The future of topical vaccines
Bioengineer Michael Fischbach studies alternative vaccine delivery methods, like self-administered creams with no needles, health professionals, or side effects.
He teases a day when vaccines that don’t make you feel bad come in the mail in ketchup-style packets. Such innovations would greatly improve vaccine uptake, especially in developing countries, and speed global response to novel viruses. It would change how we think about vaccines, Fischbach tells host Russ Altman on this episode of Stanford Engineering’s The Future of Everything podcast.
Transcript
[00:00:00] Russ Altman: This is Stanford Engineering's is The Future of Everything, and I'm your host, Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. And it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody. In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here, and that you'll share it with your friends, family, neighbors, coworkers as well.
[00:00:48] Michael Fischbach: I would never take my kids to the pediatrician to get six shots. There'd be some kind of mutiny, uh, but your skin is a big organ. And I could ask them to rub one tab of cream behind their left ear for flu, their right ear for SARS 2, the left elbow for RSV, and so on. Uh, so I think this could be multiplexed more easily than, than other vaccines. And that could make for, for example, uh, one product that would cover you for the whole respiratory virus season.
[00:01:22] Russ Altman: This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying The Future of Everything podcast, please hit follow in whatever app you're listening to it right now, so you never miss the future of anything. Today, Michael Fischbach will tell us that the bacteria that live peacefully in our skin might be the source of new opportunities for vaccines that are delivered on your skin as a cream without any needles. Yes, you heard it right. Vaccines with no needles. They may become creams. It's the future of vaccines. Today we are continuing our new feature, the Future in a Minute where I'll ask the guest, Michael a few quick questions and he'll gimme some quick answers. We're gonna do that at the end of our regular interview. Stay tuned. Before we get started, please remember to follow The Future of Everything podcast and whatever app you're listening to right now. So, you're always aware of new episodes.
[00:02:22] So when we think about vaccines, we think about needles in our arms. The general idea for vaccines is very straightforward. You take a small piece of a pathogen, a virus, a bacteria, maybe even a cancer, a small piece, not the whole thing. You're not injecting something toxic into the body. Just a piece that the body can recognize. It can build up an immune response against that piece, so that if you ever are exposed to that virus, that cancer, or that bacteria, your body, because it's seen that little piece, will see that little piece on the pathogen, attack it, kill it, and protect you from that disease. That's the basic idea of vaccines. But they come with some costs. There's a needle involved. There's some pain, swelling, and sometimes you really feel pretty bad for a couple of days depending on what the vaccine is. Imagine if we could have vaccines delivered in a cream. Yes, as a cream, you just apply it to your skin and then a few weeks or months later, you are immune to those pathogens, bacteria, viruses, and cancers.
[00:03:27] That sounds like science fiction, except we have found recently, and when I say we at the scientific community, has found that bacteria that live on your skin peacefully and normally not causing any trouble actually induce a big immune response right under the skin. We are very aware of these bacteria, and we are watching them constantly. So, if you can engineer those bacteria to have other little pieces that are from pathogens, the bacteria, the viruses, and the cancers, then maybe you can elicit a response and you can have that same protective response if you ever see those pathogens in the future. Well, Michael Fischbach is a professor of bioengineering at Stanford University, and his lab has led in this line of reasoning with a series of stunning papers suggesting that maybe this is still a, maybe we're gonna have vaccines made out of bacteria that get applied as a cream.
[00:04:24] Michael, thanks so much for being here. You recently wrote a paper suggesting that vaccines may someday be creams and not needles, not shots. Where did that come from?
[00:04:34] Michael Fischbach: Great. I have to take you back to the beginning. Um, this, this was completely unintentional. It's a fun story and it, it came, uh, totally by surprise. So, the right place to frame this is to ask you that if, if, what do you think, if I asked you what do you think the immune system intends to do when it sees a pathogen? We could debate, you and I always do, but we would probably end up agreeing that it's trying to limit replication and dissemination, so you don't die.
[00:05:02] Russ Altman: Right. You want to contain it. It's like Michael Jordan. You might not be able to stop it, but you want to contain it.
[00:05:07] Michael Fischbach: Exactly. But, but then if I asked you, what do you think the immune system is trying to do when it sees a microbial colonist that's living on the skin or in the gut? I don't think you would know. We certainly didn't. It's confusing and I'll, I'll tell you why it's confusing because all this is work that happened before we got involved. People kept on making the same observation, which is that when you put certain organisms in the gut or on the skin of a mouse, you get a really weird immune response. If I were to tell you that the immune system doesn't see them at all because there's a barrier in the way, or it does see them somehow, but it realizes they're here, um, to, to help us not to do any harm, so it gives a friendly wave and walks in the other direction then that,
[00:05:45] Russ Altman: Right. Just as a reminder, we have tons of bacteria that are normally colonizing our body, and we live in harmony with them. And so, and we don't get inflamed, and we don't seem to be, have a, having a reaction. We, they just live on and in us and everything seems to be okay.
[00:06:01] Michael Fischbach: That's right. And so, uh, so it was a surprise when people began to see that in fact, the immune system responds to them in, in a bizarre way. Bizarre, I would say in, in three ways. First is that it's a really big response. Certain bugs when you, when you put them on the skin or in the gut of a mouse, give you a, a big adaptive immune response. Tons of, of, of a type of cell called the T-cell show up on the other side of the barrier. Um, the second thing that's odd is that this seems to happen in a way, like, if you, uh, ordinarily want to get an adaptive immune response, usually there's a breach in the barrier. There's an infection or a needle pokes through your skin, if you're getting a vaccination, it's a five-alarm fire, and all of these immune cells rush in and there's a lot of inflammation and swelling, and you might feel lousy.
[00:06:46] And hopefully that immune response clears the pathogen. But this process looks completely different. You put a bug on one side of the barrier. Nothing happens. It would seem for, for seven to ten days that the, there's no inflammation. If you look in the tissue, it seems like nothing is happening at all. It's just that about a week later, a bunch of immune cells show up on the other side of the barrier, and then perhaps most puzzlingly, they just seem to loiter there and do nothing. So, this, this is puzzling because, you and I know, the immune system doesn't trifle when it acts. It has a purpose. And so why is the immune system mounting this big adaptive immune response that does, that doesn't seem to have a purpose?
[00:07:26] Russ Altman: And just to clarify, this is even for these kind of normal bacteria that we don't think of as causing disease generally.
[00:07:33] Michael Fischbach: Absolutely. It seems to happen for every bacterium that's been studied.
[00:07:36] Russ Altman: Okay. Alright, so, so there we have it. Um, how did you take that observation then? And like what there, there must have been a couple of leaps.
[00:07:45] Michael Fischbach: That's right. So, Erin Chen in my lab was puzzled by this and, and felt that, that something didn't add up and so she did an experiment. I'll tell you what she did and then I'll tell you why she did it 'cause it, it's backwards, but it works better that way. She, she wanted to know what are those cells there to do. She didn't believe that they were there to do nothing and so she had come up with a way of genetically engineering this very common skin colonist named staph epidermidis. This is a bug that lives on every square centimeter of skin on every human, uh, on the planet. This is a relative,
[00:08:18] Russ Altman: And just to be clear, is this the staph that we talk about when we talk about a staph infection?
[00:08:22] Michael Fischbach: This is a different staph. So, the staph we talk about when we talk about a staph infection is staph aureus. And, and that's a, a more dangerous bug. This is its cousin staph epidermidis who, it's a friendly bug, uh, uh, colonizes every human. So, Erin figured out a way to genetically engineer staff epidermidis, and she did something, um, uh, completely wild. She, uh, figured out a way to coat its surface in little pieces of a tumor, little antigens from a tumor. Why did she do that? Because she wanted to trick the immune system of the mouse into developing immune cells that the mouse thinks are specific for the bug, but we know could also recognize a tumor that's gonna be somewhere else in the mouse.
[00:09:07] Why did she do that? Because she wanted to put these immune cells to a test. There are two completely diametrically opposed possibilities. One is that those immune cells could sit right under the skin like everybody else had seen them do and loiter and do nothing. Which is I think what she thought they would do and probably everybody in the lab was expecting. The other possibility, of course, is that they could do what any self-respecting immune cells should do, which is to leave the site of colonization, go to the tumor and kill tumor cells. So, she wanted to distinguish between these two possibilities.
[00:09:38] Russ Altman: She kind of made these bacteria look a little bit like tumor cells because of adding all of these tumor-like proteins on the outside of the, of the bacteria.
[00:09:47] Michael Fischbach: Precisely, and, and so she, she did the experiment, low, low expectations, the experiment's, very simple. Uh, these mice have a, have a tumor growing in under the skin in their flank, so above their hip. And, um, we don't prepare the mice in any way. These are normal, uh, mice not genetically modified at all. Uh, we don't shave them or scrub them. All Erin did was to dip a Q-tip in a bacterial culture and rub it gently on the head of the mouse. That's the whole experiment and just walk away. And, uh, I, all the, all the best data come through in a, a text message or a Slack message. And I remember this was a few days before Christmas. Um, seeing it, it was just a picture. There were the, the mice that were in the control group and the mice that were in the treatment group, and the mice that were in the control group had these giant tumors. It's, it looks gruesome. The mice that were in the treatment group, the tumors had disappeared.
[00:10:41] Russ Altman: Wow. Okay. So that means that those cells that were hanging out on the skin did indeed, uh, perceive what was going on those bacteria. And they did act, in fact, they went ahead and attacked the tumor that shared the same kind of, uh, markers, so to speak, that she had put on the bacteria the tumor also had, and they went after the tumor. Am I following?
[00:11:03] Michael Fischbach: Precisely. We found that they left the skin went through the bloodstream, entered the tumor, and killed tumor cells, which is, um, uh, so, so there's, there's a few things here. I think the, the most important for me to say is that this was a big surprise to us. We did not, the, the stories we'd been telling each other, not just within my lab, but among people who study this, um, in, in the, the field of microbiome research, especially people who are interested in immunology, we had all come to think that the immune response against friendly bugs was the, there were, the words we used were homeostatic. It was sort of there to keep the peace, gentle neutered, and so seeing an immune response that was set off by a friendly skin colonist kill a very difficult tumor, um, was a, was a huge surprise to us.
[00:11:52] Russ Altman: Also, physically separate. I mean, you said you put this, the bacteria on the head, but that the cancer was some, I think you said somewhere on the leg, which means these guys are not just sitting there. There's some kind of communication going on.
[00:12:03] Michael Fischbach: That's right. There's some kind of communication and, and moreover, this is not an immune response that's just localized to the site of colonization. This is a systemic immune response, and we hadn't realized that before.
[00:12:13] Russ Altman: Did, was there redness, like, so this is a kind of a crazy random question, but on the scalp where you had put, um, these cancer looking, uh, bacteria, was there redness and inflammation because they couldn't tell the difference between the real cancer and the bacterial cancer, so they just said, let's attack everything. Or how did they, or did they distinguish?
[00:12:35] Michael Fischbach: This is a really important question. There's no redness at all. We've looked very carefully. The, the, this is a peculiar case and I'm gonna come back to this later, uh, in which you get a, a potent adaptive immune response, but the, the mouse doesn't feel lousy in the same way that you would if, if I had vaccinated you.
[00:12:53] Russ Altman: Okay. Alright, so this is huge. How do you follow this up? Of course, as a scientist, whenever you get an unbelievable result, you have to become a skeptic. You have to doubt that everything was done correctly, you know, because this is a big deal. So, so how does this story unfold?
[00:13:08] Michael Fischbach: For sure, and, and now it gets stranger. So there, uh, Erin, uh, Erin Chen, who led that work in my lab, um, was, was working alongside a newer member of my lab, Djenet Bousbaine. So, Djenet, uh, is a, she, she's an immunologist by training and, and a, a very skeptical person. I think Djenet saw all of this firsthand and, and thought that something doesn't add up here. There's, there's more than we had realized. And so ordinarily, and this is, this is Djenet's reasoning, when the adaptive immune system really goes after something, both of its arms are engaged, not just that the cancer killing T-cells, which we just talked about, but also the B cell, which makes antibodies.
[00:13:48] Russ Altman: Antibodies, yes.
[00:13:50] Michael Fischbach: Djenet, and so Djenet was wondering, is it possible that there, there is an antibody response against this skin colonist. Now, I have to say in my own defense, um, that, that's an absurd question because there's a, the skin is in the way, plus the bug is not here to do any harm. So, what business would the immune system have mounting an antibody response against a bug that's, uh, sort of living in a friendly manner on the other side of the skin.
[00:14:18] Russ Altman: You also said that it's all over all of our skin, which would mean it would be a huge resource allocation for an organism to mount a big response against something that's literally everywhere on the body. It would be a huge investment, uh, in this, uh, of energy and resources in a bug that you don't really think is gonna attack.
[00:14:37] Michael Fischbach: Correct. It seems, it seems, um, uh, you know, like worthless and farfetched. So, uh, so of course she did the experiment anyway, I, uh, again, uh, our hopes were not high. She did the same thing that Erin had done. She took a Q-tip, dipped it in a bacterial culture, and just rubbed it gently on the head of the mouse. Um, and then she tracked the level of antibody in, in the bloodstream of the mouse. Now here, I gotta remind you the, of what data looked like when you're looking at antibodies in the bloodstream. Ordinarily, you and I would've seen graphs like this during the pandemic, uh, looking at antibody in the bloodstream following vaccination, you would get your first shot, and there'd be a spike of antibody, and then it would come back down and you would wait three or four weeks and you'd get a booster and it'd go up a little further. So, this is, uh, yeah, so
[00:15:27] Russ Altman: Kind of multiple exposures to get the body used to seeing it and kind of kick it into action in terms of building a response.
[00:15:33] Michael Fischbach: Exactly. And so, in this experiment, Djenet just started colonizing the head of the mouse as Erin had done. Um, and we saw two things that were a big surprise. One is that the level of antibody in the bloodstream just kept on going up and up and up. We couldn't believe this until we reached about six weeks where it topped off at, at a level that we, we would've been shocked to see even if we had vaccinated the mice. Even if we had used an mRNA vaccine, for example, this, we got more, more antibody just from having colonized the mice.
[00:16:04] Russ Altman: And, and I, this is almost needless to say, but these mice must be in some way special that they hadn't seen this bacteria before.
[00:16:11] Michael Fischbach: That's correct. They hadn't,
[00:16:12] Russ Altman: It's a new exposure.
[00:16:13] Michael Fischbach: It's a new exposure. Um, having said that, this also happens, uh, against the bacteria that, that live naturally on the skin of the mice. And so, we would, we would learn that later. Um, the second thing we learned that was even more surprising is that the antibody response never goes away. Djenet, a couple of weeks ago, sent me a data point from an experiment like this, but where she had let it go for nine months, and the antibody level is exactly the same as it was at six weeks and she hadn't touched the mice in the interim.
[00:16:44] Russ Altman: Right. So, it's been nine months, but without swabbing the head every day. This is just, the last one was nine months ago.
[00:16:51] Michael Fischbach: So, it would seem that the process of colonizing the skin of the mice with staph epidermidis was making them immune in some way against this skin colonist.
[00:17:02] Russ Altman: Gotcha. Okay. So, um, this is so far very interesting. We have a, an unexplained immune response, and you said there were two arms to the immune system, and both arms are kind of, uh, activated by this exposure.
[00:17:16] Michael Fischbach: Right. And so, um, there's a, a couple of things that Djenet did. The first is that, and, and I'll just leave this as a little island because we're, we're following up on this now, but this is all we know. She wondered, is there any chance this is happening in humans as well? And so, the experiment she wanted to do would've been that she would've come to you, swabbed your skin, isolated your staph epidermidis, and then drawn your blood to ask, are there antibodies in in your bloodstream against your own? But we were in a rush, and so she did an experiment that was almost as good where she went to the Stanford Blood Bank and got ten blood samples and then asked whether there are antibodies in those blood samples against the staph epidermidis strains that we had in the freezer. So, they're not a perfect match, but, but close enough. Let's just have a look.
[00:18:06] Russ Altman: 'Cause these are humans, and we do expect them to be colonized by the bacteria just like all of us are. And so, let's see what they show.
[00:18:15] Michael Fischbach: That's right. And every human we looked at, every human we've looked at since, um, has extraordinarily high levels of antibodies against staph epidermidis. It is as though you'd been, even if you'd been vaccinated recently, uh, we would've been impressed to see levels this high. So, um, and of course this is a bug that nobody's been vaccinated against, so that doesn't guarantee that what we're about to talk about, um, is also happening in humans, but I think it, it makes it more likely than it would've been.
[00:18:42] Russ Altman: Right, right. 'Cause you have this one correlation point between mice and humans that at least keeps hope alive that this is a general phenomenon.
[00:18:49] Michael Fischbach: That's right. So, okay, so then what, what Djenet did that, uh, that kind of captured everybody's attention is, is a, um, is it starts with she was asking an innocent question. What, what exactly are the antibodies targeting on the bug or the, what, what structure are they seeing and binding to? Through a series of clever experiments, she figured out that they're, they're binding to this giant tree-like protein that sits on the surface of the bug. It has a trunk that sticks straight up through the Kevlar-like mesh work that surrounds the, the bacterial cell. And to display, um, a, a domain that sits above the arbor, as it were, um, whose function we, we don't understand at all. It's this big tree-like protein is getting bound by these antibodies.
[00:19:36] Russ Altman: Great. I mean that, that actually, uh, some people who have followed COVID have heard about the spike protein, and it's not the same. But we've learned that these organisms, viruses and bacteria, sometimes just have these things poking out that we sometimes understand and sometimes we need to understand.
[00:19:52] Michael Fischbach: That's right. And, and, in this setting, the, um, yeah, the similarity between this giant protein, whose name is Aap and the spike protein on, on COVID or the, the big protein called HA on flu is that they're a major target for antibodies. And so Djenet had an idea, um, she figured if colonizing mice with staph epidermidis leads to antibodies against this tree-like protein, she wondered, what if we put something into the tree-like protein, what if we engineered something into the tree-like protein that we want antibodies against? She, she chose tetanus toxin, uh, and wondered,
[00:20:31] Russ Altman: Certain antibodies against tetanus.
[00:20:33] Michael Fischbach: That's right because we've all been vaccinated against tetanus. And so, she wondered if she splices, tetanus toxin into this, into this tree-like protein above the arbor, could, could she by colonizing mice with, with an engineered bacterium displaying tetanus toxin on its surface, um, could she trick the immune system of the mouse into making antibodies against tetanus?
[00:20:55] Russ Altman: Yes. Now I just wanna be really clear, we are not turning this bacteria into the tetanus bacteria. It only has a small piece of tetanus, um, that it's, that's been, as you said, engineered in. So, the antibody, uh, if it works, might recognize this little piece, but we're in no way putting, uh, the mice at risk of getting tetanus.
[00:21:15] Michael Fischbach: That's correct. And this little piece that we've taken from tetanus toxin is non-toxic. It's, it's completely harmless. And so, this is, this is a piece that you would find in a vaccine. So, but I, but I, I have to, uh, point out here that this is a, just a giant protein, fourteen hundred amino acids has to snake itself, single file, through a, a tiny pore on the surface, and then autonomously refold on the outside. And as you and I both know, ordinarily when we engineer something in the lab, we usually break it. So, she, this is a lot to ask that she could put, uh, a new protein inside of this big tree-like structure and that it would, it would,
[00:21:54] Russ Altman: Without mucking it up.
[00:21:56] Michael Fischbach: So, so she tried anyway. Um, a few of the things she tried did not work, and one she tried, worked amazingly well. Um, we could see that it was on the surface, and, and we, we were kind of surprised. And so, uh, same experiment. Djenet takes a Q-tip, dips it in a bacterial culture, rubs it on the head of the mice, and then we wait, and we start monitoring antibody levels against tetanus. And you can imagine, uh, my surprise when starting around the same time, five or six weeks, we see an antibody level against tetanus in the bloodstream of these mice that, uh, was probably a hundred-fold higher than it needed to be to protect the mice against a lethal challenge with tetanus toxin.
[00:22:40] Russ Altman: So, these are tetanus vaccine levels of antibodies, as if you had vaccinated with the good old-fashioned tetanus shot, or is it even better than that?
[00:22:49] Michael Fischbach: Even higher than that. More, more, more than you would've gotten with a conventional tetanus shut.
[00:22:54] Russ Altman: This is The Future of Everything with Russ Altman. We'll have more with Michael Fischbach next. Welcome back to The Future of Everything. I'm Russ Altman. I'm speaking with Michael Fischbach from Stanford University. In the last segment, Michael described the initial set of experiments that indicated that a bacteria that lives on our skin may be a vessel for delivering small pieces of pathogens that can then be used to develop immunity, vaccinations. These would be vaccinations that are delivered on skin. In mice it seems to have worked great, but it's a long way between mice and people. Mice are not just little people. In the next segment, he's gonna tell us what the benefits of such a vaccine system might be, where we are in terms of basic understanding of the mechanisms, and what are the next steps to see if this is really gonna be a thing. Don't forget, we're gonna end this episode with our new feature, the Future In a Minute, I'm gonna ask Michael a few quick questions. He's gonna gimme some quick answers.
[00:24:00] So Michael, now we really are talking about a potential vaccine. Like this looks and smells a lot like a vaccine for a mouse. So, um, what would a vaccine look like if this can make it past mice into things like humans?
[00:24:15] Michael Fischbach: Great. I think it would've four characteristics that set it apart from the vaccines you and I are used to. The first is that there would be no needle, and that means there's no need for a healthcare worker. So, this is the kind of thing that could arrive in a ketchup packet in the mail, maybe from Amazon, and you would apply it to yourself. And, uh, I think that would not only be convenient, but, uh, it, it could make certain things possible that wouldn't ordinarily be possible, uh, that would change,
[00:24:41] Russ Altman: Life faltering for many populations.
[00:24:43] Michael Fischbach: Life faltering for many populations, both here and in low- and middle-income countries. The second is that, and I think this is a very important point that I, I'm not sure I appreciated until recently. Uh, when, when you get a COVID shot or a flu shot, you feel lousy for a day or two. That's called reactogenicity, and it's the feeling of your innate immune system kicking in. For reasons we don't fully understand, um, the mice don't seem to be feeling any of that reactogenicity. And if that holds through monkeys and into humans, then, um, it would remove one of the most important barriers, a stubborn barrier, uh, so in, in the way of vaccine update.
[00:25:24] Um, the third, and this is a bit of a connoisseurs point, is that most vaccines that, uh, poke through your skin and into your muscle give you a lot of antibody in your bloodstream. But, uh, the, the connoisseurs in the audience will appreciate that people who are making vaccines, new vaccines these days are, are looking for something in addition to that, which is antibody in the mucus that lines your nostrils and your lungs, that could help protect against respiratory pathogens. And for reasons that I think we're beginning to understand, when you colonize mice with staph epidermidis, you get a robust antibody response in, in that, not just in the bloodstream, but also the mucus. That could, that could make for a very potent vaccine.
[00:26:04] Russ Altman: So, you get kind of a more complete distribution of the protective antibodies throughout the body.
[00:26:09] Michael Fischbach: That's right. In a way that I think would protect not just against infection if you've already been infected but could help prevent you from being infected in the first place and spreading it to other people. Um, and then finally, you know, I would never take my kids to the pediatrician to get six shots. There'd be some kind of mutiny, uh, but your skin is a big organ, and I could ask them to rub one tab cream behind their left ear for flu, their right ear for SARS 2, the left elbow for RSV, and so on. Uh, so I think this could be multiplexed more easily than, than other vaccines. And that could make for, for example, uh, one product that would cover you for the whole respiratory virus season. Which I think would be really impactful.
[00:26:50] Russ Altman: Great. Okay. So, this is very exciting and that, you've painted a picture of vaccines that I think many people would find very attractive. Um, of course there's a lot of basic science that you've already done and probably a lot to learn. Um, do you, uh, are you comfortable that we understand enough about how this works? You, you made a very intriguing reference to monkeys and then humans, so we all heard that. Um, uh, do we understand enough to get ready for those monkey trials or is there still basic understanding still required? Or can you move forward while also getting the basic understanding in parallel?
[00:27:23] Michael Fischbach: Yeah, we're doing them in parallel, so lemme make a comment about the basic science first 'cause we're, we're extremely excited about that. This is preliminary and so I, um, it, it could, might not end up being true, but we, we believe that the way this works is that there are immune cells in your skin that are reaching little finger-like projections, across the skin, into the outside world while you're well, um, pre-emptively grabbing antigen, bringing it back inside, and developing an antibody response against it. And if that is true, then in, in some sense, your immune system is vaccinating you, um, all the time against stuff that it finds, uh, uh, on the outside, which is definitely not the way we thought the immune system works. And uh, it's really interesting from a basic science standpoint, it could end up being quite useful.
[00:28:14] Russ Altman: Really, really exciting. So, okay, so paint a picture for, um, what you or others need to do to push this forward. I think you've gotten us excited. It kind of makes sense, uh, at a high level, what are the next steps?
[00:28:29] Michael Fischbach: Next steps are, yeah, are interesting and exciting. So, most vaccines are tested first, most new vaccines are tested first in a monkey. And that's because when a vaccine works in a monkey, there's a very strong probability it'll work in humans too. And so, we're gearing up for experiments where, where we try this in monkeys. Ordinarily when you do that, you're using a type of vaccine that's been, that's been tried before, so you have a bit more of a template. Here we're trying to sort out the details of how do we formulate it into a cream? Where do we rub that cream on the monkey, and how do we measure whether it's worked or not? So that, that's, uh, those, those are the, the planning conversations we're having right now.
[00:29:06] Russ Altman: So, a couple of quick questions on that. Are we still using that staph epidermidis bug or do we have to find a different bug because it's a monkey.
[00:29:13] Michael Fischbach: It's a great question. We're, we're considering our options, but my guess is that we're gonna work with a, a human isolate of staph epidermidis.
[00:29:20] Russ Altman: Okay. The other question is, it seems like you can piggyback on many, many decades of, um, of vaccine research and use the little fragments that are currently delivered in a shot, but is that true or do you have to find new fragments for some technical reason?
[00:29:35] Michael Fischbach: No, that's absolutely true. In fact, there, there, there are lots of, you and I have colleagues who spend their, their whole research careers just, uh, uh, discovering and engineering the fragments that go into the vaccines. And so, we're, we're not gonna redo any of that work. We're gonna use the, the same antigens, the same immunogens that other people have discovered and engineered and, and just put them onto the surface of staph epidermidis.
[00:29:57] Russ Altman: Great. And then the third question is, what's your hit list of things of vaccines to develop and in what order? Like, uh, you could do it randomly, but I'm thinking you're trying to be intentional about this. How do you prioritize the, um, the vaccines to build? For example, you could recapitulate the, um, the current, um, vaccines or you could say, no, no, we need a whole new set of vaccines. Or both. So how do you prioritize?
[00:30:22] Michael Fischbach: Yeah, that's a great question. It's a timely question too, because I, I have a spreadsheet and, and it has an order, uh, and that order might change. There are certainly compelling targets in, um, in the developed world. I think that, uh, you can imagine that if, if you could take your annual flu and COVID shots, uh, in this way instead of with a needle, that, that, that would be preferable. In fact, if they were broader spectrum and covered you against other pathogens, that, that too would be preferable. So, we're thinking carefully about that. There are, um, it's much harder than you might realize in developing countries to vaccinate against pathogens that cause real trouble, like polio and rotavirus. And so, if we could make those vaccines, if we could turn them into something topical, that would have a big impact as well. So, we're, we're, um, working on both in parallel.
[00:31:11] Russ Altman: Um, and, and as we think about moving towards humans, the other question, you know, um, I'm always an enthusiast, but I try to put on my, my skeptical cap. Um, we are messing with a, with a, with an, you, you, you said that the staff epidermidis is on all people, pretty much everywhere on their skin, and we're starting to mess with that. So, I'm sure that you and others are thinking about what are the unexpected things that could go wrong if we mess with that system that might be kind of coming out of the blue, and it's like, oh shoot, we didn't think of that. So how do you even, uh, begin to think about, uh, the risks of engineering these long-lived relationships between a bug that hasn't caused us problems, uh, traditionally. By the way, as a physician, I know that when you're immune suppressed, staph epidermidis can become a problem, and it's kind of consistent with everything you've been saying. So how do you turn, or with all the optimism that you have about this work, how do you put on the skeptical cap and think about the, the things that could go wrong?
[00:32:09] Michael Fischbach: Well, you're right, things can go wrong. Um, we think that because people, including immune compromised people are, are, uh, are heavily colonized by staph epidermidis we're, we're less concerned than we would be if we're introducing something non-native. But, but we still wanna be extra careful. And so, we won't allow people who are immune compromised into our initial human studies. And, uh, maybe most importantly, we've come up with new ways of attaching antigen to the surface of the bug that do not require genetic engineering. And so, the, the bug will divide, and over time the antigen will go away, and the bug will become wild type again. So, you won't be left with anything unnatural. And so, I think that, um, even though we might return to genetic engineering in the future because I think it would, it would have a, a durability edge, um, this is the way that we'll start in humans. And, and I think it will be, um, the, the safest way to test this for the first time.
[00:33:04] Russ Altman: And, and then my final question, and this is very exciting, is you, you're a professor at a university. You, you do teaching, you do research. You are not, I'm guessing, and I know to some degree, you're not set up to become a drug company or a vaccine company. So, when is the appropriate time to move this to professionals in, in industry to scale up and to really kind of make this be a thing.
[00:33:27] Michael Fischbach: Well, that's a really interesting question. Um, I, I think we're, uh, I would've given you a different answer even a couple years ago. We're at a moment in biotechnology where it's very difficult for, for, it's, it's easy to found a company, but it's very difficult for that company to exist sometime between its inception and its first data in humans. Um, at the same time, we're actually pretty well set up at Stanford to do, um, to do early translational studies, proof of concept stuff. And so, I think we're going to do the, the, all of the monkey work, and hopefully our proof-of-concept human study here at Stanford. And that this is, this is a fantastic time to start a biotech company once you have a little bit of data proving that something like this works in humans. I think since what we're doing is brand new and as you pointed out, there's a real risk, uh, that it, it just won't work. Um, it's on us to demonstrate that it will and to work out the, the kinks in, in the technology, uh, to make the early prototype functional. And I think that's gonna be the right place to hand it off to, to professionals, um, who could take it from there.
[00:34:31] Russ Altman: Very exciting. Well, thank you so much to Michael Fischbach, but before we let you leave, we're gonna go to our new segment, which we're calling the Future In a Minute. Um, we've briefed you about this because otherwise it would be unfair. Um, I'm gonna ask you five kind of rapid-fire questions and I'm gonna ask you for some rapid-fire answers. So, um, I think you've seen these questions before. Um, are you ready to go, Michael?
[00:34:52] Michael Fischbach: Fully.
[00:34:53] Russ Altman: Okay. What is one thing that gives you most hope about the future?
[00:34:58] Michael Fischbach: It's a special time in biology. Uh, our, our colleagues in the School of Engineering say this all the time, but I think that, uh, it, it is a time in biology that's like computer science was thirty years ago, where you can see the impact that biology can have in the world and it can happen really fast. And, uh, and so, uh, I feel fortunate to be in this discipline at this point in time. That makes me feel really optimistic.
[00:35:21] Russ Altman: What's one thing you want people to walk away from this episode remembering?
[00:35:24] Michael Fischbach: If vaccines were to arrive in your mailbox in a ketchup packet and they didn't make you feel bad, then uh, the way we would use them would change substantially.
[00:35:34] Russ Altman: Aside from money, what is the one thing you need to succeed in your research?
[00:35:39] Michael Fischbach: Extraordinarily creative and fearless coworkers. And I, I've been extremely lucky to have them. I told you about Erin, and Djenet and I have a whole lab full of them.
[00:35:49] Russ Altman: If all goes well, what does the future look like?
[00:35:51] Michael Fischbach: In other areas of medicine, um, there's been coalescence around a common scaffold. Kinase inhibitors for cancer or antibodies for a variety of diseases all look pretty similar. In vaccines this hasn't happened. There are, there are dozens of different kinds of vaccines. I think if we develop a platform like this that induces a potent response and is safe and durable, um, that there is a chance that there could be coalescence around a common scaffold in vaccines that would make it much easier to deal with, uh, new infectious disease problems that arise.
[00:36:22] Russ Altman: And finally, if you were starting over again and you needed to get your degree, uh, or training in a different discipline, what would that be?
[00:36:30] Michael Fischbach: My PhD is in chemistry, uh, but I, I, I would stick with biology. Um, it's, it's such an exciting time and, and I, um, I, I'm so much more excited about the upsides of biology right now than I am concerned about the, the headwinds that we face, which I think are temporary. Um, I might add a minor in applied math to make sure that I could handle data myself.
[00:36:53] Russ Altman: Thank you very much. That was the Future In a Minute.
[00:36:56] Thanks to Michael Fischbach. That was the future of vaccines. Thank you for listening. Don't forget, we have a huge back catalog of 300 episodes or so where you can spend all day and all-night listening to The Future of Everything. If you're enjoying the show or if it's helped you in any way, please remember to rate and review. We like to get a 5.0, but only if we deserve it, and we like to hear your comments as well. You can connect with me on many social media platforms including LinkedIn, Bluesky, Mastodon, and Threads @RussBAltman, or @RBAltman. You can also connect with Stanford Engineering @StanfordSchoolOfEngineering, or more simply @StanforENG.
