WEBVTT

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Test one two testing

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Good evening, ladies and gentlemen. This is Gego.

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Biological, high-resistance, low-noise information grief.

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Brought to you by a biologist since the 8th of October, 2023.

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And we're breaking through, man. Don't you feel it?

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Gotta break this pattern of a misleading the young. We can do it.

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We can do it.

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I know we can.

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Oh, we got a two-inch teachin' the history and not let this recent history be erased.

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Make sure they don't get their history from the New York Times and not from these charlatans.

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Things are gonna be okay. I can feel it.

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But we are at a critical moment right now and the theater is still in full effect.

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Some people can't see it. Some people can't see it. And they need our help.

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There was no spread in New York City, ladies and gentlemen. It's not in the data.

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Infectious clones are the only real threat out there in the molecular biology world.

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The placebo batches were most likely distributed in the EU and elsewhere.

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The transfection has always been dumb and healthy mammals.

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Brought to calls where murder gained a function is a mythology. The Scooby-Doo mystery is real that you don't need to solve it

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because the players are committed to lies, spectacularly so.

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How's that for an opening song? Hello.

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That would be fish from 2001 live at Clifford Ball on August 16th, 1996.

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How's that for some Star Trek radio station? Thank you very much for joining me ladies and gentlemen.

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This has been Kiggle and Biological Eye Resistance Low Noise. Information brief brought to you by a biologist.

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It is the 8th of October, 2023. My name is Jonathan Cooey. Coming to you live from the back of my garage with some sound effects provided by

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you. How do I do that? I need to stop that and go back over here.

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Do you hear this extra wind? Oh yeah, the heater is on. Do you hear that extra wind in the background or not?

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If you do, I can go behind the curtain and turn it off really quick but hopefully it will warm up in here and then it will stop.

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I can really turn it down at some point.

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So anyway, thanks for joining me. Don't take the bait on social media and TV.

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And by no stretch of the imagination, should you misconstrue that to think that I'm saying that the stuff about whatever's happening in the Middle East is somehow bait.

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I don't know what's happening there. It's not that I don't know that something's happening there but I don't think any of us know what's happening there because we're getting all of our media

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and all of our information from sources that are wholly controlled.

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And we've been trying to get a grasp on this for quite some time and I thought it would be a good night to go back into the archives.

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I went back about, it's a little more than two years to try and look at my first few slide decks to see if there was anything that I started with that still just stays really relevant.

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I thought I'd bring some of those up tonight.

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It's not a matter of what is true that counts but a matter of what is perceived to be true.

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This is supposedly a quote from Henry Kissinger.

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We are being governed by a set of mythologies that is not limited to, of course, not limited to public health but encompasses most or all of foreign policy and what we've been up to for the last 20 years.

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Really with regard to how we spend our taxpayers money.

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And this combination of over pricing and embezzlement and loss and whatever has resulted in our children being cheated out of a future that they should have had as a result of what was a prosperous nation at the start of its history.

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And this has sort of exponentially careened out of control in the last 30 years, mostly orchestrated by a group of people that can be largely identified by simply looking for people that have been in government for about 25 years.

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And I think if you just took all the people that are in the bureaucracy from the top to the bottom that have been in for 25 years and risen to an executive level of authority or a congressional level of authority in those 20 years and put them against a wall, I would bet 90% of them are more are guilty of lying during this pandemic.

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Maybe all of them.

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And so that's really where we are. It's just a matter of what's perceived to be true and I've been making this argument that there's an illusion of consensus if people on the talk shows in the morning, people on the Fox News programs at night, and the people on your social media streams and feeds all agree that something is really great.

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Let's say an mRNA vaccination, or is a really good idea like let's say shutting down schools and putting masks on children when you're out in public.

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And these kinds of consensus ideas that can be very difficult to discard even with a person with common sense, a person with experience to speak against it.

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It can be very, very, very difficult to go against that consensus if you drive out in public and see the consensus on the street represented by everyone wearing masks, everyone in their cars wearing masks, nobody on the street.

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This is the illusion of consensus that was created by fear, uncertainty and doubt at the beginning of the pandemic and many of these people are to blame.

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Many of them were primed. Many of them were offered, coerced, coached, gently coerced. I don't know what the right words would be to use how many different way they were fluent. I have this slide back from 2021.

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And what this slide was originally intended to do was try to portray how it was that we have been misled about the biology of a pandemic.

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And before I really understood the biology of coronavirus is before I really understood the biology of infectious clones before I really even understood the biology of the swarm.

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I was already here.

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This graphic right here represents my family when we were growing up and the idea that whatever your common narrative is about hard work and being honest and showing up on time gets you well paid and then you know you get a good job and everything is great.

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You tell the truth, you go hunting, whatever this represents is also on the TV.

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And even though there was a blue and red on TV when we were young, the common narrative shared between the blue and the red was the same.

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And so that meant that even though people might be blue and red, they all had this common narrative of what they thought was the right way to go about living your life.

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The right way to go about taking responsibility for your actions. The right way to go about saying what you mean and meaning what you say.

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And so, as the world changed and the media started to lie to us, these people who've grown up in a traditional pre-social media TV and media landscape are just kind of angry because they see that the list that's in their head

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doesn't agree with the list that's on TV anymore.

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And that disagreement doesn't result in so much stress as it does frustration because we understand that what the truth is, we understand what's being contorted because there was no reason to change this back here.

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And you might call this a conservative attitude, but what we're not changing over here is the idea that a mom and a dad should raise some kids and that it's okay for a mom to dedicate herself to a dad and it's okay for a dad to dedicate himself to a mom.

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And it's okay for the main focus of their relationship and their lives not to be a giant careers and big bucks and travel and prestige, but it can actually be those children and their well-being and raising and enjoying those children as they grow up.

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That can, that's okay. That was okay back then. It was okay for your family to be a priority, for your husband or your wife to be your priority.

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It didn't have to be a job and a career and hobbies.

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But that's all changed now because now, behind my head here, you can see that there's many, many more channels.

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And on those channels, everybody's angry at the other channels and you don't just have your family on the couch with you like you did up here.

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You don't have just this common narrative of, you know, maybe what your, what your grandma says or whoever your head of the family is or how you all get together for Thanksgiving or whatever that common thing is that makes up your living tradition of your family.

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Is now infinitely diluted by these TV channels, but more importantly, all these people that have access to your children and have access to you through this mobile device that used to hang on the wall and be shared among everybody.

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Back in this pre social media era, mom, dad, my sister, myself, and my brother all had the same phone number and the same phone rang on the wall for all of us.

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And so that whole thing that you and I have been told is convenience and you and I have been told is like the advancement of technology is actually the physical, mental and spiritual fractionization of our family unit and the fractionization of our common narrative

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because now it's harder and harder for, for people to really understand reality in the same way because again, the algorithms could be used in such a way as to encourage people to do certain things and, and they are.

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It's just what things are they being encouraged to do. They're being encouraged to separate from one another to doubt one another to be overly sure of themselves to be overly concerned with the amount of burden that they receive from the world and less concerned about the amount of effort that they put into their daily lives.

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And these messages are subtle, but they're there.

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These messages are incongruent. And so right away, people are unhappy right away in this world.

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The list doesn't agree no matter what you can find many, many channels and many, many people on the Internet that absolutely positively do not agree with anything you think.

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And that results in you sort of feeling a level of fear that allows you or forces you to become programmed. You choose a corner and safe corner. It's almost like you're in prison and you have to choose a gang.

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And once you choose a gang, you feel very comfortable in it and very comfortable in the idea that the other gang is definitely not your gang.

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And if you're not in a gang, then you feel really bad too.

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And is America so different than this cartoon? I don't really think so.

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I think you might say that we've progressed through this over the last 20 years and now we're kind of here.

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Where there's, I don't know, there's like people that get it and are angry. There's people that get it and are kind of like frustrated but don't want to do anything.

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There are people that think the red is right. There's people that think the blue is right. There's people that don't want to pick a side and they're not happy either.

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But they've all picked a TV channel or they've all believed in a social media influencer and so they're more or less programmed.

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They're not even thinking for themselves anymore. They're just holding on to that Z-Dog guy or Joe Rogan or whoever.

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And so we're in a very crucial time because all of these people are more or less ready to be rescued but very, very afraid to look away from the wall.

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They're all in the crash position right now facing the wall of their cage. Well not the two people on top but those are us.

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But our common narrative has kind of been destroyed if you think about it. If we're fighting about whether men and women are real or not.

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And some people are fighting for the idea that there's this whole other spectrum of feelings and things to do and how our biology is expressed and should be talked about and how kids should be raised.

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Our common narrative is kind of being destroyed. And it's unfortunate but that is where we are.

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And that common narrative is really from my perspective as a biologist very much, very much thick with biology.

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It is the biology that unites us. And yet right now with this gender ideology and everything else with children to do with gender studies or gender sciences or whatever this is and teaching children that this is a word and a concept that they need to think about

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is inherently wrong in my humble opinion and that means that we're bifurcating our nation on this idea but really, really weird ladies and gentlemen and you must see it this way.

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Is that the bifurcation is happening on a clearly already existing fault line between red and blue.

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And so if we can show.

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If we can show our family and friends that that doesn't make sense.

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That this particular.

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Break.

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In our understanding of our biology as a species.

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Would break along political lines. It also doesn't make sense that our basic uptake of the vaccine would break on political lines unless.

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It was by design.

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Unless we are piling wood on the same divided fire so that not only are we now separated by our.

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Imaginary differences on gay marriage, our imaginary differences on abortion, but now we're separated on our imaginary.

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Ideas about COVID vaccines are imaginary ideas about the dangers of COVID about whether long COVID exists or not.

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About racism and about transgender rights.

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And again it's about rights because then it comes back to some kind of.

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Thing that you think everybody should have rights.

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And it's not about the biology anymore.

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So we've got to be very careful because we're here we're really far we pushed the ball so far that I decided to play some really great music in the start.

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But we've got to be careful about how we move forward now because there are traps everywhere and everybody's coming for us now.

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Because mice die in traps because they do not understand why the cheese is free. Do you remember when I was saying this all the time.

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Oh, that's a long time ago.

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And so this is the trap right this is the story that they told us the mythology and the faith.

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There's a novel virus we had to do something what we did was mRNA and it saved at least 14 million lives.

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We gave it Nobel Prize for it. It could have been done better with the higher quality control and maybe used to only process one.

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But we'll have a next time because this was again a function virus that will definitely come again that's the faith.

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This is the biological brown truth the real immunology and all viruses are not the same to our immune system.

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This is what I was saying three years ago right so this is a little dated.

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You know it's still the no virus people are going to hate me but we as far as the cartoon biology as far as the biology and the books behind me goes.

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If you believe that are some viruses and that some viruses interact with our immune system there are viruses like measles for which we have measured immune responses.

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There are there are diseases like flu and polio and other diseases that we've looked at and think that it might be viruses that are triggering them.

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But we've also been very very very carefully able to characterize the fact that some of these viruses whatever they are some of these diseases whatever they are activate our immune system in a very different way than whatever coronaviruses are.

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And so three years ago when I used this slide to describe the biology as I understood it then it was pretty dang accurate with regard to the PubMed status of virology and the immunology in response to them.

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And in that standard or in that canon of literature I assure you that measles is more immunoreactive than mumps is more immunoreactive than coronavirus and therefore the more immunoreactive you are to a virus that tends to be easier to make a vaccine to.

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And to get your body to react something that it doesn't normally that react that much to like a coronavirus is difficult because again you're trying to augment an immune system that you don't fully understand.

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And you don't understand why it immune the immune response mounted to a coronavirus is so meager compared to that of a measles virus.

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But nevertheless you do you.

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And that's what we all also were saying that neither are all immunizations and this is where we were talking about Christine's to Bell Ben over and over again from 2021 onward.

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And what did Christine's to Bell Ben's show everybody she showed that live attenuated vaccines.

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Versus dead subunit vaccines.

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Produced a five times higher mortality rate in those dead subunit vaccines.

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Kids didn't have a higher rate of the disease.

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The disease is that the vaccine was supposed to protect from I think this was a detail.

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But of all the mortality in the children is five times higher in the ones that had that didn't have the live attenuated vaccine and that's extraordinary.

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So not all vaccines not all immunizations are the same either and while they were telling us that antibodies equal immunity I was saying that it's D to T to be because these T cells are the main response to a coronavirus T cells are the main immune response in the body period.

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For cancerous cells it's T cells and not all humans are equally vulnerable to disease you could say to respiratory distress respiratory disease because it does really matter how healthy you are does matter how old you are does matter whether you exercise or not.

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And it does matter what you've been eating for the last 20 years.

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Do I need to say this every night.

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I mean really do I need to say this every night intramuscular injection of any combination of substances with the intent of augmenting the immune system is dumb.

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I've been trying to look at these people maps and figure a little bit out and a couple nights ago Denny and Peter Ron please check it out.

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We also did a show very recently about Phillip Buckholtz and his speech before the South Carolina Senate about the DNA that has been found in the RNA shots.

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He lauded MRNA as a technology and assured us that this technology would be wonderful if it wasn't for the DNA or for the poor choice and antigen.

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And he's also intimately involved from the beginning with the PCR shenanigans.

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And this is the result. So we've added him to the map.

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We also a couple three weeks ago looked at Kevin McCarron and Charles Wixie as they appeared on Veijon health conference and that was the 26th of August.

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And that was quite interesting because we have been following Phillip McMillan for some time here on GIGO and biological because he's had cared for in Bosch on his stream more than anything else.

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Now I haven't done that many streams of Phillip, but I assure you I've had my eye on him for a while.

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And of course that was also just after we had had this huge run in with George Webb where first he was swearing at us and telling us we were terrible and we were we were amateur hour.

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And then he was being real nice to us after we said no your liar and Paul Catrell is a liar and you guys were laying down the worst case scenario in 2020 as part of a necessary campaign to make sure that there was going to be enough time.

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For them to roll out the new vaccines.

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I mean it had to be a big enough emergency otherwise they weren't going to be able to do it.

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It had to be as it said in the Nobel Prize statement, one of the worst crises ever to face mankind in history.

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And that narrative was laid down on purpose deliberately.

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People were encouraged to do it, maybe even given comfort, prestige, promises of fame and fortune to do it.

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Many of them, you can't underestimate how many of them.

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And you can really tell them by how many of them can actually tell the whole story or ever bother to try when they're put in front of a microphone.

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You know like Mike Eden does when he says well first of all you got to know that everything was a lie.

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How many of the people on this screen start like that?

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Now it became very interesting the other day because suddenly here comes Dr. Phillip McMillan again into the scene and this time he's live streaming with Robert Malone.

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Now that of course becomes very curious because if he can stream with Robert Malone, Robert Malone was streaming with Paul Cottrell already in 2021.

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Then he also said he was streaming with Vajon Health in 21.

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So in June of 21 he streamed with with Paul Cottrell, Vajon Health Phillip McMillan and Brett Weinstein like that was the network.

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And so since George Webb is really connected to Paul Cottrell and Robert Malone has streamed with Paul Cottrell and with Vajon Health and continues to stream with Vajon Health.

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And Kevin McCairn was streaming with Paul Cottrell like for three months straight at the beginning saying there's going to be a billion people dead.

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And then when I left drastic because I didn't want to pay attention to the diffuse proposal anymore and I wanted to fight transfection Charles Rixie tried to bring me back in.

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Then we went to the CHD conference Charles Rixie told me three times that Robert Malone remembered him for my podcast but not me and how funny that was.

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I don't know why or how or whether they're just you know pen pals or they exchanged emails somewhere at the Boston conference maybe and in the beginning of the year I don't know of 2020.

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But something's really screwy because Vajon Health is nobody that should have connected all of these people together.

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There's no reason for that to be the case.

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There's no reason for that to be the case because remember I told you Vajon Health has been streaming with with Heron Fund and Bosch quite some bit.

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And who worked together at Solvay with Heron Fund and Bosch mom are Robert Malone did.

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They've known each other since 2007.

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There's quite an interesting network of people that has been slowly crafting the narrative on our side close slowly crafting the narrative of doubt but not really doubt.

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You can't doubt that there was ever a coronavirus spreading like mad around the world.

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You can doubt whether it was natural or whether it was a lab leak.

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You can't ever doubt that the majority of the people were killed by the virus.

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You can't suggest that the majority of the people were killed by the protocols or those people won't talk to you anymore.

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You're just being crazy. There's a bioweapon.

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That's how you can see.

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They're all they're all exactly on faith.

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They're all wearing the robes.

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They're all altar boys because none of them question it.

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They won't even dare question it because that's exactly what their job is not to do to perpetuate the novel virus narrative the novel virus narrative that requires some novel things to be done.

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That requires us to know nothing at the beginning of the pandemic about what to do or what would work.

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And that we don't have any idea what could go what what could be the worst case scenario a billion people dead.

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I don't know. Let's let you see else simulate it.

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Wow. I got this video that says that Remdesivir is going to work in Taiwan.

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This illusion of consensus about a worst case scenario is a possibility in the beginning.

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This illusion of consensus of the mystery that needed to be solved whether it was a natural or lab league.

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This illusion of consensus that we know nothing about what would work for a respiratory disease that manifests itself as a RDS.

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Which is a lie, but they did it together as a consensus.

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Some of them were speaking out in 2020. Some of them were still trying to get contracts in 2020.

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Some of them spoke out in 2021. Some of them didn't speak out until 2022.

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Some of them had lots of choices that they could have made other than pushing the worst case scenario other than pushing the lab league other than arguing about never get this virus because you never know what could happen.

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It's flying AIDS, but they didn't.

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They didn't question the narrative. They didn't question the faith and we need to wake up and realize that anybody that's not questioning the faith right now is a problem.

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If they're not saying first and foremost, they have lied to us about how these people died and that they have tried to increase all cause mortality by every possible means at their disposal including

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increasing the number of opioid deaths and rolling it in, including rolling in suicides, including decreasing the use of antibiotics, including

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decreasing the way that they resuscitate people who had heart attacks, including increasing the number of people that they ventilated, including paying $35,000 for people to declare dead as COVID.

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They did all of that and yet some hour and now there are all of those people on that last screen still don't talk about any of it.

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They don't talk about the PCR fraud either.

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They don't talk about none of it except for the fact that there was a novel virus and it must be somebody's fault and we've got to solve that mystery before we can ever move forward and maybe we won't even be able to solve a mystery because it's fifth generation warfare.

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And the fifth generation warfare continues of course. Why doesn't Robert Malone call this fifth generation warfare this he says well I accepted that's the way it is.

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I get what they mean they meant there you know it's very limited language yada yada yada.

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I already called and congratulated them.

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I'm not jealous I'm not mad it did kind of hurt but it almost just ripped the scab off of my of my PTSD.

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Medium turkey chili.

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Medium crab bisque.

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Let's watch this first one and then the second one the first one is a it's a video from.

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Two years ago so it'll be right at the release April 19 2021 the release of the virus of the of the shot.

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And I just want you to see this is another person who in 2021 was likely.

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I think the best description is still auditioning she's auditioning for.

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Possible elevation by the algorithm possible elevation by the controllers.

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Depending on how this video does but here she's already sponsored.

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Somebody paying her to make this video what is the video she's going to make she's going to sell something at the end.

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She's going to make a video about how the mRNA works and she's going to get a lot of things really wrong.

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But this is very powerful the course of course you will know.

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This is exactly why my brother thinks I'm an idiot why my parents don't talk to me because they believe these kinds of things they believe these kinds of.

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Productions that are edited to be extra snappy even though this girl probably had to take three takes for every lie.

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It's painful but I haven't said at 1.5 so it'll be over in three minutes.

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Thanks to Brilliant for supporting this episode of SciShow.

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Check out brilliant.org slash SciShow to learn more.

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Two of the vaccines we have for COVID-19 have the distinction of being the first mRNA vaccines to see widespread use in humans.

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It's a vaccine technology that uses a type of molecule called RNA to teach ourselves how to resist disease.

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So how do they work and how are they different from the litany of immunizations you probably got as a kid?

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Let's take a look.

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All vaccines do one basic thing they imitate a disease causing agent or pathogen with the goal of ratting it out to your immune system.

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Then your immune system knows what to do if the pathogen ever shows up.

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mRNA vaccines do that too but they represent a departure from the way we've introduced pathogens in the past.

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Most of the time we've used a bit of the real thing like killed pathogens or living ones that have been weakened or just pieces of them.

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There are even substances that bacteria just make.

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In any case, these bits are immune systems can spot are called antigens.

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Each antigen has a shape unique to a particular pathogen.

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When you get a vaccine, your immune system sees the antigen and sounds the alarm.

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That triggers the formation of memory cells that remember the bad guys as well as antibodies that disable the pathogen if it tries to invade in the future.

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Now think about how simple that is.

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Memory cells in antibodies.

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How is this informed consent?

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How is this in any way shape or form accurately representing what happens during a transfection?

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Of course it's not.

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But remember what this does.

38:38.000 --> 38:40.000
PBS NewsHour was saying the same thing.

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Bill Gates said the same thing three months ago.

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Vice Nude said the same thing.

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Vox said the same thing.

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And so seeing another cartoon like this.

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Well, it's an illusion of consensus that it's so easy.

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We can draw a cartoon with some cells that have little police sirens on the top of them and everybody will take it at face value.

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Of memory cells that remember the bad guys as well as antibodies that disable the pathogen if it tries to invade in the future.

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Now, mRNA vaccines still accomplish that goal.

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But instead of pieces of pathogens or any other strategy we've used in the past, they contain messenger RNA or mRNA for short.

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It works sort of like giving ourselves a build your own antigen kit instead of the actual antigen.

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The end product is the same.

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But we've asked ourselves to do the heavy lifting.

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That's because cells are kind of better at this stuff than we are.

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We can mess around with pathogens all day, but cells already know how to make antigens if we just supply the instructions.

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See, but that's just awful.

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Cells already know how to make antigens if we just supply the instructions.

39:41.000 --> 39:47.000
So again, it's this very disingenuous representation of the biology that they are manipulating.

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The very disingenuous representation of the fidelity with which they can manipulate it.

39:53.000 --> 40:00.000
And the very disingenuous representation of the biology that they don't understand by not telling you about it at all.

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Lies on top of lies on top of lies.

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And if it's oversimplification to the point of lying, it's the same thing.

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And you must see it.

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We must be able to show it.

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There are countless examples of this on the Internet that need to be archived.

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So that we can see it.

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I mean, think of this girl as saying something like, you know, we can put those people with those hats on those trains.

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And we can put them in those camps because they're making our, they're making our cities unclean.

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And now it turns out that that was really a crazy idea.

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An absolutely ridiculous idea, a racist idea.

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But we didn't care three years ago, but there's the video right now.

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This is what this is.

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This is very bad biology.

40:58.000 --> 41:01.000
It's very bad advice.

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Everybody that took the shot and was damaged by it could use this, in my humble opinion, as evidence of some sort of malfeasance.

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It's got to be.

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And the companies that made these kinds of videos and sold out and probably took money to do it or applied for grants to do it.

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They all need to be punished.

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Because people got comfort from this.

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People got rich from this.

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We need to take this into account and then fix it.

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I'm ready to make long lists of these creeps.

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I don't need to drag them out in the street or anything like that, but they need to pay some recompense because I got student loans to pay off.

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The solution is to copy out the instructions and send a message outside the nucleus.

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You might see where this is going.

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That message is made of messenger RNA, which contains a copy of the DNA instructions for use in protein making.

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The message exits the nucleus and makes its way to a ribosome in the cell.

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This piece of machinery reads the mRNA and translates the message into a protein.

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This is where the clever part comes in because we know the genetic code, so we can write our own message for the cell to translate.

42:30.000 --> 42:36.000
That's what an mRNA vaccine is, a coded genetic message from us to our cells for them to work out with their molecular decoder rings.

42:36.000 --> 42:39.000
Instead of an antigen, they contain the mRNA template to build an antigen.

42:39.000 --> 42:43.000
In the case of our COVID-19 vaccines, the message codes for an antigen called the spike protein.

42:43.000 --> 42:47.000
These spikes stick out of the virus, which uses them like a key to unlock and infect people's cells.

42:47.000 --> 42:54.000
When the shots go into people's upper arms, the mRNA molecules inside make their way into cells into ribosomes, which are more than happy to do their job and translate the message.

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Our cells display the finished spikes on their surface. Our immune system spots them and starts taking action.

42:59.000 --> 43:02.000
From there, it's thought that things work pretty much the same as more traditional vaccines.

43:02.000 --> 43:08.000
The immune system makes memory cells and antibodies, and once those defenses have kicked all the way in, boom, you're ready to fight off the real deal.

43:08.000 --> 43:11.000
But while we hope those memory cells will last a while, the message doesn't.

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It never finds its way out.

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It's the way it's going to be.

43:15.000 --> 43:16.000
It's the way it's going to be.

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It's thought that things work pretty much the same as more traditional vaccines.

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The immune system makes memory cells and antibodies, and once those defenses have kicked all the way in, boom, you're ready to fight off the real deal.

43:28.000 --> 43:31.000
But while we hope those memory cells will last a while, the message doesn't.

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It never finds its way into the nucleus, so it can't mess with our DNA master blueprint.

43:34.000 --> 43:41.000
It never is not a good word to use in biology. It never is a terrible word.

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Because it implies a certainty that almost never exists.

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Really, really, really bad.

43:49.000 --> 43:52.000
Which means it's not manipulating our genes or anything.

43:52.000 --> 43:55.000
The effects really are a lot like every other vaccine you've ever gotten.

43:55.000 --> 44:02.000
The effects really are a lot like every other vaccine you've ever gotten.

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Think about how insulting this video is now. No one what we know.

44:07.000 --> 44:10.000
These mRNA vaccines were designed pretty quickly in response to the pandemic.

44:10.000 --> 44:12.000
But that doesn't mean they came out of the blue.

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In fact, scientists have known about the potential of mRNA vaccines for decades.

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But it's taken years of testing and tweaking to get the technology right.

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For example, researchers had to figure out how to make the RNA molecules last long enough in our bodies to actually get translated.

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And when they figured that out, they awarded the Nobel Prize for that trick.

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They had to work out the perfect delivery vehicle to get the mRNA into cells and minimize side effects.

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The perfect delivery vehicle that could be manufactured into billions of doses.

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Yep, the perfect delivery vehicle.

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Even with all that in hand, before now, no RNA-based vaccine had ever made it out of the clinical trials.

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And there was no guarantee they'd ever work.

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But the ones we have for COVID-19 do work.

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At least to the best of our knowledge so far, they're safe and effective enough to help get the pandemic under control.

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And with the technology showing such promise, there's renewed interest in some older mRNA vaccine efforts for things like rabies and Zika.

44:54.000 --> 44:55.000
Some could even fight cancer.

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So that's what an mRNA vaccine is.

44:57.000 --> 45:01.000
A novel form of vaccine that teaches ourselves how to make something your immune system can learn from.

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They're not as different as you might think.

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But they have a ton of potential.

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mRNA vaccines are an elegant way to address a global crisis.

45:06.000 --> 45:11.000
And if you're ready to step up your appreciation of all the elegant signs and math have to offer, you might enjoy a course from Brilliant.

45:11.000 --> 45:14.000
Like their course on complex numbers, which will help you master algebra...

45:14.000 --> 45:18.000
So you see what we're up against, right? It's really not good.

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Because the people that aren't willing to work are very vulnerable to someone like that.

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So it is my pleasure now to introduce Dr. Drew Weisman.

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Dr. Weisman is one of the recipients of this year's Canada Gardener International Award for his pioneering work with Dr. Greco in developing new...

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So first of all, I would like you to notice that this woman who is announcing Dr. Weisman is maskless in 2022.

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The reason why I chose this lecture versus another one that I was going to watch is coming up in a second.

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The content of this lecture is also quite fun.

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I don't know if we'll make it all the way through.

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Probably going to go until about 1030 or 1045 and then kill it.

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Thanks for seeing me.

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Cle aside, modified mRNA therapeutics.

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Of course, the foundational technology for the highly...

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Ninety-three. Good to see you all here.

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He is the Roberts Family Professor and Vaccine Research Director of the Penn Institute for RNA Innovation and Director of Vaccine Research.

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Infectious Diseases Division at the University of Pennsylvania, Pearlman School of Medicine.

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So I am delighted to turn it over to Dr. Drew Weisman.

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Thank you.

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Thank you very much.

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I'm highly honored to receive this award.

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We've been treated great in Canada visiting all ends of it from the sounds of it of all the other awardees.

46:32.000 --> 46:39.000
What I wanted to do in today's talk is to give you an idea of the potential breadth of RNA technologies in the future.

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Hopefully everybody in this room has received a vaccine in their arm, but there's huge potential for what RNA can do in the future.

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Let me just start by telling you the difference between RNA vaccines and all the other vaccines made.

46:50.000 --> 46:53.000
Making an RNA vaccine is very simple.

46:53.000 --> 46:55.000
You designed the sequence.

46:55.000 --> 46:56.000
Katie described this.

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You in vitro transcribe it.

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That's a two-hour reaction.

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You puree of value.

46:59.000 --> 47:02.000
You might ask the question, why is he wearing a mask?

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But you shouldn't ask that question.

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He's wearing a mask because it's his job.

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Remember, there is a Scooby-Doo being played here.

47:13.000 --> 47:16.000
And the Scooby-Doo is not just about who did it.

47:16.000 --> 47:27.000
It's about crafting this entire ethos on one side, which doesn't think wearing a mask is ridiculous,

47:27.000 --> 47:33.000
but also doesn't think it's his place to tell everybody else in the room that they have to have a mask on.

47:34.000 --> 47:40.000
But if this is a national security psychological operation on the world,

47:40.000 --> 47:44.000
and it's very easy to see why he's got to wear a mask.

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He just gets a phone call.

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Hey, Drew, by the way, I need you to wear a mask today.

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What?

47:49.000 --> 47:50.000
I don't want to wear a mask.

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You got to wear a mask.

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We need you to be on screen wearing a mask the whole time.

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We need people scratching their head, Drew.

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Please wear a mask.

47:58.000 --> 48:00.000
You're not going to win the prize.

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No, obviously I don't know if he got that phone call.

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But what I'm suggesting to you is there's a reason why he's doing it.

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It's not because he knows better.

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It's not because he really believes in it.

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It is because he's part of the governance structure.

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It is governing our world right now.

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He's part of the machine.

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It's like a little cog in the wheel.

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And that's why he got the Nobel Prize because that cog in the wheel is necessary.

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A guy that will actually accept the Nobel Prize.

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And a lady that will actually accept the Nobel Prize with him for such a minuscule,

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ridiculously tiny idea that they know isn't theirs alone.

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It would be like giving me a Grammy.

48:58.000 --> 49:03.000
You know, it's like, okay, but I didn't really earn it.

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I've got some good papers on my CV.

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I mean, you know, you could, oh, whatever.

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But I mean, this is not, again, it's not revolutionary.

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As Robert Malone himself says, you can say it.

49:18.000 --> 49:21.000
They've been talking and thinking, trying this for decades.

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And it's not this that made it happen.

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But they needed a guy who would be willing to do this.

49:33.000 --> 49:37.000
Then that same guy is willing to wear a mask if he's told to wear a mask.

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It's not, it's not a, this is real.

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It's for all the marbles.

49:43.000 --> 49:43.800
You put into an

49:43.800 --> 49:45.000
sequence Cainie described this.

49:45.000 --> 49:46.000
You in vitro transcribe it.

49:46.000 --> 49:47.000
That's a two hour reaction.

49:47.000 --> 49:48.000
You pure of value away.

49:48.000 --> 49:50.000
The contaminants.

49:50.000 --> 49:52.000
You mix them with lipids that forms nanoparticles.

49:52.000 --> 49:54.000
You get rid of the ethanol and salts.

49:54.000 --> 49:56.000
And you put it in a bile and you've made a vaccine.

49:56.000 --> 49:59.000
If you want to change the vaccine, you change the sequence design.

49:59.000 --> 50:01.000
Everything else is identical.

50:01.000 --> 50:03.000
For all other vaccines, when you change the vaccine, when you make a new vaccine,

50:03.000 --> 50:04.000
you start over.

50:04.000 --> 50:07.000
You figure out how to produce the protein, how to purify it.

50:07.000 --> 50:08.000
Everything is different.

50:08.000 --> 50:10.000
Everything is a huge amount of work.

50:10.000 --> 50:16.080
Listen carefully to that, that absolutely awful, inverted,

50:16.080 --> 50:20.920
complainer, whiner, vaccine, suck, narrative.

50:20.920 --> 50:25.560
Listen to it, come, we got to play it back because it's just extraordinary.

50:25.560 --> 50:27.920
Private, that's a two-hour reaction.

50:27.920 --> 50:30.160
You puree value away the contaminants,

50:30.160 --> 50:32.840
you mix them with lipids that forms nanoparticles,

50:32.840 --> 50:36.400
you get rid of the ethanol and salts and you put it in a vial and you've made a vaccine.

50:36.400 --> 50:38.040
If you want to change the vaccine,

50:38.040 --> 50:40.840
you change the sequence design, everything else is identical.

50:40.840 --> 50:44.760
For all other vaccines, when you change the vaccine, when you make a new vaccine, you start over.

50:44.760 --> 50:47.800
You figure out how to produce the protein, how to purify it, everything is different,

50:47.800 --> 50:49.240
everything is a huge amount of work.

50:49.240 --> 50:52.120
No, everything is different, everything is a huge amount of work.

50:52.120 --> 50:57.880
I could throw my monitor against the wall right now that's, oh, angry, that makes me.

50:59.720 --> 51:01.320
That's how disrespectful it is.

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That's how lacking of respect for the sacred that is.

51:06.680 --> 51:12.040
What he's saying is, is that if we don't have to figure out a way to make a pure protein

51:13.080 --> 51:16.200
in order to add it to an adjuvant and make a vaccine,

51:16.200 --> 51:19.240
if we don't have to figure out how to make a pure protein,

51:19.240 --> 51:24.120
because that's always a pain in the ass, but we can let your body do it.

51:26.680 --> 51:33.880
Well, that's a lot easier, but it's not a lot safer and he's equating the two.

51:34.680 --> 51:41.560
He's equating the fact that the process of making different RNAs is the same,

51:42.520 --> 51:47.320
but the different processes of making different proteins is not the same,

51:49.000 --> 51:51.640
because different proteins purify in different ways.

51:51.640 --> 51:57.320
Different proteins have different levels of purity and production, blah, blah, blah, blah.

51:57.560 --> 52:04.280
And none of those variables change when you transfect somebody with an RNA,

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but those variables are now under the control of the thing that you're transfecting,

52:09.240 --> 52:14.120
and therefore, what? You're the vaccine factory.

52:15.080 --> 52:19.480
So what if you're a vaccine factory also doesn't make the protein very consistently,

52:19.480 --> 52:26.360
makes random errors, folds it incorrectly, etc. Like the moth cell would have done.

52:28.200 --> 52:30.920
Like the recombinant bacteria would have done.

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Like the whatever host you're growing the protein in for your recombinant.

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I'm not able to be very clear because he's so frustrating,

52:47.720 --> 52:53.000
but it's an extraordinary dumb, simple version of biology that says,

52:53.080 --> 52:57.080
okay, look, it's very easy to put mRNA in vials.

52:58.360 --> 53:02.360
It's very easy apparently to put mRNA in lipid nanoparticles in vials.

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And since that's really easy in mRNA and lipids are all in your body, this is very safe.

53:11.720 --> 53:13.320
And transfection is fine.

53:15.160 --> 53:20.040
And the only real problem with other vaccines is that you've got to purify a new protein

53:20.040 --> 53:22.520
or a new proteins. And man, is that a pain?

53:25.000 --> 53:27.480
Drew Weissman has no concern

53:30.120 --> 53:32.120
over the health of the vaccinee.

53:33.080 --> 53:35.960
No concern over the safety of the vaccinee.

53:36.840 --> 53:41.720
He has only concern over the production of the product.

53:42.520 --> 53:44.920
The process is the product said,

53:45.720 --> 53:49.480
Joe Josh Getsko the other night with John Campbell.

53:51.160 --> 53:54.520
The process of making an mRNA is stupid easy.

53:57.160 --> 54:01.960
And therefore it's so much better than making a protein from scratch

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and having to purify it and test it.

54:03.800 --> 54:05.720
And oh my gosh, what a nightmare.

54:08.360 --> 54:10.360
This is the ultimate lie.

54:10.920 --> 54:12.920
Because it's the ultimate lie.

54:12.920 --> 54:16.120
It is just so deceptive and so awful.

54:17.320 --> 54:21.320
And my only thoughts are that he is actually dense enough to believe it,

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that he really doesn't get it.

54:24.200 --> 54:28.680
That his lack of depth of understanding of biology is so great

54:28.680 --> 54:32.520
that he believes this exact stuff.

54:35.560 --> 54:37.640
And people have told him he's so smart,

54:38.120 --> 54:41.400
and people have told him he's so smart so often that he thinks,

54:41.400 --> 54:44.280
wow, this is pretty easy, this biology stuff's really easy.

54:45.160 --> 54:46.840
I mean, it's just cartoons and stuff.

54:47.560 --> 54:50.920
So when we started looking at vaccines, we looked at influenza.

54:50.920 --> 54:53.240
This is just the review of the current literature

54:53.240 --> 54:55.800
when we were first investigating influenza vaccines.

54:55.800 --> 54:58.200
The first two are similar to the human vaccines,

54:58.200 --> 55:02.440
the live virus we give to kids, the inactivated virus that we give to adults.

55:02.440 --> 55:05.720
And what's in parentheses are the viral titers you see in mice

55:05.800 --> 55:07.320
after two immunizations.

55:07.320 --> 55:09.320
This is, it's called an HAI titer.

55:09.320 --> 55:11.320
It's a pseudo neutralization titer.

55:11.320 --> 55:12.760
But you can see with all of these,

55:12.760 --> 55:14.760
titers in the one to 100 range are typical.

55:15.320 --> 55:18.040
One to 40 is protective, so this is considered a good titer.

55:18.040 --> 55:20.040
So do you understand what titer means now?

55:21.080 --> 55:24.280
Thanks to this brilliant teacher's explanation.

55:24.280 --> 55:25.400
Do you understand what it means?

55:25.400 --> 55:26.360
Because I sure don't.

55:27.240 --> 55:29.640
When we looked at HA encoding mRNA,

55:29.640 --> 55:32.920
and we're now comparing it to a live virus or an activated virus,

55:32.920 --> 55:35.480
the titer from mRNA was one to 2,500.

55:35.800 --> 55:38.280
That's 50 times better than an activated virus.

55:38.280 --> 55:39.400
50 times better?

55:39.400 --> 55:40.040
Is it really?

55:41.800 --> 55:42.520
Is it really?

55:43.960 --> 55:46.680
So like if I'm lighting my barbecue,

55:46.680 --> 55:50.200
and I want to put some lighter fluid on it to get the brickheads going,

55:50.760 --> 55:53.720
if I put some on and it burns for a little while,

55:53.720 --> 55:55.320
then it smokes for a little while,

55:55.320 --> 55:56.120
and then it's lit.

55:56.920 --> 56:00.040
If I put more on there and it's 50 times brighter,

56:00.040 --> 56:02.600
that is that guaranteed to be good?

56:02.920 --> 56:09.000
Or is it possible that putting 50 times the amount of lighter fluid on there

56:09.000 --> 56:12.360
will waste my charcoal and my lighter fluid and my deck?

56:15.320 --> 56:21.400
Is it possible that he is so naive as to think that activating the immune system

56:21.400 --> 56:26.920
is good and therefore overactivating the immune system by 100 times is even better?

56:29.320 --> 56:31.880
Is it possible that these people are so dumb?

56:33.560 --> 56:36.520
That they think that that's the way the biology works,

56:36.520 --> 56:41.720
that if we have a signal that we see in a naturally immune person,

56:42.600 --> 56:45.880
and we can make that signal stronger in a vaccinated person,

56:45.880 --> 56:50.280
that that obviously means that the vaccinated person is better off?

56:52.440 --> 56:54.440
Is there anything stupider than you?

56:55.000 --> 57:02.280
Is it possible that a graph so simple could be so stupid and presented so stupidly?

57:03.000 --> 57:09.240
Without any justification for the idea that these high titers are an indication

57:09.240 --> 57:10.760
of greater health outcomes.

57:11.320 --> 57:12.520
Are you joking?

57:14.760 --> 57:16.040
He's getting an award.

57:16.040 --> 57:17.480
He's accepting an award.

57:18.360 --> 57:19.400
He's a laureate.

57:26.040 --> 57:28.040
Five times better than live virus.

57:28.040 --> 57:30.920
This excited a lot of biotech and pharmaceutical companies,

57:30.920 --> 57:34.840
because typically in this excited a lot of biotech and pharmaceutical companies,

57:34.840 --> 57:40.920
not immunologists, not pediatricians.

57:43.560 --> 57:44.520
Vaccine research.

57:44.520 --> 57:47.560
If you can double a tighter with a new vaccine, people are excited.

57:48.280 --> 57:52.600
But as an immunologist, we wanted to understand why this vaccine was working so well.

57:52.600 --> 57:55.240
So this is a cartoon of how a B cell response develops,

57:56.200 --> 57:59.160
except there's no antigen presentation here at all.

58:01.400 --> 58:03.560
So we don't know why the T cell is talking.

58:05.960 --> 58:07.880
We don't know why the T cell woke up.

58:12.680 --> 58:15.640
But of course, there wouldn't be any matching peptide.

58:15.640 --> 58:20.760
No, this T cell wouldn't exist if an antigen presenting cell hadn't presented an antigen

58:20.760 --> 58:25.960
that this B cell recognized or an antigen that was conjuncted to it.

58:25.960 --> 58:34.200
And that means if there's T cells here as CD4 helper cells,

58:34.200 --> 58:36.840
then there are CD8 positive cells that are also activated,

58:36.840 --> 58:39.720
which is just not in this picture.

58:41.880 --> 58:46.440
So Drew Weisman, the immunologist, is teaching immunology based on antibodies.

58:47.960 --> 58:49.240
T cells is what they do.

58:49.240 --> 58:50.360
They make antibodies.

58:51.320 --> 58:56.120
B cells, they just activate B cells, so B cells can make antibodies.

58:56.120 --> 58:57.640
That's how the immune system works.

58:57.640 --> 58:58.760
This man is a liar.

59:01.000 --> 59:03.720
Molecular B cells interact with particles, viruses,

59:03.720 --> 59:05.080
antigens, adjuvants.

59:05.080 --> 59:09.480
They get help from CD4 positive T cells and form germinal center B cells.

59:09.480 --> 59:12.920
The germinal center is the site where the B cells rapidly proliferate,

59:12.920 --> 59:15.960
affinity, mature, and form plasma cells and memory cells.

59:16.520 --> 59:18.680
So we measured all of these populations.

59:18.760 --> 59:22.200
These were measuring the number of antigen-specific B cells of each type.

59:22.200 --> 59:24.920
We have a fluorescentated HA in the flow cocktail,

59:24.920 --> 59:28.440
and then other antibodies that identify each of these three populations.

59:28.440 --> 59:30.120
What you can see is that in all of them,

59:30.120 --> 59:33.800
we have about a 50-fold increase in the number of antigen-specific B cells.

59:34.520 --> 59:36.680
That accounts for the increase in antibody titer.

59:36.680 --> 59:40.440
We left some mice for over a year and went back and we measured the long-lived plasma cells

59:40.440 --> 59:41.480
in their bone marrow.

59:41.480 --> 59:45.640
Again, we saw huge numbers of these cells still present after a single immunization.

59:46.440 --> 59:48.120
But that didn't explain the mechanism,

59:48.120 --> 59:52.200
and we wanted to understand why we were getting these huge antigen-specific B cell responses.

59:52.920 --> 59:55.880
It came down to what are known as T follicular helper cells.

59:55.880 --> 59:59.320
These are a form of CD4 helpers that form germinal centers,

59:59.320 --> 01:00:02.120
and they supply the help to the germinal center B cells

01:00:02.120 --> 01:00:05.560
in order for them to affinity, mature, proliferate, and make memory in plasma cells.

01:00:06.760 --> 01:00:09.640
We used a macaque model system, and in these macaques,

01:00:09.640 --> 01:00:13.240
we gave them either an mRNA that encoded the HIV envelope,

01:00:13.240 --> 01:00:17.960
or we gave them that same envelope protein with a double-stranded RNA adjuvant.

01:00:17.960 --> 01:00:22.120
We chose that because that was one of the best-described adjuvants for inducing TSH cells.

01:00:23.080 --> 01:00:25.800
A double-stranded RNA adjuvant.

01:00:28.440 --> 01:00:33.480
Did you ever hear anything about a double-stranded RNA adjuvant being involved in this vaccine?

01:00:36.920 --> 01:00:37.880
That's weird.

01:00:37.880 --> 01:00:41.720
Could that be a proprietary thing that they don't mention anymore?

01:00:41.720 --> 01:00:44.600
Because it's proprietary that it's a double-stranded vaccine?

01:00:45.640 --> 01:00:47.080
RNA, is that possible even?

01:00:48.840 --> 01:00:51.800
That's weird. He did say that, right?

01:00:53.320 --> 01:00:53.960
Below.

01:00:53.960 --> 01:00:58.680
Or we gave them that same envelope protein with a double-stranded RNA adjuvant.

01:00:58.680 --> 01:01:02.760
We chose that because that was one of the best-described adjuvants for inducing TSH cells.

01:01:02.760 --> 01:01:10.040
Okay, so the middle one is the protein with a double-stranded RNA

01:01:10.040 --> 01:01:11.560
as the adjuvant, I see.

01:01:11.560 --> 01:01:16.840
And so then the envelope RNA, LNP, is transfection.

01:01:16.840 --> 01:01:17.320
Okay.

01:01:17.320 --> 01:01:18.440
FH cells.

01:01:18.440 --> 01:01:23.080
But as you can see, there's no comparison to the effect of the mRNA LNPs

01:01:23.080 --> 01:01:25.240
and the double-stranded RNA adjuvant.

01:01:25.240 --> 01:01:28.760
Huge numbers of TFHs were induced by the mRNA LNPs.

01:01:28.760 --> 01:01:30.200
We did a calculation.

01:01:30.200 --> 01:01:33.560
Typically for most vaccine adjuvants, double-stranded RNA,

01:01:33.560 --> 01:01:39.000
ALM, MF59, 5 to 10% of the CD4 helpers are TFH phenotype.

01:01:39.000 --> 01:01:41.320
Now keep in mind, he keeps selling the same thing.

01:01:41.320 --> 01:01:44.360
These immune markers, these activation assays,

01:01:45.640 --> 01:01:49.720
having a tenfold increase in these assay outcomes

01:01:50.760 --> 01:01:55.080
is a being assumed to be a more robust immune response.

01:01:55.880 --> 01:01:59.480
Rather than being, for example, an immune response

01:01:59.480 --> 01:02:03.800
that's overreactive, an immune response that's overstimulating,

01:02:04.360 --> 01:02:06.520
an immune response that's overpriming,

01:02:07.080 --> 01:02:12.280
or an immune response that's sort of weakening other immune responses

01:02:12.280 --> 01:02:20.120
by somehow occupying this space with so much of this one antigen or antigens.

01:02:21.400 --> 01:02:22.440
We don't know.

01:02:22.440 --> 01:02:23.880
He doesn't know for sure.

01:02:23.880 --> 01:02:26.280
I mean, you can hear from when he's not thought about it.

01:02:27.240 --> 01:02:28.920
And that's what's extraordinary here.

01:02:32.040 --> 01:02:34.040
For mRNA LNPs, it's over 50%.

01:02:35.000 --> 01:02:38.120
So this is an adjuvant that selectively induces TFH cells

01:02:38.120 --> 01:02:39.960
that drives B cell responses.

01:02:39.960 --> 01:02:42.440
That's what accounts for the huge antibody responses.

01:02:42.440 --> 01:02:44.600
You wanted to test these in an animal system.

01:02:44.600 --> 01:02:47.480
So in influenza, every year you have to make a new vaccine

01:02:47.480 --> 01:02:50.040
because the head of the virus, the HA, mutates,

01:02:50.040 --> 01:02:51.480
and prior vaccines don't work.

01:02:52.440 --> 01:02:55.960
We challenge the animals with a different subtype of HA.

01:02:55.960 --> 01:02:57.080
This is from an H5.

01:02:57.080 --> 01:02:59.560
See, that's not really a very good explanation either.

01:02:59.560 --> 01:03:00.760
The HA is changing.

01:03:00.760 --> 01:03:02.840
It's also being recombined.

01:03:05.000 --> 01:03:06.120
It's immunomethology.

01:03:06.120 --> 01:03:07.880
This guy's not teaching anything.

01:03:07.880 --> 01:03:09.720
He's bragging about his new product,

01:03:10.360 --> 01:03:12.520
and how much pharmaceutical companies love it.

01:03:13.080 --> 01:03:16.600
I had avian virus that occasionally causes pandemics.

01:03:16.600 --> 01:03:19.880
We saw complete protection with an H1 vaccine

01:03:19.880 --> 01:03:21.240
against an H5 virus.

01:03:21.640 --> 01:03:23.320
This is now going forward into humans

01:03:23.320 --> 01:03:25.080
as a universal influenza vaccine.

01:03:26.600 --> 01:03:28.360
I want to switch topics and now talk about

01:03:28.360 --> 01:03:30.040
the future of RNA therapeutics.

01:03:30.760 --> 01:03:31.960
If you've worked in this field,

01:03:31.960 --> 01:03:34.440
you know that the critical difficulty is targeting,

01:03:34.440 --> 01:03:36.600
is getting the nucleic acid or the virus

01:03:36.600 --> 01:03:37.960
to the cells of interest.

01:03:37.960 --> 01:03:39.880
With LNPs, they go to the liver.

01:03:39.880 --> 01:03:42.360
They bind APOE and they target hepatocytes.

01:03:42.360 --> 01:03:43.640
They also go to dendritic cells,

01:03:43.640 --> 01:03:44.760
which makes them a good vaccine.

01:03:45.320 --> 01:03:48.600
We wanted to know, could we target LNPs to other cell types?

01:03:48.600 --> 01:03:50.840
We concentrated on endothelial cells,

01:03:50.840 --> 01:03:52.680
T cells, and bone marrow stem cells.

01:03:53.960 --> 01:03:55.320
The platform that we used

01:03:55.320 --> 01:03:58.440
was to simply change the surface of the lipid nanoparticle.

01:03:58.440 --> 01:04:00.920
We attached antibodies, pieces of antibodies,

01:04:00.920 --> 01:04:02.920
receptor ligands, other proteins,

01:04:02.920 --> 01:04:04.840
to the surface of the lipid nanoparticle,

01:04:04.840 --> 01:04:06.920
using different types of conjugation chemistry.

01:04:07.560 --> 01:04:09.400
When we did that, we saw that we didn't change

01:04:09.400 --> 01:04:11.080
the morphology of the LNPs.

01:04:11.080 --> 01:04:12.040
They got a little bit bigger,

01:04:12.040 --> 01:04:14.120
which is the addition of an antibody coating,

01:04:14.120 --> 01:04:16.040
but they retained their surface charge.

01:04:16.040 --> 01:04:18.280
And most importantly, they retained function.

01:04:18.360 --> 01:04:20.280
So you can see and see, these are UVACs,

01:04:20.280 --> 01:04:22.280
primary human vascular endothelial cells.

01:04:22.840 --> 01:04:24.120
In the absence of targeting,

01:04:24.120 --> 01:04:26.360
you get no delivery of LNPs or mRNA.

01:04:26.920 --> 01:04:29.800
With targeting, we're using a PCAM antibody to target,

01:04:29.800 --> 01:04:31.720
and PCAM is expressed by UVACs.

01:04:31.720 --> 01:04:34.840
We see high levels of uptake and translation of the mRNA.

01:04:34.840 --> 01:04:36.520
So we could selectively target

01:04:36.520 --> 01:04:38.680
human endothelial cells in culture

01:04:38.680 --> 01:04:40.600
by targeting them with a PCAM antibody.

01:04:41.560 --> 01:04:43.800
We injected these LNPs into mice,

01:04:43.800 --> 01:04:45.720
and what you can see are really two things.

01:04:45.720 --> 01:04:47.640
The first is that, when we added an antibody

01:04:47.640 --> 01:04:49.320
to the surface of the LNP,

01:04:49.320 --> 01:04:50.840
we reduced liver uptake.

01:04:50.840 --> 01:04:53.080
We showed that we're actually blocking APOE binding.

01:04:53.720 --> 01:04:56.520
Most importantly, we're now seeing lung uptake,

01:04:56.520 --> 01:04:59.960
and about 50% of the delivered LNPs are going to the lungs.

01:04:59.960 --> 01:05:03.000
Lungs have the highest level of PCAM on endothelial cells.

01:05:04.600 --> 01:05:06.280
We wanted to see what else could we use this for?

01:05:06.920 --> 01:05:11.000
So in the cerebrovascular elements of science.

01:05:11.000 --> 01:05:12.600
You know, how many of these variables

01:05:12.600 --> 01:05:14.120
were changed in different batches

01:05:14.120 --> 01:05:15.000
in order to test them?

01:05:15.000 --> 01:05:15.560
We don't know.

01:05:16.440 --> 01:05:18.680
But they could have been changing these kinds of things

01:05:18.680 --> 01:05:21.560
in order to see if they could get more effectiveness

01:05:23.080 --> 01:05:25.240
and test a whole bunch of proprietary things

01:05:25.240 --> 01:05:27.000
in a way that they could never do otherwise.

01:05:28.120 --> 01:05:30.200
One of the things that I thought was very interesting

01:05:30.200 --> 01:05:34.120
in that thread that Mark read last night

01:05:34.120 --> 01:05:35.640
was in the very beginning of the thread,

01:05:35.640 --> 01:05:37.400
where it made it very clear that at the beginning

01:05:37.400 --> 01:05:40.520
of the pandemic, one of the things that activating

01:05:40.600 --> 01:05:46.360
the prep emergency does is it suspended a lot of regularly

01:05:47.560 --> 01:05:52.360
unsuspendable HIPAA laws so that the data around the pandemic

01:05:52.360 --> 01:05:54.520
and the data of people involved in the pandemic

01:05:54.520 --> 01:05:57.080
wasn't constrained in the way that it usually is.

01:05:58.520 --> 01:06:01.000
And those restrictions might still be open now.

01:06:03.400 --> 01:06:05.560
There's lots of games being played, ladies and gentlemen,

01:06:05.560 --> 01:06:06.760
lots of games being played,

01:06:06.760 --> 01:06:08.280
and this guy's part of the game show.

01:06:08.280 --> 01:06:10.440
Like he has agreed to play this role.

01:06:10.440 --> 01:06:11.320
He's happy to do it.

01:06:11.320 --> 01:06:13.000
He's getting comfort and fame for it.

01:06:13.000 --> 01:06:14.360
He's got a Nobel Prize for it.

01:06:14.360 --> 01:06:16.920
All he's got to do is accept the Nobel Prize for nothing.

01:06:18.120 --> 01:06:20.120
Accept the Nobel Prize for doing nothing.

01:06:20.120 --> 01:06:22.120
Think of Obama as really a cool guy.

01:06:22.920 --> 01:06:25.320
He would have given the Nobel Prize to somebody else

01:06:25.320 --> 01:06:26.440
when it was awarded to him.

01:06:28.280 --> 01:06:31.640
He'd have called up one of the other people on the list

01:06:31.640 --> 01:06:33.560
and said, hey, I think you really deserve it.

01:06:33.560 --> 01:06:35.640
So I want you to fly to Stockholm with me.

01:06:36.520 --> 01:06:38.920
And when I get it, I'm going to give it to you

01:06:39.960 --> 01:06:42.920
because I can go back home and win another presidential election

01:06:42.920 --> 01:06:44.440
with that play as well.

01:06:44.440 --> 01:06:45.640
And I don't need a million bucks.

01:06:45.640 --> 01:06:46.680
You need a million bucks.

01:06:47.880 --> 01:06:50.680
But Obama didn't do that because that wasn't his job.

01:06:51.960 --> 01:06:53.160
Because for whatever reason,

01:06:53.160 --> 01:06:55.000
they thought they could manipulate us better

01:06:55.000 --> 01:06:57.000
if they got us to do that, if they did that.

01:06:57.640 --> 01:07:00.200
Just like now they think that they can manipulate us better

01:07:00.200 --> 01:07:01.880
if they give the Nobel Prize to this thing.

01:07:01.880 --> 01:07:03.400
Maybe it's because in the courts,

01:07:04.040 --> 01:07:06.920
in a few years, Pfizer and these companies

01:07:06.920 --> 01:07:08.280
will use it as a defense.

01:07:09.480 --> 01:07:11.640
Well, I mean, we must not have done anything that bad

01:07:11.640 --> 01:07:13.720
because it got to Nobel Prize for what we did.

01:07:17.160 --> 01:07:18.520
That was one of our scientists.

01:07:18.520 --> 01:07:19.400
She works for us.

01:07:23.800 --> 01:07:25.720
The magic spell is very deep.

01:07:25.720 --> 01:07:28.120
Ladies and gentlemen, it's going to take a while to break out.

01:07:28.120 --> 01:07:29.400
Strokes are a common occurrence.

01:07:30.200 --> 01:07:31.880
Typically when a patient has a stroke

01:07:31.880 --> 01:07:34.280
and needs to make a CAT scan 24 hours later,

01:07:34.280 --> 01:07:37.960
you see a small area of dead brain

01:07:37.960 --> 01:07:39.960
that's fed by that middle cerebral artery

01:07:39.960 --> 01:07:41.160
that had the stroke.

01:07:41.160 --> 01:07:43.160
But that's not the main problem of stroke.

01:07:43.160 --> 01:07:45.080
What happens in the following days

01:07:45.080 --> 01:07:48.120
is the stroke extends and gets much larger.

01:07:48.120 --> 01:07:49.800
And that's because that initial stroke

01:07:49.800 --> 01:07:51.880
leads to edema inflammation

01:07:51.880 --> 01:07:53.880
and extension of the area of brain death.

01:07:54.920 --> 01:07:57.640
So we developed a system where we could inject

01:07:57.640 --> 01:08:00.280
TNF alpha pro-inflammatory cytokine

01:08:00.360 --> 01:08:02.120
into one hemisphere of a mouse brain.

01:08:02.920 --> 01:08:06.280
And then we treated those TNF inflamed brains

01:08:06.280 --> 01:08:08.680
with a nanoparticle that targeted the brain,

01:08:08.680 --> 01:08:11.880
targeted the blood brain barrier using VCAM targeting.

01:08:11.880 --> 01:08:15.240
We delivered an mRNA that encoded thrombo-modulin,

01:08:15.240 --> 01:08:18.200
which is an anti-clauding anti-inflammatory protein.

01:08:18.200 --> 01:08:19.880
And what you can see on the left is that

01:08:19.880 --> 01:08:22.920
when we treated animals with a VCAM targeted LNP

01:08:22.920 --> 01:08:24.280
with thrombo-modulin,

01:08:24.280 --> 01:08:26.440
we got rid of all of the vascular leakage.

01:08:27.080 --> 01:08:29.560
So that in theory would get rid of that extension

01:08:29.560 --> 01:08:32.280
of the infarct to greater portions of the brain

01:08:32.280 --> 01:08:33.480
as a potential therapeutic.

01:08:34.760 --> 01:08:37.640
My lab has had an interest in HIV for a long time.

01:08:37.640 --> 01:08:39.640
So we wanted to see, could we target T cells?

01:08:40.280 --> 01:08:41.160
We did the same thing.

01:08:41.160 --> 01:08:42.520
We added antibodies to the surface

01:08:42.520 --> 01:08:44.680
and we could successfully target primary CD4

01:08:44.680 --> 01:08:45.560
positive T cells.

01:08:46.120 --> 01:08:48.920
But most importantly, if you've ever worked with T cells,

01:08:48.920 --> 01:08:51.080
they don't have endocytic activity.

01:08:51.080 --> 01:08:54.120
That means they can't endocytose free particles.

01:08:54.120 --> 01:08:56.360
You can't deliver nucleic acids with lipids

01:08:56.360 --> 01:08:59.000
polycadions or other particle delivery systems.

01:08:59.000 --> 01:09:00.840
The only way you can do it was electroporation.

01:09:01.560 --> 01:09:03.000
Our hypothesis was,

01:09:03.000 --> 01:09:06.200
if we had an antibody that bound an antigen on T cells

01:09:06.200 --> 01:09:08.440
that was endocytosed after binding,

01:09:08.440 --> 01:09:10.920
that would bring the lipid nanoparticle into the T cell.

01:09:10.920 --> 01:09:12.360
And that's what we're seeing here.

01:09:12.360 --> 01:09:15.240
Purified human T cells targeted with embolizumab,

01:09:15.240 --> 01:09:17.880
which is a clinically used anti-CD4 antibody,

01:09:17.880 --> 01:09:19.800
gives high levels of luciferase activity.

01:09:19.800 --> 01:09:22.120
Oh, so T cells are taking up the LNP.

01:09:22.120 --> 01:09:24.600
So if we have monoclonal antibodies,

01:09:24.600 --> 01:09:27.480
though, then we can target lipids to different places.

01:09:27.480 --> 01:09:28.360
That's interesting.

01:09:29.560 --> 01:09:31.080
So monoclonal antibodies

01:09:31.080 --> 01:09:33.800
are probably going to be combined with lipid nanoparticles

01:09:33.800 --> 01:09:35.960
to get the transfection to go to the targets

01:09:35.960 --> 01:09:37.080
that it's supposed to go to.

01:09:37.080 --> 01:09:37.640
That's cute.

01:09:38.600 --> 01:09:39.160
Interesting.

01:09:40.200 --> 01:09:41.720
I don't think it's going to be foolproof.

01:09:42.200 --> 01:09:44.120
I don't think it'll be 100% targeting,

01:09:44.120 --> 01:09:46.760
but it might weight that to a particular place.

01:09:47.560 --> 01:09:49.560
And for the T cells, it might work.

01:09:49.560 --> 01:09:51.640
For things like tumors, it might work.

01:09:52.840 --> 01:09:53.400
Interesting.

01:09:54.280 --> 01:09:59.320
So antibodies are harder to patent now,

01:10:00.520 --> 01:10:02.680
which means that you don't need to worry about

01:10:02.680 --> 01:10:04.840
infringing on other companies' patents

01:10:04.840 --> 01:10:06.760
in order to make monoclonal antibodies

01:10:06.760 --> 01:10:08.360
to coach your lipid nanoparticles.

01:10:08.360 --> 01:10:09.800
But you're going to have to have the patents

01:10:09.800 --> 01:10:11.000
on the lipid nanoparticles.

01:10:11.800 --> 01:10:14.280
You're going to have to, well, that's interesting stuff,

01:10:14.280 --> 01:10:14.600
isn't it?

01:10:15.800 --> 01:10:18.920
Monoclonal antibodies, not monoclonal antibodies anymore.

01:10:18.920 --> 01:10:20.360
Can't make big money off of them.

01:10:21.320 --> 01:10:22.680
Just in time for them to be

01:10:23.480 --> 01:10:27.160
used to coat lipid nanoparticles for different purposes,

01:10:27.160 --> 01:10:29.560
you know, like embolismab.

01:10:31.880 --> 01:10:36.120
MAB, everything that ends in MAB is monoclonal antibody.

01:10:37.640 --> 01:10:38.840
Yes, ladies and gentlemen,

01:10:38.840 --> 01:10:40.680
I think the walls are visible.

01:10:40.680 --> 01:10:42.680
I think I see the back of the theater.

01:10:43.560 --> 01:10:45.320
I think I see the back of the theater.

01:10:45.880 --> 01:10:47.720
It's the RNA is released and it's translated.

01:10:49.000 --> 01:10:51.400
When we inject these into animals, the spleen likes top.

01:10:51.960 --> 01:10:54.520
But most importantly, we re-image those animals

01:10:54.520 --> 01:10:56.040
after we took out all of those organs.

01:10:56.040 --> 01:10:57.960
Electroporation isn't that big of a deal.

01:10:57.960 --> 01:10:59.400
Electroporation is really old.

01:10:59.400 --> 01:11:03.480
So using electroporation in cell lines, that's really old.

01:11:05.240 --> 01:11:06.680
And that's why Robert Malone

01:11:06.680 --> 01:11:09.880
making a big deal about his pulsed electric fields.

01:11:10.680 --> 01:11:14.520
His absolutely, it's just...

01:11:17.640 --> 01:11:19.880
I mean, he sounds like a clown when he says it.

01:11:19.880 --> 01:11:20.920
It's just dumb.

01:11:21.000 --> 01:11:24.920
It's like claiming that you're inventing a light bulb

01:11:24.920 --> 01:11:25.800
or something like that.

01:11:25.800 --> 01:11:27.080
Like it's really old tech.

01:11:28.920 --> 01:11:30.920
So don't be surprised if they use it,

01:11:30.920 --> 01:11:33.720
but the idea that it's somehow new, it's ridiculous.

01:11:34.520 --> 01:11:36.280
And what we're seeing now are lymph nodes.

01:11:36.280 --> 01:11:39.480
These are periordic and inguinal lymph nodes are lighting up.

01:11:39.480 --> 01:11:41.880
So the LNPs injected intravenously

01:11:41.880 --> 01:11:44.680
are getting out of the circulation into the tissues,

01:11:44.680 --> 01:11:45.560
into the lymphatic.

01:11:45.560 --> 01:11:46.600
And is that what we want?

01:11:46.600 --> 01:11:49.560
We want lymph nodes and a lot of cells in the lymph node

01:11:49.560 --> 01:11:51.320
transfected, even though in the lymph node,

01:11:51.320 --> 01:11:52.920
those are supposed to be an assortment

01:11:52.920 --> 01:11:56.280
and a bouquet of unique cells waiting to be activated

01:11:56.280 --> 01:11:59.800
when the right antigen combination is encountered.

01:12:01.160 --> 01:12:03.560
Do we really want to transfect all those cells?

01:12:05.080 --> 01:12:07.240
I just don't see any nuance here.

01:12:07.240 --> 01:12:09.080
I don't even see any understanding

01:12:09.080 --> 01:12:10.680
of how the immune system works.

01:12:11.720 --> 01:12:14.760
I see a rudimentary understanding in his mind

01:12:14.760 --> 01:12:16.760
of how antibodies work

01:12:16.760 --> 01:12:20.120
and how how luciferase works.

01:12:21.960 --> 01:12:25.000
But what it means is we've transfected all the cells

01:12:25.000 --> 01:12:25.880
in that lymph node.

01:12:25.880 --> 01:12:27.400
And I don't think that that's how

01:12:27.400 --> 01:12:29.080
you augment the immune system.

01:12:29.080 --> 01:12:29.960
I really don't.

01:12:31.320 --> 01:12:32.520
This is just crazy.

01:12:37.000 --> 01:12:39.320
RNA, which is translated and shows up.

01:12:41.400 --> 01:12:43.240
We switched to a model system

01:12:43.240 --> 01:12:46.760
that has a Lox-P reporter gene in it,

01:12:46.760 --> 01:12:48.360
in this case, a green fluorescent protein.

01:12:49.240 --> 01:12:51.400
The mRNA that we delivered with the LMPs

01:12:51.400 --> 01:12:53.400
and coded creorecombinase.

01:12:53.400 --> 01:12:56.680
So the creorecombinase removes the stop codon

01:12:56.680 --> 01:12:58.120
and makes targeted cells green.

01:12:59.400 --> 01:13:03.000
We injected the targeted creorecombinase LMPs into an animal.

01:13:03.000 --> 01:13:03.960
And without targeting,

01:13:03.960 --> 01:13:06.120
you get very little green protein.

01:13:06.120 --> 01:13:07.240
With CD4 targeting,

01:13:07.240 --> 01:13:09.720
you get high levels of green protein in lymph nodes

01:13:09.720 --> 01:13:10.760
and the spleen.

01:13:10.760 --> 01:13:11.960
But what's important to notice here

01:13:12.040 --> 01:13:13.240
is that on the y-axis,

01:13:13.240 --> 01:13:14.440
that's an activation marker.

01:13:15.160 --> 01:13:18.520
So we're seeing equal amounts of delivery of LMPs

01:13:18.520 --> 01:13:21.960
to resting T cells as we see with activated T cells.

01:13:21.960 --> 01:13:23.720
That's important because in HIV,

01:13:23.720 --> 01:13:25.880
the resting CD4 positive T cells

01:13:25.880 --> 01:13:27.800
are the site of HIV latency.

01:13:27.800 --> 01:13:30.280
And they have to be targeted in an animal or in a human.

01:13:31.880 --> 01:13:34.200
We also wondered, could we deliver car T cells?

01:13:38.200 --> 01:13:39.640
These are all in my mind.

01:13:39.640 --> 01:13:42.440
Performance level stunt experiments

01:13:42.440 --> 01:13:47.880
designed to make an in vitro side of the mouth argument

01:13:47.880 --> 01:13:50.360
that this technology is useful for things.

01:13:51.400 --> 01:13:52.680
But in that last figure,

01:13:53.480 --> 01:13:55.400
he points down here to say that,

01:13:55.400 --> 01:13:56.600
look, these are activated.

01:13:57.640 --> 01:14:00.040
And this is resting T cells.

01:14:00.040 --> 01:14:01.400
And these are activated T cells.

01:14:01.400 --> 01:14:03.080
And we have to get at the resting T cells.

01:14:03.080 --> 01:14:05.080
There's some of these, one of these two graphs

01:14:05.080 --> 01:14:06.120
he's talking about there.

01:14:07.000 --> 01:14:09.240
But he's getting at both populations, not one.

01:14:10.520 --> 01:14:12.680
So he's talking about transpecting

01:14:12.680 --> 01:14:16.280
almost all of the T cells in your body with one antigen.

01:14:17.560 --> 01:14:19.400
How in the hell would that be useful?

01:14:20.360 --> 01:14:23.480
How in the hell can you imagine that being a useful

01:14:26.440 --> 01:14:29.800
product, a useful way of augmenting the immune system?

01:14:29.800 --> 01:14:33.000
That's not even close to what we want to do.

01:14:35.960 --> 01:14:38.200
Think about how extraordinary that is.

01:14:38.200 --> 01:14:40.520
All of these T cells had previously

01:14:42.520 --> 01:14:45.560
unique T cell receptor specificity,

01:14:45.560 --> 01:14:48.280
and then they were transfected and activated

01:14:49.960 --> 01:14:54.120
by an LNP with RNA and an antibody

01:14:54.120 --> 01:14:56.440
that bound them and got them to be activated.

01:14:56.440 --> 01:14:57.400
That's crazy.

01:14:58.440 --> 01:15:00.440
We are not talking about even knowing

01:15:00.440 --> 01:15:02.200
how we're augmenting the immune system.

01:15:02.200 --> 01:15:03.720
We're talking about how we get these

01:15:04.360 --> 01:15:07.800
in vitro assays to turn colors and stuff.

01:15:08.680 --> 01:15:12.040
Before positive T cells are the site of HIV latency,

01:15:12.040 --> 01:15:14.520
and they have to be targeted in an animal or in a human.

01:15:16.040 --> 01:15:18.840
We also wondered, could we deliver CAR T cells?

01:15:18.840 --> 01:15:20.520
So this is what a CAR T cell is.

01:15:21.640 --> 01:15:25.960
In CVA positive T cells recognize antigen plus MHC,

01:15:26.520 --> 01:15:29.240
and when they recognize that peptide MHC,

01:15:29.240 --> 01:15:32.280
they kill those antigens on a tumor cell

01:15:32.280 --> 01:15:33.560
or a virally infected cell.

01:15:34.760 --> 01:15:36.040
An alternative was developed,

01:15:36.040 --> 01:15:37.880
known as a chimeric antigen receptor.

01:15:38.360 --> 01:15:41.560
And what happens there is that the CARs recognize

01:15:41.560 --> 01:15:42.760
a specific antigen.

01:15:43.320 --> 01:15:45.720
And the first that were developed were CD19.

01:15:46.280 --> 01:15:49.320
CD19 is expressed by leukemias of lymphomas,

01:15:49.320 --> 01:15:53.320
and CARs that recognize CD19 delete the tumors.

01:15:53.320 --> 01:15:57.480
They have clinical efficacy in the 60, 70, 80 percent range.

01:15:57.480 --> 01:16:00.120
That's a huge advance in cancer chemotherapy

01:16:00.120 --> 01:16:01.560
using delivery of CAR T cell.

01:16:02.120 --> 01:16:04.280
The problem is this is what it takes.

01:16:04.280 --> 01:16:06.360
So what's annoying about that picture is

01:16:06.360 --> 01:16:08.680
that it really looks like if they're just trying to lie.

01:16:10.120 --> 01:16:12.520
Because what the tumor cell is doing.

01:16:29.880 --> 01:16:32.600
What the CAR T cell is doing is

01:16:32.600 --> 01:16:35.160
recognizing the same MHC1 receptor,

01:16:35.160 --> 01:16:38.520
and then it's triggering the cell death of the tumor cell.

01:16:40.440 --> 01:16:43.000
I'm not really sure how that's any different than this

01:16:43.000 --> 01:16:45.560
with a cytotoxic T cell,

01:16:45.560 --> 01:16:48.520
and it's monitoring of cancer.

01:16:49.640 --> 01:16:56.360
It might be that they are able to engineer chimeric T cells,

01:16:56.360 --> 01:17:00.200
which are more capable of inducing apoptosis.

01:17:00.200 --> 01:17:01.000
That's possible.

01:17:01.960 --> 01:17:06.600
But this is not augmentation of your immune system.

01:17:06.600 --> 01:17:07.560
Do you understand that?

01:17:08.680 --> 01:17:09.800
Let me repeat that again.

01:17:09.800 --> 01:17:12.520
This is not augmentation of your immune system.

01:17:12.520 --> 01:17:16.680
This is using mRNA to create T cells

01:17:16.680 --> 01:17:21.080
that have a different kind of signaling molecule on the outside

01:17:21.080 --> 01:17:22.200
via a transfection,

01:17:22.200 --> 01:17:24.600
and then putting those T cells into somebody

01:17:24.600 --> 01:17:26.040
and having them kill a tumor.

01:17:27.480 --> 01:17:30.680
That is no way shape or form augmenting your immune system.

01:17:30.760 --> 01:17:31.800
Do you understand that?

01:17:34.280 --> 01:17:37.160
Answer chemotherapy using the delivery of CAR T cell.

01:17:37.720 --> 01:17:41.080
The problem is this is what it takes to make a CAR T cell.

01:17:41.080 --> 01:17:43.320
You have to take cells out of a patient,

01:17:43.320 --> 01:17:45.240
you infect them with a lentivirus,

01:17:45.240 --> 01:17:47.080
you expand them for a couple weeks,

01:17:47.080 --> 01:17:49.160
and then you give cells back to the patient.

01:17:49.160 --> 01:17:52.360
It works great, but it costs a half a million dollars per dose,

01:17:52.360 --> 01:17:53.400
which is problematic.

01:17:54.360 --> 01:17:59.240
What we proposed is whether we could make CAR T cells in vivo.

01:18:00.120 --> 01:18:02.760
So our idea was that if we could target T cells,

01:18:02.760 --> 01:18:05.960
and in this case, we used a CD5 targeting molecule

01:18:05.960 --> 01:18:08.360
that targets both CD4s and CD8s,

01:18:08.360 --> 01:18:11.800
and encode the chimeric antigen receptor in the mRNA.

01:18:12.600 --> 01:18:14.600
The T cell would take up the LNPs,

01:18:14.600 --> 01:18:16.840
the RNA would make CARs on the surface,

01:18:16.840 --> 01:18:18.920
and we chose a CAR that targeted fiberglass.

01:18:20.440 --> 01:18:24.760
We tested this in vitro, 80% of the T cells made the CAR.

01:18:24.840 --> 01:18:29.080
In vivo, 25% of the T cells express CARs on their surface,

01:18:29.800 --> 01:18:32.200
and we use the model of fibrosis.

01:18:32.200 --> 01:18:34.040
So if you make a mouse hypertensive,

01:18:34.040 --> 01:18:35.720
they develop cardiac fibrosis.

01:18:36.360 --> 01:18:39.960
Most cardiac diseases are mediated by the fibrosis

01:18:39.960 --> 01:18:41.880
that forms after the disease insult.

01:18:42.520 --> 01:18:43.960
This is an echocardiography,

01:18:43.960 --> 01:18:46.680
a way of taking pictures of the function of the heart.

01:18:46.680 --> 01:18:48.200
And we can see on the right,

01:18:48.200 --> 01:18:50.760
we're measuring diastolic and systolic volumes.

01:18:50.760 --> 01:18:53.240
When the heart becomes fibros that can't function,

01:18:53.240 --> 01:18:54.360
and the volumes get bigger.

01:18:55.000 --> 01:18:57.240
In the bottom right is the ejection fraction.

01:18:57.240 --> 01:19:00.200
This is the amount of blood that the heart pumps out with each beat.

01:19:00.760 --> 01:19:02.120
When the heart becomes fibrotic,

01:19:03.960 --> 01:19:06.120
the amount of blood that's released is reduced,

01:19:06.120 --> 01:19:07.960
and the ejection fraction is reduced.

01:19:07.960 --> 01:19:11.720
So gray is a normal animal, yellow is a fibrotic animal,

01:19:12.440 --> 01:19:15.080
red is those animals treated with one treatment

01:19:15.080 --> 01:19:18.760
of CD5 targeted LNPs that make fat CARs.

01:19:18.760 --> 01:19:21.480
And we can see we return their cardiac function to normal.

01:19:22.120 --> 01:19:23.880
When we stain the hearts of these animals,

01:19:23.880 --> 01:19:25.960
the normal saline treated on the right,

01:19:25.960 --> 01:19:27.560
the middle are fibrotic animals.

01:19:27.560 --> 01:19:29.560
You see high levels of fibrosis.

01:19:29.560 --> 01:19:33.640
The left is one treatment with fat CAR LNPs targeted the T cells,

01:19:33.640 --> 01:19:35.640
and we return the fibrosis to nearly normal.

01:19:36.280 --> 01:19:38.840
So with an off-the-shelf mRNA LNP,

01:19:38.840 --> 01:19:41.960
we could cure cardiac fibrosis in this animal model.

01:19:42.920 --> 01:19:46.040
In this animal model, they can cure cardiac fibrosis,

01:19:46.040 --> 01:19:49.400
but we have no idea whether this animal will go on living a healthy life.

01:19:50.280 --> 01:19:53.560
But again, I will state clearly,

01:19:53.560 --> 01:19:57.080
this is not augmenting the mouse's immune system.

01:20:01.480 --> 01:20:07.480
It was a very complicated treatment of harvested T cells

01:20:07.480 --> 01:20:10.520
to create a specific army that could do this.

01:20:10.520 --> 01:20:11.000
That's it.

01:20:12.520 --> 01:20:15.720
It's a neat trick, very expensive, very meticulous,

01:20:16.680 --> 01:20:19.080
but it doesn't augment the animal's immune system.

01:20:19.160 --> 01:20:22.120
It's no different than giving model clonal antibodies, but it's better.

01:20:22.760 --> 01:20:24.280
Great. I'm glad that it works.

01:20:28.600 --> 01:20:32.440
But now the mRNA targeting T cells is something completely different.

01:20:32.440 --> 01:20:35.640
And if this is what he did to get this picture,

01:20:36.760 --> 01:20:40.200
then he's augmented a lot of T cells that didn't need to do this.

01:20:41.080 --> 01:20:43.080
And what were those T cells doing before?

01:20:44.440 --> 01:20:46.840
Because he didn't augment just resting T cells,

01:20:46.840 --> 01:20:50.680
he also augmented activated and active T cells and memory cells.

01:20:52.120 --> 01:20:53.560
So what were those T cells doing?

01:20:53.560 --> 01:20:57.080
And has he changed what they did or can do or are capable of doing?

01:20:58.200 --> 01:21:02.520
Has he activated them in such a way that their counterparted regulatory T cells

01:21:02.520 --> 01:21:03.640
will not be activated?

01:21:03.640 --> 01:21:06.440
And therefore, instead of going back to memory,

01:21:07.320 --> 01:21:09.640
we'll go into apoptosis after activation.

01:21:11.960 --> 01:21:13.400
So you get rid of the fibrosis,

01:21:13.400 --> 01:21:18.120
but you completely destroyed the immune system because all the previous T cell memory was erased.

01:21:18.120 --> 01:21:23.800
I don't know. He doesn't know because the animals were sacrificed in order to make these figures.

01:21:31.000 --> 01:21:33.960
Another thing we were interested was targeting stem cells.

01:21:33.960 --> 01:21:38.840
So bone marrow stem cells are the source of all of our red cells, white cells, granosites

01:21:38.840 --> 01:21:42.120
that allow our immune systems and our respiratory systems to function.

01:21:44.280 --> 01:21:51.240
Sickle cell anemia is a disease that has 300,000 people born with it every year.

01:21:51.240 --> 01:21:54.040
They're mainly in Africa, but you see them across the world.

01:21:54.760 --> 01:21:58.440
The problem is, is you can't do bone marrow biopsies and viral infections

01:21:58.440 --> 01:22:03.240
on 300,000 people a year in regions like Africa and India and the Middle East.

01:22:03.240 --> 01:22:05.320
It cost about a million dollars per treatment,

01:22:06.200 --> 01:22:08.680
and the facilities to do these things aren't available.

01:22:09.320 --> 01:22:14.760
So our idea was that if we could find antigens that selectively targeted bone marrow stem cells,

01:22:14.760 --> 01:22:19.080
it's not me being able to deliver LNPs and target them, and that's what we did here.

01:22:19.080 --> 01:22:24.200
We saw that with a single treatment, 85 to 95 percent of bone marrow stem cells

01:22:24.200 --> 01:22:29.880
and progenitor cells were targeted by the LNPs, and we could mediate gene recombination in these cells.

01:22:30.680 --> 01:22:35.160
Most importantly, what you need to do is call the secondary transplant.

01:22:35.160 --> 01:22:40.360
So you treat mice once with the LNPs, you wait six months and take their bone marrow

01:22:40.360 --> 01:22:45.400
and put them into a radiated mice that no longer have bone marrow stem cells,

01:22:45.400 --> 01:22:50.920
and we found that our targeted LNPs from the previous mice, 100 percent of the red cells,

01:22:50.920 --> 01:22:54.440
white cells, and granulocytes were gene recombined.

01:22:54.440 --> 01:23:01.320
So that means with a single injection, and in this case it's 0.1 micrograms of mRNA LNPs,

01:23:01.400 --> 01:23:05.720
could gene edit 100 percent of the repopulating bone marrow stem cells?

01:23:05.720 --> 01:23:06.280
Wait, what?

01:23:09.480 --> 01:23:17.240
How the hell can you edit the stem cells if it's just RNA?

01:23:17.880 --> 01:23:21.560
I thought they told us in that previous video that it doesn't go into your DNA.

01:23:21.560 --> 01:23:23.880
It doesn't mess with your DNA at all, like anything.

01:23:26.360 --> 01:23:27.560
The hell did he just say?

01:23:27.560 --> 01:23:35.960
The single injection, and in this case it's 0.1 micrograms of mRNA LNPs,

01:23:35.960 --> 01:23:39.720
could gene edit 100 percent of the repopulating bone marrow stem cells?

01:23:39.720 --> 01:23:41.320
But these go to the bone marrow.

01:23:42.280 --> 01:23:47.240
We saw that from the Japanese data that Byron Brittle released.

01:23:48.120 --> 01:23:49.560
It goes to the bone marrow.

01:23:50.600 --> 01:23:57.240
Are you telling me, is he telling us that this LNP carrying mRNA is capable of editing our

01:23:57.320 --> 01:24:01.640
bone marrow cells, our precursor cells to all of our blood?

01:24:04.040 --> 01:24:05.160
Did he just say that?

01:24:05.880 --> 01:24:06.280
Cells.

01:24:06.920 --> 01:24:10.360
So now we can go to Africa, India, the Middle East, the United States,

01:24:10.360 --> 01:24:13.320
Europe, anywhere there are people with sickle cell anemia.

01:24:13.880 --> 01:24:18.920
We can give them a single injection of mRNA LNPs that target the bone marrow,

01:24:18.920 --> 01:24:23.400
and that can correct the sickle cell gene defect and cure their disease.

01:24:23.400 --> 01:24:28.120
So instead of a million dollars per treatment, now we're looking at a couple hundred dollars,

01:24:28.120 --> 01:24:32.520
maybe a thousand dollars per treatment, and we can easily cure sickle cell anemia

01:24:32.520 --> 01:24:38.120
with a single injection intravenously of RNA LNPs by targeting them to this bone marrow stem

01:24:38.120 --> 01:24:43.160
cells and delivering an enzyme through RNA that fixes the gene defects.

01:24:44.680 --> 01:24:46.360
You can do a lot of other things.

01:24:46.360 --> 01:24:49.320
You can deliver toxic genes to stem cells.

01:24:49.320 --> 01:24:54.360
So now when we do bone marrow transplants, you have to irradiate people or give them

01:24:54.360 --> 01:24:57.800
high doses of chemotherapy to kill the bone marrow stem cells.

01:24:57.800 --> 01:25:03.080
The problem is it also kills the gastrointestinal cells and many other necessary cells.

01:25:03.080 --> 01:25:06.200
That has toxicities and mortality up to about 5%.

01:25:07.160 --> 01:25:09.400
Now we can deliver an mRNA LNP.

01:25:09.400 --> 01:25:13.240
We can selectively kill the bone marrow stem cells and easily do transplants.

01:25:13.800 --> 01:25:16.840
We can also deliver therapeutic proteins that stimulate

01:25:18.120 --> 01:25:24.200
B cells, granulocytes, platelets, many other cell types that can be easily delivered to the

01:25:24.200 --> 01:25:24.920
bone marrow.

01:25:26.200 --> 01:25:32.680
So our conclusion is that mRNA LNP therapeutics has the potential to do many different things.

01:25:32.680 --> 01:25:36.280
We have vaccines for many different diseases in clinical trials.

01:25:36.280 --> 01:25:40.600
We're developing ways of doing gene therapy in bone marrow stem cells.

01:25:40.600 --> 01:25:45.640
We can target heart, we can target brain, we can target lungs that allows us to deliver

01:25:45.640 --> 01:25:49.400
mRNA LNP therapeutics to many different organisms in the cell type.

01:25:49.400 --> 01:25:51.800
Come on man, let me see if this is the future of mRNA LNP.

01:25:54.600 --> 01:25:57.400
I need to thank all of the people in my lab and all of the lab lab.

01:25:57.400 --> 01:25:58.840
Let it go, let it go.

01:25:58.840 --> 01:26:00.440
I'm taking this your boo wiggle.

01:26:00.440 --> 01:26:03.400
I gather for a dollar to be at least 5% of my mRNA.

01:26:03.400 --> 01:26:04.600
Like this, back to the back.

01:26:04.600 --> 01:26:09.400
See this colony, including the telceletus therapy, which is a company that computer

01:26:09.800 --> 01:26:10.040
started.

01:26:13.320 --> 01:26:17.840
Bellamy LNP and my other lab got installed.

01:28:09.400 --> 01:28:16.000
Don't do it. Keep yourself in the control group ladies and gentlemen. Keep

01:28:16.000 --> 01:28:21.280
yourself in the control group. Keep it in the control group ladies and

01:28:21.280 --> 01:28:30.880
gentlemen. Check out Broken Science Initiative. Please check it out to Greg

01:28:30.880 --> 01:28:35.400
and Emily. You guys are doing something really great there.

01:28:39.400 --> 01:28:48.400
Thanks guys. I'll see you tomorrow. That's 33. 33. You know Russell Brand has a tattoo of 33 on his arm.

01:28:48.400 --> 01:28:52.200
I just did 33 days at a row. Thanks for joining me.

