 Hi, I'm Jay Fidel. This is Think Tech and more specifically, this is Likeable Science, a show, a show that Ethan Allen designed and invented and developed some time ago. And we're still doing it, aren't we, Ethan? Yes, indeed we are. Because we're back doing the show again, right? Yeah, same here. So today we have the title of So How Do You Make a Vaccine? Anyway, it's a rhetorical question. But we thought we'd look into that because everybody talks about vaccines. It's the saving grace. It's what's going to get us out of this terrible pandemic. And to get all this various information from various people about when Gordau is coming, when is he going to ride out of the east or the west, whatever. And that could be either way. And save us. He needs to save us all. But exactly what we need to educate ourselves, what is a vaccine and how do you make one? You want to start, Ethan? Sure. So you've got to understand vaccines. To understand vaccines, you have to know a little bit about our immune systems first, our body's way of fighting off diseases. And because we live in a very dynamic world where disease organisms are always evolving, our immune systems, the ones that are successful, have evolved to deal with changing foreign entities, changing pathogens, nasty germs, basically. And so what vaccines do is crime our immune systems. They give them a little taste of a nasty invader and get them ready, basically. So they're now prepared to launch a full-scale attack on any subsequent ones that come on here. That's sort of a very crude but general picture of what vaccination is all about. Can you always do it? We've developed a lot of vaccines against a lot of things. Many of them have been incredibly effective. Vaccines are rightly credited with huge reductions in public health burdens from polio, from just a number of diseases, typhoid, diarrhea. They've reduced mortality from the flu, disease after disease after disease. Vaccines have been a huge blessing with very, very minimal effusive side effects, despite what the anti-vaccine crowd insists. We should talk about them too. Okay, well, so I decide I'm a researcher or a company that has the facility to do research that I want to jump into the fray. I want to make a vaccine against COVID. Wow. And furthermore, from the Chinese, you remember the Chinese, the clone food Chinese, the Chinese gave us the, what do you call it, the genome for this virus. That was pretty nice of them. And we have it now from them. So one step of the research is already done because we know what this virus is thanks to them. And then we can look at it and slice it and dice it and figure out exactly what it is. But given the genome which we have, what do we do at that point? Because we have to find a way to, as you said, provoke the body's immune response to this particular pathogen in order to make us immune. This is not easy, especially with a virus as complex and tricky. This is more complex and tricky than other ones we've dealt with. So what's step one? Well, there's a lot of different routes you can take. That is you can take the whole virus and kill it basically, inactivate it, soak it in formalin, for instance, and essentially inject some of that. A now dead virus basically. So your body sees that, knows that virus, it will recognize in the future and hopefully will be immune against it. That's fine. It's tough to make enough of that in big enough quantities to be good. You've got to be sure you kill 100% of it too before you use it. You can take that same virus and sort of weaken it, selectively breed it for a bunch of generations and make it weak, and then use that and inject alive, but weakened virus. And your body can use that to build up immunity. You can take a fragment of the virus, like one of these poking spikes that it has, that corona on the virus, a crown of little spikes, which are what are recognized and combined to the cells, and use one of those, or a bunch of them. The new thing now they're doing though is using either DNA or RNA from the virus, and the corona virus, RNA, because it's an RNA virus, and that has some real interesting potential. It's a brand new technology, it's been tested in the lab and looks really good. If it works the way they think it will, the Pfizer folks say they've got a version that self-amplifies. Basically, you get one copy into a cell and it, rather like a virus actually, causes the cell to crank out a lot more copies of that, and give a stronger immune response. So it has not yet been extensively tested to people that RNA or DNA vaccine technology, but it would skip a number of the steps in making it cheaper, easier to produce, faster to produce, cheaper, a lot of advantage. They talk about, well, they talk about candidates, and it sounds like they're, you know, this is like Edison finding the right kind of filament to put in his light bulb, you know, Eureka, and he found Tungsten or something back in about 1885 or so. That was the right candidate. So what is a candidate? How do you even select somebody, something you would consider a candidate for a vaccine? So, basically back in January and February, labs around the world that deal in vaccines, basically saw this, or that, and even developed stuff for vaccines, even earlier stage, saw this need and began testing a lot of candidates. And I'm sure they tested all those things. I'm sure they, you know, some labs took the live coronavirus and killed it and, you know, began working with that and seeing how that worked. I'm sure some took and started breeding that virus and attenuating strength and developing that line. Others took chunks out of that virus, you know, pieces of its spikes of its protein coat, and others have been working now on the DNA and RNA. There was something, as I recall, like 150 different candidates, can the vaccines, of which, you know, a dozen or so will probably prove pretty interesting, you know, half a dozen will look like pretty good and we'll settle on one or two or three. So I take it that if I'm a laboratory working on this, I'm going to go through a bunch of candidates, and then I'm going to settle on the one that's most promising and focus my attention, my resources on that one, and work with that to the exclusion of other possible candidates, at least in the effort of the moment. Am I right about that, or do they continue to work on a number of candidates in parallel? I would think most labs would work on one or at most two or three very close to related approaches, just from how it has to be done in the lab, the process that has to be done are all going to be specifically the same lab that's doing whole virus work, can't be doing the RNA work necessarily, those are two very different kinds of approaches, so requiring sort of different equipment and different mindsets, really. Is it dangerous? There is some danger to doing that kind of work, yes, absolutely. I mean, particularly if you're transferring live virus around, you need to take some precautions. Yeah, so what do I need? I need a laboratory. I need some samples, I guess, of the virus, and then I need people to help me deteriorate the virus in order to the point where it's safe enough to be a vaccine, and I need people to test it once I have a candidate worth looking at. So what's the magnitude of the facility? I mean, we're talking about a city block worth of laboratories, or just a little wee 5,000-foot space. Yeah, again, it sort of depends on the approach, because again, well, what you described is a fairly typical process, which could probably be done in, yes, could be done in 5,000 square foot laboratory. You'd never produce much vaccine out of that, but you could do the process and show proof and principle. But the RNA, DNA vaccines, basically, you don't really even need a virus to start with. You can actually build that RNA now yourself. Basically, it's sort of tinkered white hits and put together a sequence. We know what the sequence is, because we've got, I should point out, we got the genome from it. So we know what sequences are needed, or might be useful. And so you can just build those yourself without ever sort of seeing the live virus. And that moves on to the next day to testing those. How do you build it from the genome? I mean, you don't need people for this. You don't need human subjects for this. You just need to be able to look at it with a microscope and sort of take a look at the genome, map the genome again. It's not, it's sub-microscopic. I mean, smaller than you're going to see in a microscope. This is essentially fancy biochemistry, but it's the folks who do CRISPR and allied technologies have developed a lot of basic kits where you can start slapping the core elements of our reproductive material, of our DNA or RNA together, base by base, basically, and build strands with certain sequences, just as you want them, literally from little starting blocks of the individual nucleotides and individual backbone bases. You can just build them up in whatever sequence you want. And so, yeah, once we, since we know the virus is genome, you can, if you figure out what codes for what, you would take an RNA that codes for the spike proteins, basically, and select that and just build that little stretch of RNA, which is actually sort of smaller and cheaper and simpler to do that than sort of going through all the process of inactivating a bunch of viruses or attenuating the viruses or all that. And plus, once you have that recipe, you can then just crank it out en masse and you can crank out a lot of it. I want to talk about that, but what about the strands? You've talked about the strands of the RNA. Would they have a long drug store? Where do I get that? There's about a mile of it in every cell in your body. So we've got a lot of it. I don't know. That's actually basically true. RNA is a little different, little shorter, easier to work with than the big DNA molecules. But it's, again, it's a same, it's parts that same structure, parts that same sequence of molecules that are spelling out, that are basically a code that tells prokines how to build, how to assemble themselves together. And so probably going with a little pincer there and you move things around. I mean, how do you change the elements of the RNA? More or less, you do that biochemically. They have developed these kits, which allow you to sort of add a teaspoon from packet A to a teaspoon from packet B and you're guaranteed that you're going to get a bunch of compound C and then you take another teaspoon from compound D and add that on and that lets you add in compound E and just builds itself up. Literally, you're synthesizing molecules from the ground up. So it's synthetic. This is not living material. Right, right. The RNA stuff they're doing now, they're not extracting it from cells. They're building it, actually. This is, yeah, this is, again, it's nanotechnology. It's material science. It's sort of, I don't want to say. Is it CRISPR? You and I have talked about CRISPR. You can use CRISPR in this to get in there and start editing stuff. So you could yank out a chunk of the RNA or DNA from the virus and then edit it using CRISPR if you wanted, for instance. Okay, so sorry, go ahead. A lot of them are actually just literally building it. So now you've built it to whatever specs you have in your design plan, I guess, thinking that those specs would actually give you a material that would improve your own, you know, the human immune system. How do you find out whether you're right? So they do a number of tests, ultimately leading into animal tests. There are various model animals who you can infect or you give this vaccine to and you infect them with COVID and you see if they get sick or don't get sick. And then ultimately it has to be tried out on people because that's sort of the $64 question is, does it work on us? Because we are different are model animals, the vaccines behave differently, the virus behaves differently. So just the virus and a vaccine working a model animal does not necessarily mean they'll work together in humans. So what kind of model animals are we talking about? Don't say bats. No, no, I believe they're just commonly will start with things like mice and rats. I've not looked real deeply in this. I think they oftentimes go into primates. I suspect they're skipping some of these steps and going doing a small scale test of humans pretty much, you know, soon as they have any indication of stuff basically reasonably safe in animals, it's not going to kill you immediately. They want to move fast on this and, you know, you got to be ready to scale it up and that's a problem in itself. So in the case of an animal, if we go to humans in a minute, you would infect the animal with coronavirus. I guess different animals are affected different ways. You'd have to find an animal, a subject animal that does something like a human. And then you give them what you know you have infected him, you give him this RNA material and see if it stops the virus from proliferating. Well, that's one thing that's seen and that's one of the two ways that viruses can be used. That's what you just described as so-called a therapeutic use. If you're already sick, you get a vaccine to help you get better. The real power of vaccine, though, is to use prophylactically. So that is you don't get your animal sick with COVID first, you give them the RNA vaccine first and then expose them to COVID and they hopefully don't get sick. And that's, you know, that's the real power is you vaccinate a bunch of people around the world and the virus got nowhere to go. It's not, can't find a good home, can't live happily in people and just disappears. In the animals anyway, you'd have a control group. You have one group of animals where you know that animal is going to get sick and you infect that animal and see how the virus goes. The other group, you give them the vaccine and then you infect the animal and see how that goes. And if it's better with the vaccine, you know you've got something. Exactly. And then eventually you take that same kind of trial and people first just giving them the vaccine, see if they don't react badly to that, and then eventually challenging them with COVID after being vaccinated and see, again, running with a control group who doesn't get the vaccine. And you can see why this gets very problematical. This means you essentially are asking people to take a risk and get infected with a potentially dangerous, potentially deadly virus. Well, let's talk about people. So I need subjects now. I'm convinced that my selected animal has told me enough to make me, you know, make at least a preliminary conclusion that my candidate, this RNA candidate, is likely or has some probability of success. So I need two people. One person, this is a horrible kind of analysis, but one person, I give them the virus and I just like the animals, right? I give them the virus and see how that goes or maybe he already has it. Maybe he has tested positive. So I'm not involved in that moral dilemma. I tested positive and I watch how that goes. I do not give him the RNA vaccine. The other one is, yeah, well, I didn't get this right. No, I got it wrong. You can do that. Neither one of them have the virus. Well, you're going to have to do all those. You're going to have to give it to people who have the virus and people who don't have the virus really. They tell you different things. And it depends. Yes, in this country, that's a problem setting up those groups, particularly the ones where you're infecting people and not giving them the vaccine. And if you live in a place like China, that's probably easier to do that kind of research because the power is granted to the government there and the lesser emphasis on individual human rights. But it's easy enough to find 10 or 20 subjects from a jail or whatever. Just make them your subjects. So with my control groups over here and with the vaccine over here and the non-control group, the real group, I want to see if that same vaccine that I was using on the animals has an effect of ameliorating the infection or stopping, making this particular subject immune from COVID. I guess I have to pay these people, don't I? That's why these trials are so expensive. What can you expect to get paid if you're a subject in a trial? I actually don't know what they would pay subjects. They'll do the initial small groups of literally 10 or 20 subjects. You don't want just one because one person tells you nothing really. It can be just a fluke. But if you get a group of 10 people who get the vaccine and 10 people who don't and then both get infected with the virus at the same time, three or four weeks later, you can look and say, hey, how did these 10 people do versus how did the other 10 people do? And if you see a major difference in the health outcomes, all 10 people who didn't get the vaccine are now reasonably sick. Maybe one of them very sick and only two or three of the people in the vaccine group are only a little bit sick. You say, hey, something looks really good here, right? This looks like it's a pretty good, pretty effective vaccine. Then you'll have one tested on groups of probably several dozen people, maybe a couple of hundred people. Again, trying to get a broad cross-section of population, young, old, different ethnic groups, post-sexes, people in good health, people not such good health, and track all this carefully match of groups, watch to see does it have better effects in some groups than others? It's not a straightforward business. It gets complicated because you want to put the vaccine out there to a number of people who might be exposed. You don't know who will be exposed among that group, so you have to have it big enough so that you catch some who ultimately, per chance, get exposed. It's complicated. If you do it just truly on a population of sampling, right? You have to have fairly large groups, so both groups will have exposed and non-exposed people, basically. Yeah, so I guess, and one of the things that people say that I've seen written about them is that their concern, researchers are concerned, that giving the virus, rather giving the vaccine, could in itself be dangerous. How does that work? Yeah, vaccines in general are incredibly safe. Very occasionally people are allergic to some of the the preservatives or carrier substances or things in the vaccine. You do get a few odd cases that people reckon very, very badly to either the vaccine substance itself. In general, for every real bad reaction you get to a vaccination, if you weren't using that vaccine, you probably have 100 deaths instead, compared to one for a bad health reaction. The cost-benefit ratio is tremendous on most vaccines. The RNA promises to be very, very safe. Yeah, so let's assume that the RNA candidate looks good. First it looks good in animals and a selected animal, then it looks good in people, compares well against the control group, and it looks like you need to go to the next step. I know the FDA requires a number of steps, three steps, a larger groups of people, more testing, more data gathering, and so forth. How does that work? Right, so phase one trials are very small, literally maybe 20 people. Yeah, give it to 10 of them, don't give it to the other 10, expose them to the virus, check it out. Phase two is sort of intermediate, and then phase three, you want thousands of people in these trials ideally, so you really get a good sampling across the population. You can have statistically meaningful subgroups of men versus women, people under 20, people 20 to 40, people 40 to 60, people over 60, statistically meaningful groups of different ethnic groups. When I say statistically meaningful, you've got to have probably several dozen people, or at least dozen or so people in your control group and in your trial group from each of those subgroups, so that's why it needs thousands of people, and yes, as you say, you're taking a lot of data, you're following them for reasonable periods of time, those are big expensive things to do, phase three trials. You have to have all kinds of, as you can imagine, legal protection written in for those. Well, they say, they started saying this back in February, that to design and find a vaccine would take a year. Where does that time go that year? Is it all in these trials? A certain amount of it is in the trials, yeah, a certain amount of it's also in the actual development of the vaccine. That latter part's gone very quickly for some of these some of these vaccines have literally been designed and built in a matter of days almost. That's how our new technologies are really allowing us to do things. So yeah, then you've got to begin to determine safety and efficacy, and that does take a while. You can't rush those human trials, you can't be sloppy with how you set them up because if you don't do them right, they can give you misleading results. You've got to be sure every T is crossed, every I is dotted. They're fancy legal contracts basically because when you and your test groups, because those people are putting certain things themselves at risk, right? So you have to follow the protocols for testing. I don't know if that's the FDA or the CDC, but one of those two agencies, and you're going to follow the protocols, but you also have to follow the data, and you have to determine how many people have an effective reaction and how many people don't, how many people have a bad reaction, something happens to them, and who knows why, or you got to really follow them closely. So I guess it means you got to talk to them all the time. If you have thousands of people in this phase, what you call it phase three, phase three trial, you got to talk to them, you got to call them in, you got to take blood samples, examine them. Yeah, so it involves a lot of doctors, a lot of patient time. Yeah, they're hugely, I mean, this is for a typical drug, right? A pharmaceutical company will spend now billions of dollars developing, and a lot of that is in the big testing phases, you know, because it was just, yeah, they're expensive to do. So I'll be looking for a vaccine that's perfect, or nearly perfect. Nearly perfect would do, halfway perfect is probably good enough. You know, if it's 30 or 40% effective, it's probably better than nothing, you know. When you say 30, 40%, you mean 30 or 40% of the time, it protects the individual patient from getting sick. Right, either stops them, or it reduces the severity, you know, so far fewer, you know, only a small portion of your patients proceed to the more extreme forms of the disease. You know, they, when they do get hospitalized, their stays are significantly shorter. Fewer of them go on ventilators, you know, all these, you know, you can measure in a lot of different ways how effective a vaccine is. Yeah, but it's graduated. I mean, it's nuanced, because you're not, it's not yes or no, it may be very nuanced in how long does he stay in the hospital? What kind of side effects does he have? What kind of residual medical issues does he have? Oh, wow, there must be, you know, hundreds of fields on that database. Yeah, and then how long does that immunity last? You know, ideally it gives your life's long immunity with, you know, one or two doses of the vaccine, like with the, say, being saw polio vaccines. But a lot of other things like our annual flu vaccines, right, we have to change those each year. The flu virus is sort of constantly evolving and new strains are popping up. And we don't yet know is coronavirus, it looks reasonably stable. It's not as tricky as HIV, for instance, which evolves extremely quickly and morphs into different strains very, very fast. Yeah, makes it very hard to treat. Although we don't know for sure, we're only, we're only six months into this virus and we could have a mutation in our hands. Exactly. It could be next season. It could come back in a, you know, altered form of the vaccine. This one might not work against, you know. But let's assume there's lots of pressure to develop the vaccine and therefore, and lots of expectation it'll be done in a year. Although I, I don't think if Anthony Fauci were here with us today, you know, you look a little bit like him, actually. If Anthony Fauci were here with us today, he would say, no, it's not a year, it's a year and a half, maybe more. He's a conservative person. And so the question is, if you only have a year, a year and a half, you can't do trials to determine how long the effect of the vaccine will last. You can, you have to wrap it into that period. So we will not know exactly how long the vaccine will last. Right. Yeah. That's one of the things we're not going to know as we start distributing our first rounds of vaccine, probably, is whether it's a three month, you know, protection or lifelong protection. We'll probably have some clues, but yeah, we won't know for some years, really. Okay. Well, let's go to the penultimate thing. And that is, how do you manufacture this in large doses? You know that it works on your sample, your sample, or at least you're satisfied that the doses you gave, and you determine the right doses, by the way, by virtue of these trials, now you have to take those same doses and put it in a little thing, a little test tube or whatever you put it in. And you have to make how about 8 billion of them. How do you do that? Yeah. I mean, and that's a problem, the traditional way of doing, of making vaccines on mass involves basically culturing them in eggs, literally in chicken eggs, individual chicken eggs had to be injected with a virus, cultured for some period of time, the virus pulled out a very tedious process, very hard to scale up, I mean, handling egg after egg after egg, literally, the new RNA viruses, that's one of the beauties of them, the new RNA vaccines, potentially they can just be cranked out with any sort of, you know, molecular synthesizer kit, basically. And so they will be cheaper, they'll be easier to produce in larger quantities. So there's a lot of people hoping very strongly that these RNA vaccines will work, because that will make everyone's lives much simpler. In terms of producing them, so I guess you take the RNA material and you put it in some kind of solution, and you put that in a little tube, and then the person who administers the vaccine is going to take a hypodermic, draw it out of the tube, and then put it in your arm, is that what the substantive arrangement is? Yeah, I mean, again, there's different ways, the polio vaccine, they went from the shots to the oral vaccine. The sugar. Right, on sugar, you probably remember from your childhood. I like that. I like the sugar cube much better than the needle in the arm. And, you know, I don't know, I'm guessing RNA stuff is going to have to be injectable, just because unless it's, but they may have coatings now, they can wrap it up in indigestible things, and protect it from the digestive system. There's the packaging for sort of viral vaccines. It's getting, or for any drugs these days, it's also getting very fancy. They can put protective coatings on it, but dissolve them under certain conditions in your body and, you know, let it circulate. As long as I don't have to stick it up my nose. The big issue now is there are 8 billion people plus in the world today. And the first question is, how many of the 8 billion do we need to inoculate? Before we get the desired population result. So, yeah, and there's some debate about that. The estimates I've heard range from somewhere probably around 60% of the population ultimately should be vaccinated to really get a good herd immunity going, to really spread the vulnerable individuals out so far that the virus will basically lose its hosts. So, that would say we're going to need, you know, 5 billion doses of it. Again, there are people who can do these calculations, epidemiologists, who say, oh, a lot smaller percentage of the population will begin to see a good effect already, particularly if you focus it. You vaccinate most at-risk people in the most at-risk places. You'll break, you'll stop these spikes from occurring in a big way, you know. But again, that's a very tricky thing. When you get, yes, you have the first few million doses who gets them, you know. Right. Well, the first people who have to get them are Donald Trump and his family, am I right? Only joking. Is it the first line, doctors and nurses and public health care workers, EMTs who deal with these people? Yeah, because they're going to be out there administering this vaccine, you know. Yeah, and they're good. But I suggest that there could be a huge and very socially unjust disparity who gets it first. And there could be corruption involved in that because everybody wants to be saved. You bet there will be, you know, there's certainly pressure for it, you know. Who wants to give it to the people in Bangladesh, right? We're going to give it to the people in Cincinnati. I mean, we've already seen that this, the COVID pandemic has made very clear there's a real, there's real inequity in our culture, you know. The haves get COVID at a lot low rates and have nots basically, you know. People who are sort of at the bottom of the socioeconomic scale suffer disproportionately from in terms of the rates of infection, the severity of the infections, the death rates they get from it on all those measures. You know, you see that. Well, that's one reason why we should have the World Health Organization involved in the distribution of any vaccine because they're likely to be more fair and equitable about it on a global basis. And as I remember, there were three places in the world where they're working on a vaccine. One was Germany. One was the US and I can't remember the third. Somewhere in Europe, it was France or England. UK is doing some very good work. China is doing some very good work. They have, of course, a high vested interest in developing things and saving the world from the disaster they unleashed on it. But yes, a lot of US labs, labs all around the world are working. A lot of them are collaborating very freely and well with each other because the people who do this kind of work understand, you know, you work together on this and you get the solutions a lot faster. You spot the error and somebody else's work probably before you'll spot it in your own. They'll probably spot the shortcomings of your design before you'll see them. That reminds me of something that happened a couple of months ago where Trump went to a particular pharmaceutical research laboratory in Germany and tried to buy their work and their scientists and take them away from Germany. And Angela Merkel and the individual scientists involved said no. I'm not going to do that. That would have been the opposite of what you're talking about in terms of collaboration. I wanted to ask you one more thing and that is, what should we be looking for? I mean, let's say we all have an interest in knowing about this. And there are so many news sources, so many people, so many media, you don't want to be helpful and don't want to tell us what's going on, but we have to be discerning in what we read and hear and think about it. How can we best track on this? What should we be looking for to either be encouraged or discouraged over the next few months? Well, I mean, I would hope that the good, the people who are mapping in the cases, for instance, like Johns Hopkins has a very good interactive map and all kinds of trend line analyses, all kinds of fancy stuff. And I would hope that we will see the US and for that matter of case all around the globe, start to level off and go down. Certainly individual countries have done that very successfully. Some of them places like Iceland, people don't even socially distance, don't wear masks, and they're fine. They basically sort of close the whole book on it. New Zealand has done a grand job too. New Zealand has virtually no cases. Some of the small Pacific Island nations by shutting themselves down and closing their borders did find that they've killed their economies, of course. That's not so good, but they've kept themselves COVID free. So, yeah, you look at it. The one thing you don't want to do is to believe the hype that you'll hear, the latest Facebook posts, the latest Twitter feed from anyone from our president going down that says Miracle Cure is here today, send 995. Right, exactly. You know, so follow, yeah, follow all sorts of like Johns Hopkins, go to the CDC website, you know, they have good accessible information about COVID. It's up to date. It's edited and edited by experts, you know. So there are places to get good information. Yeah, and then one day, one day the assistant to your favorite doctor will call you on the phone or send you a little email message and say, it's time for you to come down and get a shot, Jay, and I'll be down there in about six seconds. How about you, Ethan? Oh, yeah, oh, yeah. No line will be there ahead of us. Well, this has been very instructive, very educational, and a very important discussion to have to sort of clarify where we are and where we're going and how we're going to get there. Thank you so much, Ethan, for looking into it and talking to us about it. Well, thank you, Jay. It's always a pleasure talking to you. You asked such good questions, you know, have such a good mind about thinking ways to think about this thing. Well, thank you. You're a pure scientist, Ethan. I really appreciate that. And we'll do this again, I promise. Promise me now, too. Sounds good. Take care. Stay safe.