 Robots made of frog cells. Wow. Exciting. We don't pay enough attention to biogenetics. Ethan Allen, our Chief Scientist, joins me here on likable science for the ThinkTech 5 o'clock show on a given Tuesday. I'm Jay Fidel, and I'm looking forward to learning more about what do you call it, biogenetics, biocopying. Ethan, tell us what's going on. We don't know enough about this. Sure, Jay. So it's really pretty intriguing stuff they've figured out, and they just really started, this work was really pretty new. Started last year, they found if they take skin cells off of embryos of this particular frog scientist love called Xenopus larvis, and that's why these are called Xenobots. Nothing fancy about the frog. Garden variety frog. Well, it's an African clawed frog, technically, but yes, it's been around for years and all, but they discovered that the skin cells of these embryos, if you sort of put them just in a dish by themselves, it's like they don't know they're supposed to be skin cells anymore, and they start doing different things in different environments, and they'll start clumping together spontaneously, and they'll start working in a coordinated fashion when they've got some hundreds or thousands of cells gathered together into a little ball, and then what scientists discovered is they could actually take some heart muscle cells to get embryonic heart muscle cells and stick them into the little cluster of cells, and they actually build these things cell by cell by cell and stack them up in certain ways, and the muscle cells allow it to contract, and then it could start to move, and it could move in organized fashions as all the cells would get together, and they line up in certain ways, and they can make coordinated movements, and so it's been very interesting, and they'll start spontaneously doing things like gathering up other cells into piles together. Well, one exactly understands why they're doing this. There's no nervous system, there's no sense organs, these are just skin cells basically, but they don't know they're skin cells. It shows importance of context, right? Normal skin cells, we lie on a basal lamina, we're packed in other skin cells in very organized fashions, and getting signals telling them to behave like skin cells, these don't, and so they start doing other things, and some of these things are pretty amazing actually. Well, we always knew that the DNA of a given organism is found in any one cell, am I right? Right. So that, you know, the idea is to take that one cell and make it into the whole organism, and now it looks like, you know, they've found at least some example of how that might work is pretty exciting. Yes, it's very intriguing these things, and there's a great deal of potential down the road. This is just one of the first steps, it was only last year they first built these things called Xenobots, and now they've actually refined them to where they're exciting just recently, they've built Xenobots that will reproduce themselves, but it's not like biological reproduction, that is, biological reproduction is either a cell splits into two half daughter cells, you know, doubles its chromosomes and splits in half, or they split into haploid cells and have so-called germ cells, sperm and egg, right? These Xenobots, if you form them in a certain way, and they're for a pac-man formation, they then gather cells up, apparently using the little pac-man type opening, these other cells into, essentially into pac-man type shapes exactly like themselves, these go on to sort of grow up a little more, and they will then start gathering up cells and build more pac-man type shapes out of the cells that are around, so it's not cells actually reproducing, cells actually building models of the same organism they are, if you call them an organism, it's sort of a question, what these things really are, they're very strange interfaces, not exactly life forms, not exactly machines, oh, did the scientists have to do anything to make this robot come alive that way to activate the robot, or they just leave it sitting there? Apparently they, it took a great deal of work, and this was the University of Vermont's Advanced Computational Center or something like that, that figured this out, they had some sense that if they put a bunch of these cells together in certain forms, they could get them to start doing certain kinds of things, and so they literally did computer models of, if you put a thousand cells together into a tube, or a star shape, or a line, or whatever, what's gonna happen, and they ran some computer models, fairly sophisticated computer models, and eventually settled on a smaller subset of cells of shapes that looked interesting, and then began building these, and literally they would take individual cells and hold them with essentially a little pipette and move them around and stick them on to other cells, one by one by one, and so they actually build these things out of a few thousand random cells basically, and once they put them together in these shapes that had been predicted to do interesting things, they began doing interesting things, you know, they began moving around, and moving around, not just like one of them, but if you put several of them together, they'd all move around in concert, and how they're doing this, and why they're doing this is sort of a puzzlement, I mean they have no sense organs, they have no neurons in there, how are they knowing what this other one is doing, and how are they coordinating their actions? So the scientists had to put the cells together in a certain way, I mean not just that they moved them around with pipettes, as you say, but they had to stack them in a certain way, and that may be critical to activating them as a robot, but what was the what was the way, you know, what was the architecture? Well, that's the one that they've gotten very excited about, is what they call a pac-man, because it's a blob with a big wedge cut out of it basically, and that turned out to be, for regions that aren't clear, a very active thing where it will use that wedge that's cut out of it to apparently gather more cells together and then it somehow knows how to build itself, so out of these other cells it builds something very much like itself that then goes off on its own, and you know finds yet more cells and builds, so they've done this multiple generations now, so these things are great, I mean that they're, so unlike machines, one, they heal themselves, like life forms do, you know, you can actually injure them and they will actually regenerate the tissue, two, they're obviously completely biodegradable, they're tissue, you know, they're biological tissue, they're not machines, so they're not going to pollute anything, they don't need an outside energy source particularly, other than whatever, they're getting out of their local environment in terms of chemicals and all. You have to feed them? I would guess their environment must contain stuff that they use, you know, the right balance of ions and various types and probably some sort of precursor molecules to enable them to keep their metabolism going and keep building cell parts and repairing themselves, you know, you probably couldn't just stick them in distilled water and expect they'd work very long. Yeah, but is this all at the microscopic level, you couldn't see this with the naked eye? I guess once they build them with a few thousand cells, you know, they're less than pinhead size and maybe a millimeter or a fraction of a millimeter, so you can just barely see them apparently, they're up about that scale right down magnifying glass to microscope level, you know. This is fascinating, you know, I mean, I just, you know, maybe it's a statement of the methodology, but so I'm a scientist, I'm a biological scientist, I like microscopes and things, I like to operate at the cellular level rather than the atomic level, I suppose, and I wake up at two o'clock in the morning and I say, frogs, we have to do this with frogs, frog cells, I mean, how could they have made that choice? I mean, there were a lot of other organisms in the world that they might have chosen at two in the morning, why frogs? Xenopus has been a very favorite so-called prep, an animal that has been widely used by a lot of biological scientists for years, particularly in developmental studies. So they have studied how Xenopus eggs and sperm come together and fuse into a little zygote and build itself up and grow and two cells become four cells, four become eight, et cetera, et cetera, and they followed this for many, many decades. I mean, they were working on Xenopus when I was in graduate school, it was not a new prep at that point, so it's well established, it's developmental thing, it's developmental characteristics, so they knew that the properties of the cells and what they would do depend upon where they find themselves, who their neighbors are, and what their environment is, and so it wasn't really a big leap in some sense, I mean, somebody obviously was pretty bright to figure this out, but to think, gee, maybe if we put a few hundred of these cells together in an interesting conformation, maybe they'll do something interesting, and indeed that's exactly what happened, and as I say, they apparently ran a computer model to figure out what might be interesting, you know, confirmations to build, given a few hundred to a few thousand cells, and tried literally apparently hundreds and hundreds and hundreds of these potential shapes, and then selected the best few for different things. Now, what I get out of that is the reason they went to frogs is because they've been working with frogs for a long time. If they had been working with some other organism, they might have used that organism, so I guess the question I would put is, is a frog, is a frog cell, the biology of frogs, the chemistry of frogs different, then, you know, why is a frog different from all other things that make it special for this, and I get the answer as well because we've been working with it, because we're familiar with frogs, we know how we have to handle frogs, we know how to, you know, provide nourishment or whatever you need for an environment for so frog cells can grow, but if we had known, you know, I don't know, catapellas just as well, we might have tried catapellas for the same experiment. I would be willing to bet dollars to dominance at this point that are already trying, we're probably with mouse cells now, I'd probably take embryonic mouse cells, because again they've pretty well established what environment they need, and they're probably, you know, trying to pull groups of mouse cells, individual mouse skin cells together, maybe with some heart cells stuck into it and build them into certain configurations. There's no real fundamental reason it shouldn't work just as well in a mouse or a person as in a frog. Yeah, I thought you said person there for a minute, Ethan. Yeah, there's no person, human being person. Yeah, you could take embryonic human cells and just again, we're not that special, you know. Yeah. Animals just like everyone else, you know. Well let's make a wild assumption and assume that the same process could be achieved, maybe you'd have to, you know, tune up the environment for the growth environment for the cells and the way you handle them, but let's assume that you can achieve the same process, not only for mice, but for human skin cells. Let's assume that, what do we learn from all this? What do we learn about cellular biology? What do we learn about biochemistry on the microscopic level? What do we learn about life? Well, I mean, it tells you very interesting things about some of the factors that control function. So it is indeed a classic case of, you know, form yielding function. Literally in this case, they build certain forms and get certain functions out. But what they get out of really is it should be possible eventually, for instance, if these things will go around and gather up selected objects in their environment, for instance, you could envision putting these in your bloodstream and having them go around and gather up atherosclerotic plaques out of your arteries and chew them up and digest them away for you. Just like a little Pac-Man. Yeah, exactly. You know, or, you know, set them loose in the environment and if you have some that were essentially trained or programmed to go after microplastics, they could perhaps bring all little bits of microplastics together and form them into some little macroplastic conglomeration. Did you say trained or programmed? Yeah. Is there a suggestion from where we are now to training or programming a frog skin cell to do a somersault, for example? Yeah. I mean, that's very much that is these different shapes they built, did different things. Some were more or less just big spheres and they apparently run around and will gather other cells together in nouns in their environment, but they won't reproduce themselves after a week or two weeks that they just die. This peculiar Pac-Man shape they developed is the first one now it reproduces itself. So that was very exciting to them because, you know, that serve as you can build something that can last and not only do a task, but then it can build its next generation of beings to go on and continue that task. So the potential for doing a lot of useful work suddenly has expanded immensely, you know. It's mind-blowing. I mean, I have a vision of Star Trek, you know, how they could heal anything wrong with you and it wouldn't necessarily be, you know, working on the skin or in the body. It would be taking the cells from the body and putting them in this this auger dish somehow and letting them develop and then, as you say, programming them, training them, tuning them up so that they achieve a certain purpose, maybe healing. And then you put that cell from the auger plate back into the body and it does its job. Sort of like that book years ago, a fantastic journey was it? There's microscopic healing things. What's your reaction? Absolutely. There's no reason, for instance, and again, we're just speculating wildly here. But if you could, for instance, train little Xenobots, these might be human bots, instead to go after certain tumor cells to recognize and glom on to and kill off tumor cells, you could use them to get rid of tumors in your body and they might do so very, very efficiently. You could use them, yes, in wound healing conceivably. There might be ways to do all kinds of things. One can speculate wildly. You could go off and they could circulate in the brain and remove skull tangles and plaques in the brain and help actually reverse Alzheimer's ultimately. There's really, if you start speculating, there is no end to how useful they could be. Well, to get to that level, seems to me that we're going to have to know more about the atomic level, the molecular level of the frog cell that's reproducing this way or whatever, whether it's the mouse, the human, we're going to have to look deeply into that cell to see the mechanics and how exactly that works. There's a researcher in the cancer research institute. His first name is Clarence. He's a Clarence Naguma or a name like that. He's been on our shows. I want to get him on again. He's been doing AIDS research and he looks into that and he can give you charts, electronic microscope, you know, graphics of exactly what's going on in a given cell at the molecular level. I think that it sounds like this research is not really yet at the molecular level. I would want to know how the molecules interact and activate each other in order to achieve the reproduction. What's your reaction to that? Yes. I think one of the next things that will happen, and you and I have talked about CRISPR technology where you can go in and essentially manipulate DNA now with some reasonable degree of precision, cutting out bits you don't want and inserting bits you do want. I suspect that's going to get combined with this technology and that they'll take the embryonic cells, run some CRISPR alteration on them and insert DNA sequences that they know generate, for instance, generate more cilia, let's say more of the little protrusions from cells and then put a bunch of those things together and they'll have a highly ciliated little or whatever, which probably can do different kinds of things on without cilia. Cilia turn up to have a lot of interesting properties. So yeah, it's absolutely they're going to, I'm sure they're looking at sort of why these behave the way they do. A lot of it apparently actually has to do with sort of the biophysics that actually the structure of the cell and how that structure is determined by its neighbors, its environment, the chemistry of its local neighborhood as it were, almost. Well, you know, this is pretty interesting because it's sort of it's a parallel to CRISPR. It's a parallel to do the remarkable things that the molecular level or even smaller than that at the table of elements, if you will, and how the atomic elements connect with each other, then all these things are like we find out about them and they run parallels. But when we figure out how to connect these disciplines and these laboratory, I don't want to say tricks, but these laboratory procedures to implement one procedure and another procedure, have them both at the same time, connect them up, then God, the possibilities are unimaginable. And so I wanted to ask you about that. So okay, I mean, I'm thinking fictionally of Star Trek. And I'm thinking fictionally of a fantastic journey, voyage, whatever that book was called. But I don't think we're that far from it. I mean, for example, we had a show not too long ago by a woman who wrote a book on COVID. And her really remarkable aspiration was that one of these days, we're not only going to figure out how to deal with the viral particles that make up COVID, but we're going to be able to anticipate their mutations, their variants. We're going to be able to determine how they will mutate in the future and head them off. Because we will know the process of mutation and therefore, we will be able to deal with anything they can come up with. Now that will change life on this planet. I'm not sure exactly how, but it will change life on the planet. Now if we could get these Pac-Man things, okay, to go after virus particles, anticipate them, train the Pac-Man robots, not from frogs, but human cells, to go after antigens of one kind or another, we could attack all kinds of things that are happening at all kinds of levels in the body. I mean, it's the fountain of youth. It's beyond imagination. You know, I don't think you actually need to use this whole Xenobot technology in a sense, because once we begin to understand how that mutation is happening and can anticipate it, then using something like CRISPR, you can go in and just hit your own immune system cells and plug in the right DNA so that they will already be sort of primed and ready and expecting that it's sort of almost like they've been vaccinated for this new variant that they've never seen. So yeah, fascinating stuff, but to your point that bringing these different disciplines together is very interesting, that's certainly proven true in the past, say five or six decades of science. You see much of the really interesting work is happening at interfaces between traditional branch of science, between biology and physics, as the Xenobots are, between chemistry and engineering. These fields of chemical engineering now are very popular, very productive fields. People are developing really interesting stuff through them. I know you shared some very interesting articles with me on some of the bioengineering stuff that some of the research groups in Israel have been doing. So yeah, it's where a lot of the action is these days is at the interface of traditional fields. Well, you know, all of this raises, when you talk about Xenobots, about living, you know, for living cells, and these really fantastic intelligences that we find in living cells that we never fully understood, we never knew that they were there, that they could behave this way. You know, it does suggest that we step into a godlike role of being able to change living organisms, build them, create them. I mean, it's almost, it violates our notion of where man ends, or humans end, and God begins. We can create organisms that we've never seen before, or recreate them. We can create organisms, for example, that are extinct. We can make them happen yet again. We can build a whole new world for this. And that suggests, and we have four minutes to do this, that suggests the ethical considerations that are right out there, and that scientists have to study at the same time. What are your thoughts about that? Oh, exactly. There was the Japanese or Chinese scientist a little bit ago who did some genetic engineering on human embryos, and was, has been widely criticized for that, basically, the rest of the community feels very much that that's not an ethical thing to do. We don't know enough. He's screwing around with stuff that we don't really understand well enough to be screwing around with. And it's, you know, it's a whole, it's a big issue in a lot of sciences. The whole thing with climate change now, people looking at geoengineering, right? The Chinese are, they're definitely looking at that. Everyone's looking at it actually. And again, there's all kinds of ethical considerations, because when you pile stuff out in the atmosphere to make your place a little cooler, what are you doing? You know, that stuff that you've put in the atmosphere goes around and around, and it's pretty soon everywhere in the world, and it's affecting your neighbors and the Arctic and the equatorial regions. And so yeah, I mean, those ethical considerations that you mentioned are increasingly large, I think, in scientists minds. I think people worry about the science fiction movies and the, you know, the, the valley of the walking dead, that sort of thing, these aberrational organisms that might be people or were people. I mean, it's, it's out of science fiction and it's out of scary science fiction. And I think that's what scares people about not wanting to go there. But, you know, you imply by your answer, Ethan, that there will come a time perhaps when we understand the connection, the connection with, with these xenobots and with bio, biological processes in general and, and as CRISPR and, you know, this molecular biology that Cancer Research Center is working on and atomic, atomic understanding of the atomic interactions. I mean, all of this is right out there. We know the disciplines. We just haven't put them together yet. Something like that. And we're, we're, you know, University of Vermont does this. Well, what about the University of New Hampshire? They do that. They may not talk to each other enough. If they talk to each other, maybe there's something come out of it. But the problem is, is this how much you're going to hate this question? How much do we have to know about this before we can get comfortable about doing clone work or manipulation of human cells and tissues and bodies? Where's the point of comfort there? Do you see where that would be? What would be the standard before we could go there? Well, they ran into this when the whole issue back in the 1970s of recombinant DNA first came up, and they realized this is a potentially life life altering technology. And actually they had a, they called a big conference and it wasn't just with scientists. They had theologians, philosophers, government people, all kinds of people there to hash things out and say, Hey, look, look what's happening here. Look at the doors. This is opening. How do we deal with this? What do we say is basically our standards? What are we going to say is okay, you can do this experiment? No, you can't do this sort of experiment. Yeah, you've got to hash these things out, because of course, as we know more, we keep opening up doors on what we don't know, which is always larger, and there's always more that we don't know out there. So we're never going to get to a point where we say, Hey, we really we've got this when we know it all now. If you get that point, you know, you're you're fooling yourself. Well, I mean, it suggests two things to me. One is that maybe there has to be some international regulation of this sort of threshold threshold standards. So we don't go to places which are too scary to a panel of scientists that has looked into the ethical hyphen science issues. That's one thing. But the other thing, you know, not that it's settled, but there are those even still today who believe that the Wuhan laboratory was actually weaponizing virus, not necessarily limited to COVID-19, but other viruses that could be weaponized. And I mean, and that's a logical possibility, of course, but everything you and I have talked about in this half hour could likewise be weaponized. And God knows, and I'm using that term advisedly, God knows what that could would that could do to humanity. What are your thoughts? There are big groups talking and debating on this dual use technologies. And how do we how do we control that when you have a technology that, for instance, you make take a deadly disease and make it more transmissible now, more easily transmissible? That's like, is that okay to do? I mean, maybe you've learned something about transmissibility and all, but you've also potentially then you've made it, you've made a nasty weaponizable thing at least, if not an actual weapon. And yeah, large debates happen about this kind of work. And it's a good thing. It needs to happen. Discussions need to be taking place. You can't have people just working on these areas by themselves, talking to others, because they'll go right ahead and do that. They'll go right ahead and take that next step without thinking, you know, without considering all the ramifications. They'll just see their little narrow piece of it, like, oh, this is going to make this piece better. It's going to make me famous. And but I'm not considering, yeah, what if you let the xenobots loosen the world and they start reproducing and reproducing like like the tribbles in Star Trek, right? Well, I'm thinking of I'm thinking of the boys from Brazil, where I mean, this is all fiction, but what is fiction today is fact tomorrow. I'm thinking of the boys from Brazil with a bunch of scientists aside, they would make a generation of Hitler's, and they create that biologically. And we we don't need a generation of Hitler's. I'm thinking of the Clay soldiers in Xi'an, China, which were, you know, a clay, of course, but you could build a soldier that would be stronger than the other guy's soldier. And before you know it, you could you can have a very indefatigable group of soldiers, you could build people are very smart. You could change humanity by changing the groups that would predominate. This is pretty scary stuff. I prefer the natural myself, however flawed that might be natural Mendelian, you know, selection. But I mean, it's irresistible for a scientist who may not be so much interested in the ethical aspects of it. And, you know, he could be working in a laboratory in the Ural Mountains and invent these things and then pop up with a weaponized technique that would change the world. And so it's hard actually to stop it, because that scientist in the mountains can read the material from all the other scientists and not share his work. So, you know, I mean, every scientist should be trained in ethics. Absolutely. Absolutely. And then more and more of more are getting that way. But absolutely, you're quite right that that should and must be a requirement in science to understand that implications of your work. Yeah. So what's your sense of the horizon on this, you know, we you and I have talked about this kind of thing, you know, from one show and then another show and it all kind of comes together is that biology is moving very quickly. Microbiology is doing things every time you look that are more remarkable. When are we going to see some changes that are, what do you say, you know, life changing? That's the wrong word, isn't it? Life changing. When are we going to see that happen? Well, I mean, arguably, we've seen some of those. I mean, our lives are much different if you think about how you spent your time during COVID than how you would have 10 years before that, 15 years before that in terms of the internet and cell phones, all your communication devices and the way you and I are running this show right now. You know, it's already changed big aspects of our lives. The whole world of commuting for work is probably never going to be the same. I mean, yeah, and biology is, you know, sort of right behind that. I mean, they're already, you know, working on they have new vaccine from malaria now. You know, that's remarkable news and is going to likely going to save hundreds of thousands of lives per year. So there are, you know, changing people's lives in a big way, right? Families won't lose children. So it's a, you know, I'm fundamentally an optimist. I think scientists in general are pretty good people. I hope enough of them are ethical enough to realize that the implications of their work. And I believe that they are. They've shown a good deal of willingness to step up and say, hey, let's, let's put a little pause on this and talk about it before we sort of run down that alley. And it's going to move on. It's going to move on. Science never stands still, you know, and the question is, yeah, can we keep it in sync with our ethics and our humanity, you know? It's biblical, Ethan. What I mean is, let's assume for a moment for this discussion that there is a God, and the God gave humanity, you know, the skills to look deeply into our world, including the natural world in the planet, you know, vis-a-vis climate change. But what we haven't understood until now is that we not only have the ability to look and improve, we have the ability profoundly to change things, to change our own species, our own natural biology, our, I mean, the physical planet, the physical condition of humanity, we now can change it. And that's the biblical test, you know, beyond anything we expected before. And you and I live in that time. We live in that time. And I suppose, from an observer's point of view, a journalist's point of view, you know, we are very, we should be very happy that we can observe and see this and participate and have this conversation together. Absolutely. I feel truly lucky indeed. Thank you, Ethan. Let's do it again soon. Ethan Allen, our chief scientist who takes us far and wide around the universe, from the planets and the stars, right down to the microbiology in our skin. Thank you, Ethan. You're welcome, Jake. Aloha.