COVID-19 Vaccine Deep Dive — Safety, Immunity, RNA Production, with Shane Crotty, PhD
There is, perhaps, no better person to discuss RNA vaccine safety and COVID-19 immunology with than Professor Shane Crotty, PhD, La Jolla Institute for Immunology, Center for Infectious Disease and Vaccine Research.
MedCram co-founder and producer, Kyle Allred, had the opportunity to interview Professor Crotty on December 16, 2020. In their conversation, they take a deep dive into vaccines and vaccine safety, the process of mRNA vaccine production, and how the Pfizer-BioNTech and Moderna mRNA vaccines made their way through FDA and CDC trials. Professor Crotty explains the idea behind “immune memory” and the central role it plays in the efficacy of vaccines.
Watch the full interview here, or read through the transcript below.
Professor Crotty’s Research on SARS-CoV-2
Kyle Allred: Professor Crotty, the research from you and your team that’s been featured in the New York Times and has been recently held up by Dr. Fauci at a congressional hearing has been key to our understanding about how our immune system reacts to this new coronavirus and its implications for vaccines. I’ve gathered a lot of questions from our viewers about immunity and vaccines including the basic question, how safe are mRNA vaccines? But before we get to those questions, can you briefly explain your most recent research about SARS-CoV-2?
Professor Shane Crotty: Sure, the most recent was to ask, essentially, do people have immune memory to this virus or not? And what does that memory look like? An immune memory really is a lot like brain memory; it’s, you’ve seen something before and your immune system has figured out how to recognize it and remember it. It’s really one of three major parts that you’ve got: antibodies, then you’ve got helper T cells, and you’ve got killer T cells. And the simple way to think about those is antibodies are really good at stopping a virus outside of cells, but once a virus has infected the cells, then you really need T cells. T cells are specialized for dealing with infected cells and antibodies get made by B cells, and so in terms of memory, you’ve really got memory B cells that can make the antibodies.
You’ve got the antibodies that are actually circulating in your blood and then you’ve got these two kinds of T cells that can either kill cells or have other jobs, and so what we did was to ask in people who had had COVID-19, do they have these four kinds of memory and some sub flavors of those? How much of that, and how long did it last? And the quick answer was essentially like 95 percent of people at six to eight months post-infection really had a robust amount of immune memory based on these measurements we did, and this is the largest study of immune memory ever in people to actually measure all of these different parts of immune memory.
So it was a lot of work, but the results were pretty interesting that people’s immune system do tend to be remembering this virus pretty well. So that was our recent study.
Kyle: SARS-CoV-2 is made up of, what is it, 25 or 28 major proteins?
Professor Crotty: Correct.
Kyle: The scientists at Pfizer and BioNTech and Moderna have isolated the messenger RNA for just the spike protein. Is that correct? Is this spike protein made up of one protein or of multiple proteins?
Professor Crotty: It’s one protein, so it’s a trimer, so it ends up being three copies of the same protein, so it’s all encoded by one RNA. It’s the same sequence just three folded together three times.
Spike Protein as Target for COVID-19 Vaccine
Kyle: Got it. Why did both companies choose to use spike protein for their target for this vaccine?
Professor Crotty: Right, so there are about 29 licensed human vaccines, depending on how you count, and almost all of them work on the basis of protective antibody responses, and so when you’re trying to move fast with with vaccine development, the most obvious target is to try and make antibodies against the protein that’s on the surface of the virus, because antibodies work by binding to the surface of a virus and essentially covering the virus and keeping the virus from doing anything.
That’s really the simple way to think about antibodies working, and so for previous coronaviruses, it was known that there are a couple of different proteins on the surface of of the virus, but it’s really the spike protein that’s the major one and probably the most important antibody target, and sure enough, in the months subsequent to those decisions, lots of data have accumulated that have said, essentially, all of the neutralizing antibodies, the important antibodies against SARS-CoV-2, are against the spike protein.
So the spike protein is the best target to focus on for antibodies, and when I talk to you about, you know there really being three parts of the immune system, one of the concerns has been that sometimes antibodies aren’t that great at stopping all viruses, and then you really need the T cells to kick in, and the T cells don’t necessarily recognize spike. They might recognize some of those other 25 proteins, and so that was actually our first major scientific study on COVID-19 was to ask infected people: do people make T cells that recognize spike also or only other proteins?
And what we found was that it infected people, actually people make a lot of T cell responses to spike also, and so that was a really that was a good sign supporting the vaccine development at all that. If you are, some viruses you have to choose more than one protein. For this virus,
it looks like, “yeah just choosing one protein is a reasonable way to try and get antibody responses and T cell responses.”
Kyle: Along those lines, if this virus mutated, well we know it’s mutating all the time, but if there was a mutation, I guess, is it possible that there’s a mutation where this virus could infect and can cause harm without the spike protein?
Professor Crotty: No, not without the spike protein. The question’s really about whether you know if this is the spike protein. Can it mutate the spike protein so it looks a little bit different and now antibodies are recognizing the three-dimensional structure they’re physically binding? It’s sort of like if, well I mean, it’s like anything. It’s like, you know, it’s like my mouse, right?
And it’s like, well, maybe the antibodies are really recognizing this little knobby wheel, and if they’re just recognizing that and the virus mutates that, well now you’re in trouble, because you’re not seeing the other parts of it, and so that’s something people have been spending a lot of attention to.
Of where exactly are those virus mutations? And then, where are the antibody responses people are making? And viruses behave different ways, so flu is a really big problem in that way, where flu is clearly able to mutate, but lots of other viruses aren’t. So like measles, there’s been a measles vaccine for, what, 70 years now? And the virus has never managed to mutate away from that. And same thing with polio and hepatitis B, and so far it looks like 95 percent of people still had antibodies that neutralize that virus very well, and that’s probably because every single person is making multiple different antibodies, so even if the virus has one mutation, that doesn’t escape, because it’s only escaping one little part of the immune response.
Kyle: The scientists have been able to isolate this one strand of mRNA that just codes for the spike protein, and then they’ve packaged it into what are called lipid nanoparticles, is that correct?
Professor Crotty: Yes, that’s correct.
Kyle: Basically just little fat droplets, if you will, right? Very small uh microscopic fat droplets.
Professor Crotty: Super tiny butter droplets. Yep, that’s basically what you’re talking about.
Kyle: So, why do they package it that way and also how do they package that way? They have this mRNA, how do they get it into the lipid nanoparticle?
What is RNA and Why Use it in a Vaccine?
Professor Crotty: Yeah, so um and so I think for that we also need to deal with just what is RNA, and why is an RNA vaccine a reasonable approach? So RNA is a really common molecule in your body; essentially all living things use RNA as messages, and those messages encode within a cell. At any one of your cells, at any given time, you’ve got like 5,000 different RNAs and those RNAs are each encoding different messages that tell the cells to do different things, make different proteins, and RNAs are made to be transient, so they’re really a lot like, it’s like 5,000 Post-It notes, and they’ll be around for minutes or hours, and then they get shredded up, and they’re gone.
They’re temporary, and so an RNA vaccine is same thing, it’s a temporary message, but it has to get into the cell, and so if it’s in the cell, the cell will now read that message and do what the message says, which helps then instruct the immune system. And then the message goes away okay. So RNA are these temporary messages, or like snapchat messages was the other analogy that I’ve used. There’s a message and then it it expires.
Technologically one of the big challenges there is that RNA is temporary, it gets shredded up really easily — again like just shredding up a Post-It note — and so you got to get it into the cells without it all getting shredded up. So if you just inject RNA from a syringe into somebody’s skin, it doesn’t get into the cells. S the the trick that people figured out over the past 10 years was, “oh you can put it in these little butter droplets, and those little droplets will basically fuse with the cells and release the RNA into the cell.” So now you’ve got, the message has now made it into the cell where it needs to be read, and then it can be shredded up afterwards. So it’s just, it’s a delivery system to get them all get the RNA into the cells.
Kyle: The lipid nanoparticle that’s taken this mRNA vaccine, what cells in our body does it actually go into? Is it just muscle cells in our arm where we get the injection?
Professor Crotty: Yeah, it’s a good question. So it definitely goes into muscle cells, and I think, and scientists are still learning which cells are the important cells, basically. Most of the cells that are getting the RNA are the muscle cells, and it’s possible that specialized cells of the immune system that aren’t very common, but they may get the RNA, and those may be the more important for starting the immune response, but yeah most of the RNA is going into the muscle cells and I’m sure the protein expression there matters. It’s just, that might not be the only cell type that matters.
Kyle: A question a lot of people have had is, once that mRNA gets into our cells and codes for that spike protein, does it just code, does each strand of mRNA just code for one spike protein? And then does the Post-It note, or the mRNA get destroyed or dissolve, or does it code for multiple proteins and last for maybe an hour or a day? Like how long does the mRNA from this vaccine actually last in our cells, approximately?
Professor Crotty: Yeah, it’s a good question. So the goal, so the RNA gets read multiple times, so it’ll just keep — it gets read over and over and over again, so that you make a lot of the spike protein, which will then get expressed on the surface of the cell to stimulate the immune system. And I’d say average RNAs in your cell will last some time, generally minutes to hours, but some of them will last a day or more, and these, the RNA vaccines are engineered to be stable, and so um the information I’ve seen is that they’ll last a couple of days.
Kyle: So we have the mRNA inside of a lipid nanoparticle, what else goes in in the vaccine obviously it’s got to be some type of saline solution or something?
Professor Crotty: Right, that’s it. It’s basically, um, it’s basically just delivered in some, essentially, some, yeah, salt water set to match the saltiness of your own body. So that it’s essentially as “natural” as possible.
Kyle: It seems like a question that a lot of people have with vaccines in general is, “okay, well what else do they put in them?” And from my understanding with this Pfizer and BioNTech vaccine, they came out and said, “we didn’t put any adjuvants or preservatives in this particular vaccine.” Why are adjuvants used sometimes in vaccines?
Professor Crotty: Yeah, that’s a great question. So essentially, usually adjuvants are are used, and it goes back to what I said about immune memory at the beginning, you know your immune system, some remembers some things really well and remembers other things really poorly, and there are complexities there, but the the rule of thumb is that the bigger the threat, then the bigger the memory.
It’s a lot like, you know, you might not be able to remember what socks you put on two days ago, but if you’re almost in a car accident at some particular intersection, you’re going to remember that intersection for a very long time, right? Because it was a memorable event, and so vaccines have to deal with the same thing: that the immune system is good at ignoring things that aren’t very threatening, and so adjuvants are a way of providing the immune system a stimulation that says, “hey, this thing that you’re about to see, this is a potential threat, and you should make a substantial immune response to it and remember it,” and so that’s if you just inject a protein by itself.
That protein’s inert; it’s non-threatening; it’s not replicating; it’s not going to do anything to you. And so the adjuvant is the immune stimulus to get you going. An RNA vaccine essentially ends up encoding its own stimulation, so it accomplishes that on its own.
Kyle: The lipid nanoparticle has done its job. It’s brought the mRNA into the cell, and now it’s the ribosome’s job to actually code, or basically essentially build a protein out of that structure?
Professor Crotty: Right, so what your immune system ends up needing to see in the end are proteins, because that’s what the virus itself is made out of, proteins. The spike proteins are on the surface of the virus, and it’s those proteins that an antibody or T cells would recognize and your cells are making proteins all the time, as instructed by RNA messages. So now instead they’re going to make these viral spike proteins, and that’s what the immune system will start recognizing, and that does get triggered by just the normal protein synthesis machinery in the cells, which is, um yeah, which are the ribosomes and the amino acids already in your cells.
Kyle: Why not just skip a step and use a vaccine that uses the spike protein itself? Why go through this extra step of the of the RNA?
Professor Crotty: Right, that’s a really good question, so and one of the classic ways to make a vaccine is to have the vaccine be the protein, be the viral spike protein or be a viral nanoparticle.
And there are vaccines that work fantastically well that way, and some of the original vaccines going back to the early 20th century are that way; that’s the tetanus vaccine and diphtheria vaccine, which are incredibly successful. And in fact, some of the COVID-19 vaccines currently being worked on are protein vaccines, and there’s a reasonable chance those will succeed as vaccines.
A downside to protein vaccines is that you have to manufacture the protein, and the manufacturing process for any given protein is its own unique manufacturing problem, and so in terms of just a physical production problem, you’ve got to solve that production problem. And since that’s unique, the FDA has to basically review every step of it and agree that everything is fine about that. And viral proteins tend to be kind of unusual proteins; they’re not super simple to manufacture, so it can take some time and energy to figure out how to solve that, basically, manufacturing problem, that biochemistry protein synthesis problem.
The RNA vaccines bypass that problem, because the manufacturing process is always the same. The RNA encodes a different sequence, but molecularly, it’s the same manufacturing process, and so FDA approval and what not is all really fast, because it just looks the same from a manufacturing standpoint. So that’s why the RNA vaccines have gone through phase one, phase two, phase three trial so fast and gotten FDA approval so quick is because they were they were very fast to manufacture and very fast to approve, because it’s, largely, once they solve the problem once, it’s plug and play.
RNA Compared to Other Vaccine Types
Kyle: So along those lines, do you think this is really the future of vaccine development, using this type of technology?
Professor Crotty: I mean, the results are incredibly encouraging, right? I mean this is the first time ever in human history there’s been a vaccine developed within a calendar year, and not only that, now it’s actually been three, right? There have been three successful phase three clinical trials within a single calendar year. That’s never happened for anything. So those are phenomenal successes in the RNA vaccine showing 95 efficacy, right? And fantastic efficacy in the elderly and fantastic efficacy against severe disease.
I mean, those are huge wins and RNA vaccines are definitely going to be successful solutions again in the future. I think they’re likely to still be part of the vaccine toolbox. I don’t think they’ll solve every problem. There are some things that I think they’re good at, and there are other things that other vaccine technologies may be better at.
But in terms of speed, I mean, nothing can match this. You know, I mean vaccine development, classically, is frequently a 20-year process, right? Or, you know, let’s say a 10-year process, and instead you’re talking about a 10-month process. You know, it’s not only a 10-month process, but a 10-month process that really involved a huge amount of safety data on all, right? I mean, you know, 70,000 doses being given and tested to validate both the efficacy and the safety that clearly RNA vaccines have a very promising future.
Kyle: From my understanding, mRNA does its work just in the cytoplasm of our cells. Is that correct?
Professor Crotty: That’s correct. So yeah, I’ve gotten lots of questions about, “well wait, isn’t this genetic engineering? I don’t want to be genetically engineered.” I’m like, well, fair enough, I don’t want to be genetically engineered either, but this is RNA; it’s just messages. They’re transient, temporary, they don’t become part of your body. It’s just not the same thing as DNA.
Kyle: Now what about, speaking of DNA, the AstraZeneca vaccine candidate that utilizes DNA?
Professor Crotty: Yeah, so both the AstraZeneca approach and the Johnson & Johnson approach use a viral vector, and it is a viral vector that contains DAN, but really it’s about the virus.
So they’re using a different virus and adenovirus as a delivery system into your cells, essentially, you know, sort of like giving you one viral infection to teach your immune system how to fight another viral infection. That’s also transient DNA that doesn’t become part of your DNA, That’s just the virus’s DNA, and those viral vectors they’ve been “gutted,” so that they can’t become another adenovirus.
It’s like taking a car and taking out the engine, you know, and even and taking out the seats. It still looks like a car from the outside and you can put some new stuff in it, and you’re sort of showing that to the immune system to teach you what something looks like, but it’s not going to go drive off on its own or anything.
Kyle: Got it. Okay so going back to our kind of step-by-step process, we have the mRNA. The ribosome then codes for a spike protein. Does that spike protein then get released from our our cells? Does it get expressed on the surface of our cells or both?
Professor Crotty: Both. Predominantly, it’s getting expressed on the surface of the cells, and that’s just um, that’s where, well, that’s a good way for it to be shown to the immune system, basically.
Kyle: So it gets shown to the immune system and then what happens?
Professor Crotty: Uhhh, so, a thousand different things. [Laughter] An immune response is a really complicated, orchestrated dance but, essentially, you have in your body right now parts of your adaptive immune system that can potentially recognize any possible virus that would ever exist. But to do that, you have billions of cells that are all really rare, so it’s basically, there’s like one in a million cells somewhere that could actually make the antibodies that would recognize the virus that would stop it.
And same thing with the T cells, so what has to happen is those very rare cells have to be exposed to this new protein, and then since those cells are so rare, they’re not very useful when they’re, you know, one in a million, one in a billion cells in your body.
So those cells have to grow and divide and multiply until there are millions of them, and that takes time. And that’s one of the big goals of a vaccine is to, really, the whole point of a vaccine is to show your immune system what the virus looks like before you’re infected, so that your immune system can go through that learning process and that growth process on its own, on your immune system’s own time, and get you to a point where now, okay, you’ve got the antibodies, and you’ve got the T cells, and you’re going to have that immune memory all before you ever get exposed to the virus.
So normally when you get exposed to the virus, the virus gets the head start. Okay and then your immune system is playing catch-up; your immune system has these rare cells that can potentially protect you, but they’re rare, and they have to grow from one cell into a million cells, and usually that takes a week, and you get sick for that week in the meantime.
Kyle: So you talked about this cascade of immune system effects and response to either a vaccine or a natural infection with a vaccine. What symptoms would you expect when the immune system is really ramping up and responding?
Professor Crotty: Yeah, it’s another good question, and I get it a lot. Yeah, I definitely tell people, you know, these vaccines are safe; that doesn’t mean they’re not gonna make it not feel so great for a day or two or have a little bit of a fever, and that can be a really positive thing, because essentially this goes back to your immune system is really designed to remember things that were something of a threat, you know.
And so it’s, uh, you really do kind of have to earn your immunity some, a lot like going to the gym and working out. You know, if you get really sore, that can really be a positive sign. Same kind of thing for a vaccine; if you’ve got some swelling, if you’ve got some redness, if you got a little bit of a fever, those are basically all straightforward signs that your immune system is working, is doing its job of recognizing that vaccine and building the tools and weapons to fight the virus if they see it, and usually for most vaccines, that can go on for, you know, one day, two days, three days, and that’s been what people have been seeing with these RNA vaccines as well. Most people get a bit of redness and a bit of soreness, and some people get a real fever for a day, and that’s honestly just a positive sign that your immune system is fighting it.
Kyle: So, I mean, “side effect” is almost the wrong terminology for that. I mean, it’s really kind of an expected immunogenic response.
Professor Crotty: Exactly, and that’s why it’s important to recognize that safety is really important for vaccines, because vaccines are given to healthy people, and that’s always been a key feature of vaccines is paying a lot of attention to to safety, but that’s different than, yeah, what we’re talking about here of getting sore or feeling feeling a bit tired. Those can be sort of, essentially, “on target” effects, signs that you’re immune, signs that the vaccine is really working.
Kyle: The guidance from the FDA and the CDC with the the Pfizer-BioNTech vaccine is that even people who have had a previous SARS-CoV-2 infection should get the vaccine. I think a lot of people were initially confused by this. Why do you think they made that recommendation?
Professor Crotty: Yeah, it’s a good question, and it’s because we don’t, like as of today and certainly as of a couple weeks ago, we don’t have a good grasp of how long does protective immunity last after you’ve had COVID-19?
And we also don’t know how long it lasts after the vaccines. But, so far the vaccines are looking good. In our data, when we looked at immune memory in people, right, we were seeing something like 95 percent of people had what we consider immune memory. That looks good, but that still doesn’t prove that those people are going to have protective immunity. Really, you have to have bigger, longer studies to wait and see, you know.
How long are people protected? And so, yeah, I think the vaccine recommendation is the right one. If we knew for sure that catching COVID-19 really did give you protective immunity for a long time, then I think the vaccine recommendation would be “no, don’t bother.” But as it stands right now, we don’t know that, and so it makes sense to still recommend getting the vaccine.
Kyle: And is it possible that the vaccine can actually give longer immunity than a natural infection?
Professor Crotty: It’s possible. There are definitely vaccines that do that. So the papillomavirus vaccine is a fantastic example of a vaccine where the vaccine works way better than natural infection at generating protective immunity and long lasting immunity.
The opposite also occurs. I mean, the normal flu vaccine really gives pretty short-lived immunity, but if you actually catch the flu, your immunity to that flu is really quite long-lasting. So it can go both ways, and since RNA vaccines are new, we don’t have a historical reference point for comparison.
So far the data with the RNA vaccines has been fantastic, and really the big unanswered question with them at this point is durability. How long are they going to last? And right now, we don’t know how long durability is going to last for the vaccine compared to having had the infection.
Kyle: The Pfizer-BioNTech vaccine and the Moderna vaccines are very similar. Why does the Pfizer vaccine need to be stored at negative 94 degrees fahrenheit, when the Moderna vaccine just needs regular refrigeration?
Professor Crotty: It’s pretty cold, right? Well, I think the Moderna, one requires the very cold for long-term storage but for a shorter term, it can do better. And in fact, there are other RNA vaccine formulations that have been published later in 2020 that could actually do room temperature storage. It comes down to the nature, the precise nature, of those lipid nanoparticles, and how stable they are.
Kyle: I’m gonna put you on the spot here, Professor Crotty. If you had a family member or a close friend say to you, “You know, professor, you’ve studied vaccines in immunity your entire career. This vaccine looks promising, but it, you know as you mentioned, the timeline has been so much shorter than what we’re used to with vaccines and it’s using a new technology, this RNA technology. Should I be nervous about this?” What would you say?
Professor Crotty: Yeah, great question. And the answer is no, don’t be nervous. Definitely get vaccinated. If you can get vaccinated, I mean obviously for one right now, the COVID-19 threat in the population is horrible, right?
I mean, we’ve crossed thresholds of like 3,000 deaths a day in the country. I mean, those are, uh, it’s a really bad situation, and on the flip side, these vaccines are, you know, 95 percent effective. That, in two totally independent trials of huge numbers of people, that data is really strong.
These vaccines definitely work, and yeah I certainly get questions about safety, which are reasonable questions to ask, again, because you said, because of the speed. And so there are two parts of it: one is you would be really hard-pressed to find any medicine that has had this much safety data already by the time it becomes publicly available. Again, 70,000 people have already gotten the vaccine and been tracked for safety. That’s a huge amount of safety data, way more than most medicines get when they come to market.
So, I mean, those are — and the reason for accumulating all that was actually because of speed. That’s actually to find results quick enough, they had to have a huge number of people involved in the study, and so as a result, they got a ton of safety data, and they’ve also got safety data going, you know, for essentially six months from the earlier clinical trials that got started in the summer.
Really the best way to think about the speed of development is one: this is a technology that could move very fast through manufacturing and that’s really where a lot of the speed came from was manufacturing. The safety part of it is the same amount of time as it basically always takes. And the other thing that’s been fast about it has been problems that money could solve.
So normally for developing a vaccine, somebody goes through a phase one trial and then waits and then goes through a phase trial and waits and then goes to a phase three.
They don’t invest a huge amount of money up front, because there’s a good chance that they would lose that money, and instead in this situation, right, going back to March, companies governments, and non-government organizations were all saying, “okay, invest the billion dollars up front, you know, and sure, we may lose that money, but if it works we’ll have a vaccine, you know, a year faster than we otherwise would, because we’re just paying for the manufacturing to get going up front.” That’s just the problem money can solve. You could just be losing that money in the end, but you’re not taking any shortcuts. You’re just starting the process a lot earlier than you would otherwise and, sure enough, things worked out incredibly well, right, and these vaccines are actually working, and so now there are already vaccine doses being delivered instead of the companies now starting to manufacture them and then being delivered, you know, six months or more later.
Kyle: And as you mentioned, there’s good data and there’s a lot of data about safety in the short term. What about long-term potential side effects? I know that’s another concern.
Professor Crotty: Yeah, that’s a good question, and that was one of the main ones that the FDA wanted to consider as well, and so basically they did a review of of vaccine literature and said ,”yeah in the past for all these other vaccines, any important vaccine safety signature was clear within two months,” and so that’s why the FDA specifically demanded that there be two full months of safety data on these large trials and that’s what’s being reviewed by the FDA, and they’ve, yeah, they’ve looked fine.
Kyle: So in other words, if, based on the extensive history we have with vaccines, if you don’t see a safety concern in the first two months of use of the vaccine, it’s unlikely to see long-term side effects down the road?
Professor Crotty: Right, yeah, that’s exactly right.
Kyle: Well, Professor Crotty, thanks so much for joining us today. We really appreciate it, and, briefly, any next projects that you and your team there at the lab are focusing on?
Professor Crotty: Yeah, so, I mean, here at the La Jolla Institute for Immunology, we’re one of the best places in the world studying the immune system, and we can actually look at all these different immune responses to COVID-19 at the same time, which most places can’t. So we’re continuing to examine that both to try and understand acute disease, you know why people end up in the hospital, as well as immune memory to this virus, and it’s, uh yeah, it’s a lot of work, but it’s important. So those are the problems we keep trying to solve.
Kyle: Well, thanks so much for your time and all your research and work. Really appreciate it.
Professor Crotty: Yeah, thanks, Kyle.