Meet the tiny, see-through fish that can regenerate its brain

It swims, it buzzes, it regenerates its brain: A tiny glassfish is becoming a model species for scientists. What could it teach us?

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Ira Flatow?

  Science Friday is supported by MathWorks, creator of MATLAB and Simulink software for technical computing and model-based design. MathWorks, accelerating the pace of discovery in engineering and science. Learn more at mathworks.com.

• 0:18Flora Lichtman?

  Hey, it's Flora and you're listening to Science Friday. Move over Drosophila, step aside, see elegans. Scientists are working to establish a new model organism. It's a type of micro glass fish, so-called because, well, it's teeny and you can see right through it. Its organs are on full display, including its brain. And it has another remarkable claim to fame. The fish can regrow parts of its body, including its brain. Here to tell us about this fish head and the effort to get to know it better is Dr. Dennis Audubay, a neuroscientist at MIT's Whitehead Institute for biomedical research. Dennis, welcome to Science Friday.

• 1:01Speaker 02

  Hello, happy to be here.

• 1:03Flora Lichtman?

  Happy to have you. Where did this fish come from? How did it get on the map?

• 1:08Speaker 02

  Oh, it's an awesome question. So at the end of my PhD, I was looking for an organism that a regenerative organism that we can actually watch regeneration happen in. So I did my PhD in this field as well, regeneration of the nervous system. And we were essentially, we were getting snapshots of regeneration from the species that we studied, mainly flatworms. These are master generators. But I wanted to find a species where I could actually watch regeneration happen as it happens. So then one night, deep in the night, I was looking at this practical fish keeping magazine. And then in this magazine, there is a little article that talks about this micro glass fish being raised in a museum in Bolton, UK. And I jumped and I said, maybe this is it.

• 1:53Speaker 02

  So I followed this thread. And then, yeah, this is it. So I basically reached out to the labs at the time. This is 2000, early 2019. There were two labs, one in Utah, one in Berlin. So I reached out to these two labs and asked for this fish. So then they were kind enough to send me the starter culture. And then

• 2:13Flora Lichtman?

  A starter culture, is that like a fish in a plastic bag? Like you get at the fair?

• 2:17Speaker 02

  Essentially that, yes. We received roughly 40 fish in plastic bags. And we put them in this old fish rack that we have, which actually allowed us to do many experiments to establish the conditions that they like. Because when you're studying a new organism in a lab, nothing is known, everything is a variable. And so we played with water conditions, conductivity, pH,

• 2:41Speaker 02

  sudden changes. The fish vocalizes. So this is, there is this amazing feature of this animal as well. Only the males have this capacity. So they have audible vocalizations.

• 2:51Flora Lichtman?

  Wait, pause for a second. What does it sound like?

• 2:54Speaker 02

  It's like

• 2:56Speaker 02

  like that.

• 2:57Flora Lichtman?

  And you can hear it through the tank?

• 2:59Speaker 02

  Yes, you can actually, you can put them in petri dishes with some water and then you'll actually hear it. They do it, then they feel aggressive towards each other and doing sexual encounters as well, I think. So I did record their vocalizations and played it back to them to try to get them laying more eggs. That didn't work in our hands, but maybe, maybe it's still a way. Maybe there's a specific frequency that we need to hit.

• 3:21Flora Lichtman?

  Wait, so it sounds like the first step of making a model organism is becoming like an aquarium expert, you know?

• 3:30Speaker 02

  Oh, yes, yes.

• 3:31Flora Lichtman?

  You're becoming like a fish biologist.

• 3:34Speaker 02

  Yes, definitely. And for that, there is amazing literature, but there is also this extensive YouTube research, resource. Hobbyists, they do all kinds of experiments on their animals. So I benefited from, from their experiments as well. Finally, we were able to get them laying eggs constantly. We were able to achieve that and after that, more was possible because we were able to grow the colony.

• 3:58Flora Lichtman?

  Okay, so you, you managed to, to get the fish to reproduce. What's the next step for making an organism go viral in the scientific world? Like, do you have to get, do you have to campaign for it?

• 4:11Speaker 02

  Yeah, yeah. I mean, essentially, its biology is so interesting that it campaigns for itself. Because this fish has remarkable features. Aside from localizations, we were curious if it's regenerative, because the goal is to study regeneration, right? Majority of the teleosts is bony fish. They are regenerative. And so the first experiment is basically a remove body parts, essentially clip a little bit from the tail and then damage the brain a little bit. So it can just recover from brain injury. And we found that it's actually very regenerative, extremely regenerative. And so after seeing that, now that was possible to study. But there is another feature of the fish. It's completely miniaturized.

• 4:55Speaker 02

  Because of its size, we realized that we could actually potentially generate the complete atlas of the whole body, at single cell resolution.

• 5:03Flora Lichtman?

  Wait, before you go on, let me just jump in. What is a cell atlas? What do you mean make an atlas, a cellular atlas?

• 5:09Speaker 02

  So, you know, there are thousands of genes expressed in each cell. For humans, it's roughly 20,000 genes. And a combination, a subset of these genes turning on essentially makes a specific cell, that cell type. So across the body, there are hundreds of different cell types, all turning on different sets of genes. But we don't know essentially how many cell types exists. So we wanted to see, this is essentially to get a complete atlas of every cell type in the, in an adult vertebrate body. And we were able to get nice, healthy cells. And for each cell, we get the list of genes that are on and how much they're on in that specific cell. And then we do it for hundreds of thousands of cells.

• 5:52Speaker 02

  So internal organs, fins, cells from distant parts of the body. So this basically combined gave us the complete atlas

• 6:01Speaker 02

  at single cell resolution for, for an adult deinonyla. So this is a single cell atlas of a vertebrate, but it's also spatially resolved. So we can actually look at the brain and look at the cells in the brain and ask which cells are right next to each other? Which cells might be related in these neighborhoods? Essentially looking at the organization, a total organization of the, of a, of a complex animal.

• 6:25Flora Lichtman?

  Can that organization tell you something about why that brain is able to regenerate when perhaps, you know, when my brain is not?

• 6:33Speaker 02

  Oh, this is an awesome question. Yes, I think, because within that organizational space, you could see if there are any progenitor cells or stem cells parked at specific locations, essentially niches. So in the brain of a deinonyla, we do see these neuron producing niches. And they're distributed throughout the brain. So looking at these, you can infer that they at least exist. And then in an experiment like that, like, like where you perturbed the system or injured the brain, you can actually see the steps of regeneration essentially.

• 7:05Flora Lichtman?

  Howard Hughes Medical Institute is investing a billion dollars into developing this fish as a model organism. What is it like for you to go from, you know, finding it in a fish keeper's magazine to now it's like the it fish?

• 7:20Speaker 02

  Yes, it's, it's, I mean, surreal is positive. It was positively surreal. They also asked for validation that this fish could, could be a big new model system with a lot of new resources generated for the study of it.

• 7:35Flora Lichtman?

  Okay, so you have this cellular atlas. You've got Genelia and HHMI pouring resources in to learning more about this fish. What are the big questions that you want to use it to answer?

• 7:49Speaker 02

  Oh, I understand how regeneration works essentially. This is the first step. So this is one of the greatest mysteries of biology, the dynamics, molecular and cellular basis of regeneration. I want to understand it structurally. So how do these missing components get, get replaced? And then the other side is brain activity. So how does brain activity respond during the process of regeneration? So we know in development, when the brain is forming or these neural circuits are forming, there is a specific type of neural activity that you observe. And I'm curious if similar developmental-like processes will emerge during regeneration, when the new neurons are integrating into the old circuitry. So these are the two early steps.

• 8:31Speaker 02

  And then I'm interested in this concept called compensation. So when regeneration is not possible, how does the existing tissue reorganize itself at different stages of life to basically recover function?

• 8:44Flora Lichtman?

  I feel like we're, we must be far away from a, a medical application. But what's the bigger why for you?

• 8:51Speaker 02

  Oh, this is also a really important question, I think. Because, I mean, the fact that we are far from a medical application is because we do lack fundamental knowledge about these processes. So through studying regeneration in these types of platforms like, like deinonyla, we would be able to hopefully in time, understand the fundamental mechanics of regeneration. And some of these, through conserved biology, could be translatable to humans. I think that's one of the ultimate goals. But first, we need to understand, to translate. And for that fundamental approach, which is are incredibly important.

• 9:26Flora Lichtman?

  Translatable in what way?

• 9:28Speaker 02

  Yes, so you can also think about this in the context of neurodegenerative diseases. So certain cell types are selectively vulnerable to these diseases and they are lost. And approaches today basically are through stem cell or differentiated cell transplants to these sites that are losing these cells. And this gives patients some hope and gain time. So one approach is basically can we replace what has been lost? And then these animals, these types of model organisms would be helpful for them.

• 9:59Flora Lichtman?

  Well, Dennis, good luck.

• 10:00Speaker 02

  Thank you, thank you.

• 10:03Flora Lichtman?

  Dr. Dennis Audubay is a neuroscientist at MIT's Whitehead Institute for Biomedical Research. Coming up after the break, we're going to check in on the budding edge of regeneration research. Stick around.

• 10:22Speaker 03

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• 10:23Speaker 04

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• 10:24Speaker 03

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• 10:35Speaker 04

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• 10:52Flora Lichtman?

  How does this fish fit into the menagerie of model organisms that scientists use to study regeneration? And what new research is sprouting up in that field? Dr. Alejandro Sanchez-Alvarez has spent 30 odd years studying another superregenerator, a flatworm called a planarian, and the process that drives that worm's ability to regrow itself. He's the president and chief scientific officer of the Stowers Institute for Medical Research. Alejandro, welcome back to Science Friday. Thank you for being here.

• 11:22Speaker 05

  Well, thank you very much, Flora. It's my pleasure to be back.

• 11:25Flora Lichtman?

  It's our pleasure. How does this fish stack up or complement the other model organisms that we have for asking these questions about regeneration?

• 11:35Speaker 05

  The major fundamental advantage of this fish, so to speak, is transparency. Okay? So, most other vertebrate systems to study regeneration are intransparent. They're opaque. Things like salamander, zebrafish, the killerfish that we work with, they're not really built for observation of the internal organs, which is where the action usually takes place when we want to study regeneration. So what Daniela brings to the table is that transparency. This is not too dissimilar from the approach that was taken, you know, in the 70s when scientists moved from Drosophila, which is not particularly transparent, into C. elegans

• 12:19Speaker 05

  with the notion that the transparency in C. elegans' nematode would allow scientists to visualize cellular behaviors that were perturbed or modulated by molecular manipulation. So it is, I think, a big step forward. Now, it's a nascent system. Not all the tools are there yet, but the potential for developing them relatively quickly are definitely in place.

• 12:45Flora Lichtman?

  You know, brain regeneration, and please correct me, seems like a kind of holy grail. Could this fish help us understand how our brains work?

• 12:54Speaker 05

  Yeah, it should. I mean, it is a vertebrate. There is one particular caveat that we need to be aware of, but nonetheless, we need to understand how much that caveat will apply to understanding adult, you know, brain regeneration. And the caveat is that one of the reasons why this fish is transparent is because it underwent a process of progenesis. And what that means is that it skipped a bunch of steps in its way to adulthood. So it's devoid of, you know, bones and scales, and it makes it essentially an adult larvae, not too dissimilar from the axolotl, which is also an adult larvae.

• 13:34Speaker 05

  So we have to frame the findings in this fish in the right developmental context. And the question is, would the things that we learn in an adult larvae brain apply or have some application to our understanding of the adult, fully-developed brain?

• 13:54Flora Lichtman?

  While I have you, what's sort of the cutting edge of regeneration that you are thinking about right now?

• 14:00Speaker 05

  Yeah, I'm thinking primarily on, you know, how is it that cells actually retain their differentiated state and to what degree is that stable or plastic? And so I presume that if you have, for example, an adult brain that can regenerate, and those are neurons, right? And if you injure them, the question is, are they completely committed to being terminally differentiated into a neuron? Or is there some plasticity in their nucleus and their cellular functions that allow them to stop being a neuron for a brief period of time to allow for the production of new cells and to allow for regeneration to proceed? And so, right now, I'm beginning to lean very hard on this notion that differentiated

• 14:44Speaker 05

  cells are much more plastic than we give them credit. And so they're not really terminally differentiated, they're stably differentiated. So we're trying to test that in all of the systems that we have in the lab right now.

• 14:59Flora Lichtman?

  Is the idea that if you expose those cells to different stimuli or a different environment, maybe you can do an identity swap with them?

• 15:09Speaker 05

  Yeah, that's fundamentally the idea, Flora. Rather than, you know, kill the cells or introduce new cells, can we change the identity of the cells that are already there, the ones that we already have? Could they really, you know, reprogram themselves to make the environment conducive to more complete repair than just scarring? Is that possible at all? And nature gives us many examples.

• 15:35Flora Lichtman?

  Well, yeah, give me an example. Like, how do you make a cell forget who it is?

• 15:39Speaker 05

  Yeah, so, you know, it dates all the way back to Wolf in the late 1800s. He discovered that a pigmented epithelium of the retina in a salamander, when the lens of the eye is removed, that pigmented epithelium will actually de-differentiate. It eludes its pigments, enter proliferation, and then re-differentiate into a lens. So, nature already knows how to do this in some cases. That's one example. Another example has to do with Touritopsis dory, which is an idea in a jellyfish, that as an adult, when stressed, will actually do something remarkable, which is life cycle reversal.

• 16:20Speaker 05

  So all these supposedly terminally differentiated cells now undergo a process, which we don't understand at all, that allows that adult animal to become a Benjamin Button of nature and go back to a polyp state. Okay, so this is nature. It's not science fiction. So I imagine that, this is what's so exciting about Daniela, is that I imagine that as we invest more resources into expanding the number of organisms that we want to investigate, the more we're going to discover about what we really didn't know about. And so, it's just a very small cohort of animals we have chosen to study, and the diversity of life out there is extraordinary.

• 17:03Speaker 05

  I just don't think we know what is possible in biology. We just haven't sampled enough of that diversity to really know with confidence that, oh, I know exactly what's going to happen if I do this to this animal. And then the animal says, no, I do something completely different. I don't really follow those rules, so.

• 17:23Flora Lichtman?

  I love talking to you because it just makes me so excited about where the field of biology is going. And I'm so glad to be able to witness it and be able to hear about it from you. So, thank you.

• 17:36Speaker 05

  No, thank you very much, Flora. I appreciate that.

• 17:38Flora Lichtman?

  Dr. Alejandro Sanchez-Alvarez is the president and chief scientific officer of the Stowers Institute for Medical Research.

• 17:55Flora Lichtman?

  This episode was produced by Rasha Aridi. Thank you for listening. I'm Flora Lichtman.