Portrait of Michael Levin
Big Brains podcst

How bioelectricity could regrow limbs and organs, with Michael Levin (Ep. 112)

Biologist’s innovative research on how cells rebuild themselves could be the future of regenerative medicine

Portrait of Michael Levin
Big Brains podcst

Show Notes

In the near future, birth defects, traumatic injuries, limb loss and perhaps even cancer could be cured through bioelectricity—electrical signals that communicate to our cells how to rebuild themselves. This innovative idea has been tested on flatworms and frogs by biologist Michael Levin, whose research investigates how bioelectricity provides the blueprint for how our bodies are built—and how it could be the future of regenerative medicine. 

Levin is a professor of biology at Tufts University and director of the Tufts Center for Regenerative and Developmental Biology.

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(Episode published April 27, 2023)

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Transcript:

Paul Rand: Imagine the future where organs, amputated limbs, or even damaged brain cells could all grow back on their own. Nobody would ever have to waste precious time waiting on the organ transplant list.

Tape: In 2022, doctors performed more than 42,000 transplants in the us, but there are still 104,234 men, women and children currently on the organ transplant Wait list. 17 people die every day waiting for an organ transplant.

Paul Rand: And for the millions of people who rely on prosthetics, what if that wasn’t their only option?

Tape: For people with artificial limbs or those with spinal injuries, the loss of touch can put the world beyond their grasp.

Tape: The future may be less about healing injured body parts and more about regenerating new ones.

Paul Rand: Brain damage from birth defects, injury or even drug use could be morphed back to normal. The possibilities of regenerative medicine may sound like science fiction, but they may be closer to reality than you think.

Michael Levin: There’s a huge community of people working on this problem. There are many people working on regeneration, and I do think as a society we’re going to crack this.

Paul Rand: That’s Michael Levin, professor of biology at Tufts University, where he directs the Tufts Center for regenerative and developmental biology.

Michael Levin: There is unbelievable medical suffering out there, and I’m talking from birth defects to traumatic injuries to cancer to degenerative disease. The need out there is absolutely horrendous. What keeps me up at night is not living up to the potential of this technology to relieve the current burden.

Paul Rand: For years, Levin has been working on new technologies that could regrow limbs, repair tissues, and more.

Michael Levin: I think anything that’s not forbidden by the laws of physics we ought to be able to do functionally. So the fact that some animals regenerate their limbs and there’s nothing fundamentally impossible about regrowing your limb, after all your body did it multiple times during development. If we knew what we were doing, we would all be able to regenerate limbs and various other organs. I think fundamentally this is possible.

Paul Rand: The question is how?

Michael Levin: Pretty much everything, birth defects, traumatic injury, aging, degenerative disease, cancer, all of these things boil down to the problem of a group of cells not knowing how or not being able to build the right thing. If we have the answer to this, how do you communicate an anatomical goals to a collection of cells? You could fix all of these things.

Paul Rand: We have this assumption that our cells are mindless, that they’re hardwired to only do a limited set of things, but Levin isn’t so sure.

Michael Levin: We sort of think that, “Okay, so there’s the chemistry, it’s sort of unfolds and well, what else could it possibly do? It’s just following the laws of chemistry?” That robustness, it actually lulls us into a very false sense of simplicity because, for example, if you take a human or many other kinds of embryos and you cut them in half, you don’t get two half bodies the way that you would get if you cut a car or a computer or something else in half, you get two perfectly normal monozygotic twins, and the way that happens is because that collection of cells can tell that half of it is missing and it can tell that it needs to rebuild what’s missing? That process right there is literally a kind of intelligence, and once you’ve understood that the body, much like the brain, is a collective intelligence and the morphogenesis is the behavior of that collective intelligence, you can start to ask all sorts of interesting questions. How can you train it? How do you know what it’s thinking? How do you communicate with it?

Paul Rand: Levin thinks he may have found the answers to those questions, bioelectricity.

Michael Levin: So all of the cells of your body from the time that you are a two cell embryo are forming electrical networks that process information and first information about form and later information about behavior.

Paul Rand: What if we could use that electricity to train cells? Levin believes this technology isn’t going to be the breakthrough of the next century, but actually may come in this one.

Michael Levin: I believe that I’m going to see this in my lifetime. And my hope is that through all of this, we can exploit AI as a tool and the lessons that we’ve learned from the biology to improve the world around us.

Paul Rand: Welcome to big brains where we translate the biggest ideas and complex discoveries into digestible brain food. Big brains, little bites from the University of Chicago Podcast Network. I’m your host, Paul Rand. On today’s episode, the Science of Bioelectricity and how it could shape the future of regenerative medicine.

Michael, I wonder if I can just start off on a very fundamental question and having you explain to me the concept of bioelectricity.

Michael Levin: The easiest way to get into bioelectricity is to think about there are these ion channel proteins on the surface of these cells. They enable every cell in your whole body to have a voltage potential, and they can communicate that voltage potential to their neighbors through electrical and chemical synapses.

Evolution noticed that electricity was a great way to store and process information long before neurons appeared, so even bacterial biofilms, so even bacteria can already coordinate their activity in the biofilm using electrical signaling. What evolution has done is exploit these computational properties of electrical networks with all body cells.

Paul Rand: Basically, bioelectricity is what your brain uses to make your body do things.

Michael Levin: Well. Look, if I were to tell you that just by the power of my thought alone, I can control the molecular events including the cell voltage in something like 30% of my body cells. I mean, that sounds crazy and it sounds like it’s some sort of...

Paul Rand: It does, it does.

Michael Levin: But in fact, this is what each of us does when you get out of bed in the morning, so you’re laying there, you get this high level executive decision that, “I’m going to get up.” In order for you to get up. The muscles in your body have to contract in particular sequences, and in order for them to do that, they have to have specific voltage potentials. Your thoughts and goals and intentions and your purpose and various other things that have to then be cashed out as physical behavior. What’s in between there? What allows your high level cognitive processes to actually affect the molecules in your muscles and in your glands and the rest of your body? That’s bioelectricity. Bioelectricity is this amazing layer between mind and chemistry. It is just incredibly profound.

Paul Rand: So you might be wondering, what does bioelectricity have to do with regenerative medicine? To answer that, we have to go all the way back to when you were just a tiny little embryo.

How did your body know how to build itself before you had a brain to tell your cells, to make an arm, to make a foot, how did they know what to do? Who was the architect in charge?

Michael Levin: Already there are electrical signals being used to sort out which side is left side, which side is right side. Then eventually, which side is anterior, which side is posterior, [inaudible 00:07:17] ventral, all of that. It is from the earliest moments of your unique life as a multicellular individual, that bioelectricity is already there with you.

Paul Rand: It’s kind of mind-blowing in its own way. How do the cells have these memories, if that’s the right word?

Michael Levin: Well, I think it’s the right word. I think many people probably don’t think it’s the right word, but I think it’s exactly the right word. I think you’re right. It is mind-blowing because. look, each of us makes this journey from an unfertilized [inaudible 00:07:46], which is a little blob of chemicals. You look at that little blob of chemicals and you would say, “well, this is just physics. This is just chemistry. This thing doesn’t have any goals, any intelligence, you know, you name it.” And then eventually that little blob of chemistry turns into, nine months and some years later, it turns into a being that absolutely has an inner perspective, it has goals, it has preferences, it has behavioral [inaudible 00:08:13], and it will go on to say things like, “Well, I’m not a machine I’m a human being.” Okay, great.

What’s really important to realize is that this process of development, very robust, meaning consistent, so there’s this amazing ability for life to get to the correct outcome, meaning the correct target morphology for that species, despite all kinds of crazy things, multiple copy numbers of the DNA, more cells, less cells, bigger cells, they still figure out how to get it done.

So then it makes really a lot of sense to ask, “Okay, if you’re solving this problem, if you’re going to get to the same goal despite various things that could happen to you, what are you using to remember what that goal is? You’re navigating these spaces trying to get to the correct final outcome, but how do you know what that outcome is?”

Paul Rand: Levin thinks bioelectricity is the architect building the blueprint, so to speak.

Michael Levin: These pattern memories are encoded in the electrical network of the body of the early embryo and subsequent exactly in the way that we think of as memories about navigating three-dimensional space are encoded in the brain. Now, I should point out that we, of course, we don’t know exactly how memories are encoded in the brain. We still don’t know, and there are many mysteries about that in the body as well, but I think we should get really comfortable with the idea that electrical networks store memories, they store goal states and they facilitate these complex beings to navigate space to get to those goals.

Paul Rand: As you talk about this, it’s almost like the cells are like a hardware and the electrical patterns are almost the software. Is that a fair analogy?

Michael Levin: I think that’s a very fair analogy. A lot of people don’t like that analogy because they’re visualizing hardware and software the way that they think about their laptops. But what is really powerful about that notion and what makes that analogy work really well is the idea of reprogrammability. So what’s powerful about computers is that the exact same piece of hardware can do multiple things without rewiring. And so when I give talks about this, I ask people, “Why is it that on their computer when they want to switch from Photoshop to PowerPoint, they don’t get out their soldering iron and start rewiring?” Isn’t it amazing.

Paul Rand: Yes.

Michael Levin: Isn’t it amazing and isn’t it great? And isn’t it amazing that in modern molecular medicine, all of the exciting approaches are in fact at the hardware level? So everybody’s super excited about genome editing and protein design and changing the molecular pathways and adding genes and subtracting genes and CRISPR and [inaudible 00:10:46], all of that stuff is at the hardware level. It’s like we were stuck in the 1940s and 1950s.

Paul Rand: Levin thinks using bioelectricity to shape the software of ourselves is the key to the future of regenerative medicine. Biology

Michael Levin: Is incredibly reprogrammable. It is not a fixed, hardwired thing and treating it that way, both in medical contexts and in, let’s say, evolutionary context, leaves most of what’s exciting on the table.

Paul Rand: You speak about this very definitively, but there are skeptics. Is that right?

Michael Levin: Yes, of course. Which thing particularly? Because one general thing is that I can always tell what kind of department I’m giving a talk in based on which part of my talk makes people angry, and it’s always a different part. So yes, there’s skeptics but...

Paul Rand: Tell me what makes people mad.

Michael Levin: If I were to say that there is a collection of cells that can process information and do completely different things with no change in gene expression necessary. So if I say that in a neuroscience department, people say, “Well, no kidding be, of course we’ve known this for since the 1950’s. Yeah, action potentials don’t require transcription underneath, they ride on the physics.” If I say the same thing in a molecular genetics department, then people throw rocks because it is the gene regulatory circuits that are supposed to underlie all the information processing. If I were to say that, “A collection of cells can store and process memories and have goals,” cell biologists generally very unhappy with that kind of formulation. They say, “Look, you shouldn’t be talking about goals. You should be talking about chemistry.”

Whereas in some circles of neuroscience where people do study complex behaviors, maybe psychiatry, maybe... They say, “Of course they can. And those cells are called neurons.” And then I’ll say, “Yeah, but it’s not just the neurons,” and they say, “No, no, it’s a specialization of neurons that does this.” And then we can have a very long, as I have in various meetings, a long discussion of what is a neuron? What exactly is a neuron? And people will list, here are four things that neurons do and I say, “Every cell in the body does this.” And so they say, “Yeah, yeah, but neurons do it fast.” And I said, “Yes, but who said that you’re looking at the correct timescale?”

Paul Rand: And a lot of this isn’t just theoretical. Levin has already shown this is possible starting with an unlikely little creature called planarian.

Michael Levin: Pretty much all of the important questions of life are there in planarian. If we understood planarian, we would have the answers to most of the questions that interest us.

Paul Rand: That’s after the break.

Carry the Two. Carry the Two is the show that pulls back the curtain to reveal the mathematical and the statistical gears that turn the world co-host Sadie Witkowski and Ian Martin bring unique perspectives from the fields of mathematics and statistics to convey how mathematical research drives the world around us with each episode tackling a different topic. Subscribe to Carry the Two part, of the award-winning University of Chicago podcast network.

I guess when you talk about this, it comes down to one of your early discoveries with a flat worm called a planaria. And I wonder if you can tell us about what is a planaria and how you first began looking at them and what you’ve learned.

Michael Levin: Yeah, so planarians are a kind of flatworm. They’re free living animal. They live in ponds and slow moving streams. If you’ve got kids, you can go make a nice sort of project of going to look for them. You can put a piece of liver on a string and toss it into a pond and pull it out in a half an hour, and it’ll probably have some planarian sitting on it. planarian are similar to our direct ancestor. They’re not like an earthworm or something like this, even though they’re small, they have a true brain, they have a central nervous system, they have all the neurotransmitters that you and I have, and they have a few really interesting features. Let’s see. First of all, they are highly, highly regenerative, so you can cut them into, I think the record is something like 275 pieces, and every piece will regrow exactly what it needs to be a perfect little worm.

Paul Rand: That’s just amazing.

Michael Levin: So people have understood that plenary are exciting for a really long, long time, and in the sixties, this guy James McConnell learned that you can cut off their heads and the tail will sit there doing nothing, and then when it regenerates, they remember the original information. So this is teaching us. This is teaching us that these guys have a kind of intelligence that not only can solve problems in morphospace, meaning being cut up into pieces and then remembering how many heads you’re supposed to have and knowing when to stop growing and all this kind of stuff. But also they have the ability to move learned information from tissue to tissue because as this new brain is developed by this tail, the information that they learn has to be imprinted onto the new brain. So information is moving through the body, it’s stored outside the brain and it’s moving through the body.

Paul Rand: How do they do this? Well, you guessed it, bioelectricity.

Michael Levin: We confirm this using modern tools. In 2013, we had a paper on this, so this he McConnell was right, this does work. And so what we found was that is there’s an electrical pattern that’s stored by the tissue. You can see it, you can read it out using the techniques that we developed, and that pattern tells them how many heads they should have and where the head should go. And what we were able to do is rewrite that pattern using various drugs that open and close these ion channels. So basically manipulate the very native interface that the cells use to control each other. We just manipulate the electrical pattern within the tissue, and when it’s time for them to regenerate, the cells basically consult that pattern and build whatever it says. And if the pattern says two heads, then they go ahead and they build two heads.

Now, couple of amazing things about that. One thing it tells you is that these electrical pattern memories are instructive. They actually determine what happens next. So that’s important. The next thing is that it’s an actual memory. And what I mean by that is that if you take these two-headed animals and you cut them up into pieces, you get more two-headed animals. So once you’ve made that change, it holds. Now that’s the basic property of memory. That’s what memory’s for, is to hold onto things that are no longer true.

Paul Rand: So you kind of reprogrammed its’ body in this case.

Michael Levin: Yes, yes, yes. I think that’s a very fair way of saying it because, very much like in the metaphor of reprogrammable hardware, the genetics are unchanged. No one has ever seen a mutant line of plenary. The only weird line of plenary is our two-headed form, and it’s not genetic. Moreover, we can make them have heads that belong to other species of planarian. Planarian with a triangular head can be made to make a flathead or a round head like other species, 100 to 150 million years evolutionary distance between them with no change of the genetics. So what that tells you is exactly what we’ve learned in computer science that the same hardware, if you understand the interface and you understand how to reprogram it, the same hardware can do many other things including emulate other hardware, which is what these other species are doing by default.

Paul Rand: If bioelectricity could change the architecture of a worm, could it do the same thing for humans?

Let’s talk a little bit about regeneration and specifically getting into humans. And I think most people know if they lose a toenail, that toenail will grow back. I learned by doing reading that humans between ages of 7 and 11 can regrow the tips of fingertips. But generally, if you lose an arm, you’re not going to regrow an arm, are you?

Michael Levin: This is true. Humans do not regrow their limbs. Although, interestingly enough, there are sporadic reports in the medical literature of people regrowing certain organs. For example, kidneys, and this is very rare, but there have been reports. We do regenerate our liver. So our liver is highly regenerative. So it’s not as if regeneration is somehow impossible for mammals. It’s just that humans don’t happen to be very good at it, and this we hope to change. Now after that, you want to ask yourself, “How is that going to happen?” And I think you need two things. I think you need an informational signal.

Paul Rand: In other words, bioelectricity.

Michael Levin: That is how are you going to communicate to those cells that this is what they should be doing, that instead of going down the scarring path, they should be, for example, retreading the kinds of paths that they took during development to build the structure in the first place. So that’s the message, the informational signal that you’re going to give.

And then the second part that you need, which is some sort of delivery vehicle, you need to be able to. not only deliver that signal, but you need to be able to support the tissue as it’s growing. So for example, for the goal of limb regeneration, and I have to do a disclosure here because David Kaplan and I who collaborate very closely on this stuff, we formed a company called Pharmaceuticals Inc, which is all about limb regeneration. So I have to make that clear.

David’s lab makes these wearable bioreactors. So these are basically a kind of capsule that goes onto a limb or a finger amputation wound, and it makes an aqueous protected environment so that the cells that are there, if they want to do a sort of calculation about whether or not it’s safe to put energy into growing new tissues, they’re not going to just get ground into the forest floor as we try to walk on them, they’re not going to dry out, they’re able to do the kinds of things they do during development. So there’s that delivery technology.

Paul Rand: And you’ve done some of this. You actually regenerated a back leg of a frog.

Michael Levin: That’s correct. We started with tails on tadpoles, and so there’s a stage at which tadpoles do not regenerate their tails. Tadpole tails are cool because they’ve got spinal cord and muscle and blood vessels, and so we were able to use bioelectric signals to grow back a tail. And then from there we went to legs and we did figure out how to induce the formation of the hind leg in an adult frog, which had not been done before. And now we’ve moved to mammals. We’re in mice now. We’re trying it, I’m not claiming it works with, this is still all unpublished. So all I’m saying is this is what we’re attempting now.

Paul Rand: Okay. And then I guess the question would be it’s not just limb regrowth, but it actually could end up being like you said, organs, even the brain. And so as you started thinking about the possibilities with some type of a damage, do you envision a period where we’re going to be able to say, “He’s got brain damage, but it will grow back?”

Michael Levin: I do. I firmly believe that ultimately we are going to have complete control over growth and form, and that includes growing back brain tissue.

Paul Rand: And so then I guess if we could regenerate some of these things then when you think of treatments for illness and using bioelectricity, has that played its way into this, IE, for cancer treatments, for example?

Michael Levin: Yeah, absolutely. The bigger picture here is that currently the medical model that we currently have, one of the problems with it is that it’s fundamentally unsustainable for any, no matter how many resources we have, because every advance that we make to prolong the life of a patient ends up giving you a sicker patient, that’s the baseline for the next intervention. So the better you are at extending the last stages of the lifespan, the more expensive and more heroic the next measures have to be. Inevitably, the logic of it is inescapable. And so that’s a spiral. That’s a constant spiral that is fundamentally unavoidable and unsustainable for any society unless we figure out how to crank up the regenerative process very early on so that you never get to the stage of that sinking ship that you need to keep propping up. It means that you are not just chasing symptoms, you are fundamentally, and we can talk about what that is, but we need a completely different approach to medicine that leverages literally the intelligence of the body so that the regenerative process is happening all the time.

In addition to leg regeneration, two kind of flagship applications in our group have been, first of all, the repair of birth defects. And so we were able to show that a wide range of birth defects of the brain, heart, face, and gut induced either by genetic mutations or by chemicals, can be prevented by an appropriate bioelectrical treatment that was designed by a computational model. So there’s a computational model that tells you which ion channels you would need to turn on and off to make specific patterns. And so we’ve used that to repair birth defects in the frog model. The other side is the cancer side, and we started in frogs showing that if we understand cancer to be the breakdown of the electrical signaling that normally harnesses cells towards this common anatomical purpose, so when that breaks down, they simply roll back to their amoeba-like ancient lifestyle where they just al their goals are little tiny cell level goals, which means go wherever life is good, reproduce as much as you can. Then that’s metastasis. And so we were able to show that despite really nasty human oncogenes, we could suppress to or prevent correct tumor genesis by forcing the appropriate bioelectrical states. And we started this in frog, and we are now in human glioblastoma. So we’re working to try the same thing in glioblastoma.

Paul Rand: If Levin’s work proves right, bioelectricity may take us beyond just regenerative medicine. The future Levin hopes to create is far more expansive.

Michael Levin: One of my personal goals is in this idea of morphological freedom. So we think a lot about behavioral freedom and freedom of speech, but all of those are actually secondary to morphological freedom. And what I mean by that is each of us is born into a shape with limitations and capacities that we have no control over. So your overall IQ is what it is. If you have various disease states, if you have limitations, and all of us have fundamental limitations, there’s no reason why the standard healthy human is the top of the food chain as far as mental and physical capacities. And I think that having ultimately, someday, and we do have the ability to change our bodies and change our minds in ways to expand our capabilities and rise to various potentials, then I think we’re actually getting somewhere. Up until then, we are really limited by these very arbitrary limits that evolution has left us with.

Paul Rand: Where, if anywhere, do different levels of potential ethics come into play on this? And what do you think about in relation to any of these things?

Michael Levin: Yeah, yeah, critical. We think about this all the time. Lots of people contact me and ask me about all the ways that things could go wrong and all the different potential downsides of novel technologies. A lot of people come at it from this sort of implicit perspective that, “Well, everything’s great and new sciences better not screw it up. Don’t do anything to mess it up.” And I think this is fundamentally radically mistaken. Things are absolutely not great. There is a massive unmet need out there and the only way that all this suffering is going to get relieved, and in fact we can go beyond that and go to better life experiences for living beings in terms of improvement and augmentation, is through science and research. And I think it would be an enormous moral failing to not pursue these technologies that are going to be able to solve this for us.

Matt Hodapp: Big Brains is the production of the University of Chicago Podcast Network. If you like what you heard, please leave us a rating and review. The show is hosted by Paul M Rand and produced by me, Matt Hodapp And Leah Ceasrine. Thanks for listening.

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