminole County Regional Chamber of Commerce Board of Directors. He teaches Adult Education courses and Continuing Education for CPAs, Financial Planners, Insurance Professionals, Attorneys and the Florida Association of Real-tors. He is a published author and is a recognized expert in the areas of financial strategies, retirement planning and asset protection Chris Uzzi founder of the Veterans Listening Post. VLP is an interactive program awareness enhancing listening between the civilian's population and our veterans and military.He is a Coach is Public speaker for the VLP's Life changing Ten Step Listening program, Mentor for the Jobless Warrior program for Veterans  www.joblesswarrior.org, A Fund Raiser for Silver Lining Villages Holistic Services a 501c, 3. Nonprofit for Veterans , Veterans Listening Post is a Service Disabled Veterans Small Business Brandon Gallagher founder and CEO of Vuber Technologies. Vuber Technologies develops high quality vaporizers, and has grown from a small start-up to the leading brand in the state of Washington For more information go to MoneyForLunch.com. Connect with Bert Martinez on Facebook. Connect with Bert Martinez on Twitter. Need help with your business? Contact Bert Martinez. Have Bert Martinez speak at your event!