Unlocking the Secrets of Regeneration with Mansi Srivastava, Curator of Invertebrate Zoology at the Museum of Comparative Zoology

SPEAKERS

Mansi Srivastava, Jennifer Berglund

 

Jennifer Berglund 00:04

Welcome to HMSC Connects! where we go behind the scenes of four Harvard museums to explore the connections between us, our big, beautiful world, and even what lies beyond. My name is Jennifer Berglund, part of the exhibits team here at the Harvard Museums of Science and Culture, and I'll be your host. Today, I'm speaking with Mansi Srivastava, an Associate Professor in the Department of Organismic and Evolutionary Biology at Harvard. She studies marine worms called three-banded panther worms, which have the capacity to regenerate literally any part of their bodies, from cells to organs. I wanted to learn more about this work, and what it might tell us about ourselves. Here she is. Mansi Srivastava, thank you for being here.

 

Mansi Srivastava 01:07

It's my pleasure. Thank you for having me.

 

Jennifer Berglund 01:14

You are a curator at the Museum of Comparative Zoology, but you don't necessarily work with preserved specimens in jars as so many of the curators at the MCZ do. So what kinds of materials do you work with specifically, and how do you curate materials such as these?

 

Mansi Srivastava 01:35

That's a great question. So, my lab actually studies a live animal. We keep cultures of this worm alive in the lab, generation to generation. These are worms that I originally collected in Bermuda about 11 years ago, and we've had tens of generations of these worms that have been nurtured in the lab, and we utilize them in experiments at the bench to look at how the process of regeneration works. So you're right. We don't actually curate these. We have deposited some of this material into the museum collections, but the way our work relates to the natural history collections at the museum is that it's built on the premise that there is great value in diversity, specifically biodiversity. That our understanding of the biological world, the world around us, is incomplete if we do not consider the diverse forms of life out there. And my work on this typically unheard of worm relates to an interest in biodiversity because this worm undergoes a process that we don't see in ourselves. So, we don't regenerate, but this worm has this amazing ability to regenerate, and it is by studying this obscure species that we hope to learn how this amazing phenomenon of regeneration can be accomplished. So, one of the reasons to preserve biodiversity, which is a goal of museums all over the world, is that we know about species out there. We know the wonderful biologies that are represented in these different species by learning more about how these organisms work, understand more about our own selves.

 

Jennifer Berglund 03:29

Let's talk a little bit more about the three-banded panther worm. What is it? And why is it interesting to you?

 

Mansi Srivastava 03:38

Three-banded panther worms, their scientific name is Hofstenia miamia because the original type species was found in Miami, so that place might suggest to you what kinds of places these worms like to live in. They live among mangrove roots in beautiful places like Miami, but also Bermuda, Bahamas and Panama. And they are about four to six millimeters long. They are called three-banded worms because they have overall a brown color of pigmentation that's interrupted by three cream-colored stripes on the backside of the animal. So that's where the three-banded part of the name comes from. Panther worms because they are actually voracious mangrove predators. So they will not eat dead things. They will not eat plants. They like to hunt, so any innocent little shrimp that's swimming by will get eaten by the panther worm.

 

Jennifer Berglund 04:38

You had a bit of an adventure collecting your first panther worms, didn't you?

 

Mansi Srivastava 04:43

Yeah. So you might wonder well, how did we know to go out into the world and look for this worm? How did we know that they might be interesting for studying questions about regeneration. And here I have to give a huge shout-out to taxonomists--precisely the kind of people that work at museums. So, all over the world for hundreds of years, people have been going out, discovering new species, naming them and depositing their material as type species into museums. There's another type of worm that is more well known. That's the planarian worm that people have studied for a long time because of their amazing capacity to regenerate. You may have played with one of these worms in elementary school. So, these are googly-eyed little things. They are freshwater species. You can go to a creekbed and turn over rocks and find them virtually anywhere on this planet. Planarian worms are great. People can keep them in the lab. We can learn something about regeneration there, but what I'm driven to ask is how the process of regeneration itself evolved. So it's not just one worm that regenerates. Many, many, many different types of worms, or even not wormy things like sea stars regenerate really well. And what I'd like to know is whether all of these instances of regeneration are basically the same, that regeneration is accomplished using the same process or mechanism, or whether there are different ways of accomplishing regeneration. So you can't make a statement about evolution by studying just one thing. You have to make comparisons. So, I was specifically interested in finding other species that one could study in the lab. We were looking for a type of worm that is an acoel worm. So acoels are a group of worms that we used to think, for a long time, were very closely related to these planarian, the googly eyed worms, but when people started using gene sequence information to reconstruct how different organisms that are related to each other, we got a big surprise. It turned out that these acoel worms, which look wormy and flattish, like these planarian flatworms are actually quite distantly related to planarians. And so now, if we were to study regeneration in these acoel worms, and compare it to regeneration and planarian worms, we could make inferences about something that might have been happening in their last common ancestor, which existed 550 million years ago. The question was then which acoel should we study? Right? And for that, we had to start talking to taxonomists because these are the people who know what different types of acoels exist out there, and what parts of the world they live in, and what might they be eating because we can't really grow something in the laboratory if we don't know what it's eating. So this wonderful Swedish biologist, Ulf Jondelius, who is an expert on acoel taxonomy, told us that, "hey, maybe you guys want to go to this marine pond in Bermuda where the three-banded panther worm lives, and so that's where our adventure in collecting these worms started, where I had to first get a permit from Bermuda to collect the worms and they gave me permission to collect 120 worms, and we only gave ourselves two days to collect worms. The first day when we got there, it turned out, as I went there with my postdoctoral advisor, Peter Reddien and I, and we were supposed to snorkel to the back end of this pond, which has a barracuda living in it as well, and Peter and I discovered that neither of us had actually snorkeled before.

 

Jennifer Berglund 08:30

Oh, no.

 

Mansi Srivastava 08:32

So we quickly, you know, figured out how to snorkel, and on the first day, when we collected worms, we only got three worms.

 

Jennifer Berglund 08:40

Oh, my God.

 

Mansi Srivastava 08:40

So we were worried about the future of our project, and we were trying to do some calculations on whether, if we start with three worms, and we start cutting them, how long it would take to get enough worms to actually start studying regeneration. But then we got lucky. The next day, we got a ton more worms, and ended up with exactly 120 worms that were brought to Cambridge, Massachusetts.

 

Jennifer Berglund 09:05

So how long does it take them to reproduce?

 

Mansi Srivastava 09:07

So they're constantly making babies. They are hermaphroditic, so each worm and make both sperm and egg. And they actually do this cool process of penile fencing, where they have a little thorn-like structure that comes out, and they have a little fencing match. And whichever worm wins gets to inject sperm into the other one, and so they're constantly doing this process and laying eggs, which in about nine days hatch into little tiny versions of the worms, which over the next four to five weeks will mature and make their own babies.

 

Jennifer Berglund 09:39

Has anybody ever filmed this?

 

Mansi Srivastava 09:41

Yes, there's definitely usually a contest going on in my lab on who can with their iPhone quickly catch it because it's a very fast process. But we do have some videos of it.

 

Jennifer Berglund 09:53

Let's talk a little bit more about this regeneration process when I think of regeneration in a worm, of course, I think of what I used to do as a child, cutting an earthworm in half when I'm fishing or something like that. How does the regeneration process differ between something like an earthworm and a three-banded panther worm?

 

Mansi Srivastava 10:16

So the thing is, earthworms actually don't do full regeneration. So the head piece will make a new tail, but the tail piece won't actually make a whole new worm.

 

Jennifer Berglund 10:26

Oh, interesting.

 

Mansi Srivastava 10:27

So, you can cut its tail off, and then the part that has the head will be fine.

 

Jennifer Berglund 10:32

Why is that?

 

Mansi Srivastava 10:34

So that's really interesting. There are, across like all kinds of different worms, there can be like closely related species, some that do this process of what we call whole-body regeneration, which is, if you lop off the tail, the tail comes back, if you lop off the head, the head comes back. But many species actually can do tail regeneration fine, but they can't accomplish head regeneration. And head regeneration is much more challenging, right? You're putting in a whole new brain, and you're making a new mouth. If you have a worm, and you lop off the tail, the head piece can still eat and get energy, and still has a brain to move around and hide and whatnot. But the tailpiece has this bigger energetic challenge where it's not eating because it doesn't have a mouth anymore, and it has to regrow a lot more complex tissue. So we often see this that some species can regenerate their tails okay, but they can't make a new head.

 

Jennifer Berglund 11:31

Okay. But then the three banded Panther worms can do that.

 

Mansi Srivastava 11:36

Yes.

 

Jennifer Berglund 11:36

Wow! And there are a lot of other organisms out there that can regenerate. What are some other kinds of organisms that regenerate? And how do they regenerate differently from the three-banded panther worm?

 

Mansi Srivastava 11:48

That's a great question. So, this capacity to regenerate pretty much any missing tissue or cell type is pretty widespread. If you look at the tree of animal life, many, many, many branches on that tree have some species that can do this. So, some really amazing things are done by sponges where you can pull them apart into single cells, and then all of those cells will find each other and make a fully-functioning sponge. Then you can look at Cnidarians, which include things like hydras, or sea anemones. You can cut a sea anemone into 2-3-4 parts, and it will regenerate and become fully functional again. The same applies to many different branches on the animal tree that are wormy species. So, aceols are one example. These flatworms that planarians belong to are one example. There are among segmented worms, which is where earthworms belong, also examples of worms that can do this full, whole-body regeneration where they can make heads and all new brains as well as tail tissues.

 

Jennifer Berglund 12:57

Okay, that's amazing. So what about things if we're thinking about, you know, a different part of the animal tree of life? What about things like lizards? The lizard you know, gets its tail cut off, it can regenerate a tail. How is their kind of regeneration different from the three-banded panther worm

 

Mansi Srivastava 13:17

Species that are more closely related to us, so we are mammals. And mammals are a type of vertebrate. We do have cases of animals being able to regenerate certain body parts. So if you take a fish, it can regenerate its tail fin, or if you take a larval fish, it can regenerate its heart even. If you take a mouse, it can regenerate the tip of its digit if you amputate that. Humans can't do that as adults, but babies can sometimes accomplish that level of regeneration. Hmm, and then there are some really spectacular regenerators such as these axolotls, which are amphibians that can regenerate spinal cords and entire arms.

 

Jennifer Berglund 13:59

They're like salamanders. Right?

 

Mansi Srivastava 14:01

Exactly.

 

Jennifer Berglund 14:02

Okay.

 

Mansi Srivastava 14:02

They're a very particular type that is particularly excellent at regeneration, but they're still not able to regenerate all missing cell types. So if you chop off the head of an axolotl, it's not going to grow back a new head. We call this property of regeneration in vertebrates tissue regeneration or structural regeneration where some body parts or some tissues can be repaired and regenerated effectively. So that's comparing vertebrates to these wormy, whole-body regenerators at the level of how good are they at regeneration? There's a whole other layer to your question, which is we could ask how these different processes of regeneration work. And that is exactly the work that my lab is trying to do, and that's the vision for my research program. We don't know a lot about how regeneration really works, especially in these species that do the more phenomenal whole-body regeneration process. So we would like to, first, take a few of these species, get really good at understanding which genes enable this to happen. How do the cells pull themselves together to make a whole new brain, for example, and then we want to be able to compare this process between different species. So right now, we do know some of the processes involved in regeneration in, let us say, fish tail fins. So, zebrafish have become an excellent laboratory model organism, people are studying regeneration there, people are also looking at regeneration in these axolotls, but it's not clear right now how we can really compare the growth of an arm, or a hand, in an axolotl to making a whole new brain in the Panther worm. So what we're now doing is breaking down the process of regeneration into smaller steps. So one of the first things that has to happen is that the animal figures out that something terrible has happened. It doesn't matter whether you're trapping a panther worm, or a planarian, or a sea anemone, or an axolotl. Immediately, the organism knows that something terrible has happened. Immediately, the cells at the site of injury are sending out signals to the rest of the body--let's stop tissue from pouring out, let's stop death, let's heal. And when we break the process of regeneration down into these more digestible parts, we can start making more meaningful comparisons. So we do know now that some of the genes that are activated right upon amputation are homologous genes. So, in the Panther worm, for example, when I amputate, within half an hour to an hour, there's this gene called EGR, short for early growth response, that it becomes activated right away at the wound site. No matter what type of injury I made to the animal, this gene gets activated, and homologues of this gene, so EGR genes, will also get activated in a planarian. And remember, planarians and aceols are very distantly related, so that's sort of remarkable. Recently, a colleague of mine showed, that if you injure or amputate a sea star larvae, then also this EGR gene gets activated very quickly, and this gene, EGR, has also been studied in vertebrates in a mammalian context, so in things like mice, where we know that, upon stress, in neurons, this gene will also get activated. So there is something remarkable about the same gene being activated in so many different species when they are injured. What we would like to understand is whether the function of EGR is the same in all of these species, or whether it's different. And this is the hard work that lies ahead of us.

 

Jennifer Berglund 18:01

This is interesting because sort of built into there are two fundamental questions. How does this process work? But also, how is this distributed throughout the tree of life? How and where did this evolve? Or where did certain aspects of regeneration, where were they lost?

 

Mansi Srivastava 18:21

Right. You have very effectively captured the tagline for my research group, which is we study both the mechanisms and evolution of regeneration. So we can't really make effective statements about evolution without first understanding how the process works.

 

Jennifer Berglund 18:43

You've been talking a lot about regeneration in worms and in other parts of the tree of life--lizards, and salamanders and even mice--but does this tell us anything about ourselves?

 

Mansi Srivastava 18:59

Right, so here, I think I will first start by talking about what I think is one of the biggest surprises in animal biology. Although animals take endless and beautiful forums, they are united in the molecular and cellular processes upon which their bodies operate. So

 

Jennifer Berglund 19:23

What do you mean by that?

 

Mansi Srivastava 19:24

We used to think that humans are complex, extraordinary organisms. Compare us, say, to a sponge, or a sea anemone, which, at first glance, looks simple. In looking for an explanation for what makes humans so awesome, people proposed that we must have more genes compared to a sponge because a sponge is not doing much. It looks practically like a rock, right? When we started sequencing the entire genomes of animals like sponges or sea anemones, we discovered a big surprise which is, the numbers of genes in pretty much every animal are about the same. Most animals will have on the order of about 20,000 genes, be you a human or a sponge. Further, when you look at the types of genes that are present in these different animal genomes, we find that there is also great conservation of the types of genes. So most of the types of genes that are needed for, let's say, making a brain in my body, are also present in the genome of a sea anemone or a sponge. Sea anemones do not have a structure that looks like a brain, and sponges actually don't have any neurons at all. So, the biologies of these varied animals are operating on a very similar set of molecules that are encoded in their genomes. So there's, of course, been modifications on how these genes are working, but the sort of ground plan is very similar. Most animal cells work on very similar principles. The way we think studying regeneration in, say, a three-banded panther worm has relevance to human biology is that it will reveal to us the basic molecular and cellular principles that regeneration biology might operate on, and that can then tell us something about how humans may or may not be able to accomplish improved regeneration. So, one of the big approaches being taken and human regenerative biology is to take some of ourselves, let's say there's some organ in my body that's not working well, and could benefit with some replacement. So my organ is not going to regenerate on its own. Our livers do some of it, but not most of our other organs. So we could, let's say, take some other cells from my body and turn them into what are called induced pluripotent stem cells, and then you can use those stem cells that you've made in a petri dish and turn them into, let's say, eye cells that could then be used to cure macular degeneration, for example. So this is a big approach that's been taken in regenerative medicine. But humans are not good at making pluripotent stem cells. Our bodies don't have any cell type that can make brain cells and skin cells and muscle cells. Pluripotency means the ability to turn into many, many different types of cells. We only had this type of cell when we were embryos. We don't have it anymore. So, I do have stem cells, specific for my hair, that help me grow my hair. I do have stem cells in my intestine that help me replace my intestinal lining, but my intestine stem cells will not grow a hair, and my hair stem cells will not grow me a new intestinal lining. Now, contrast this with the three-banded panther worm. They have cells in their adult bodies that are effectively pluripotent, so they do have this cell type that can turn into neuron, or skin, or muscle. And every time the worm regenerates, those cells do it in a perfect manner. All of the new cells work perfectly. They're integrated into the rest of the body perfectly. So by studying this natural occurrence of regeneration, we stand to learn a lot about how it could work. Because, of course, in our bodies, this does not work naturally. We're trying to make it work in artificial ways, but we would learn a lot if we can just understand how it happens in a natural context when it is accomplished so effectively.

 

Jennifer Berglund 23:49

So I have another question about the worms, and this is kind of backtracking a little bit, so they have this amazing ability to regenerate any part of their body. It sounds like they're kind of immortal. Is there an argument for that? I mean, obviously, they can be eaten by something and they wouldn't regenerate then. But if you keep slicing them up, and they generate new cells, could they just live forever?

 

Mansi Srivastava 24:15

Yes. So technically, these worms are immortal. So, I still have some worms that I had collected in Bermuda 11 years ago. I can guarantee you that in the wild, there is no such thing as an immortal worm because, you're right, they get eaten, and they get disease, probably. But in the lab, with perfect food, and not getting any infections, and no predators, we can keep them alive for a long time. And we are observing that when we amputate the worms, and have them regenerate, we're seeing a certain level of rejuvenation in the worms when they regenerate. So it's not that they don't get older, it's that when you cut them, they become sort of young again.

 

Jennifer Berglund 25:01

So if you can harness this ability in the worms for use in, you know, human tissues, then that would be amazing,

 

Mansi Srivastava 25:12

Right. And I definitely want to be very careful here. The relationship of our work to human regenerative medicine, it's about investing in basic science. That we need to understand how natural processes work, and that does tell us something about how human medicine can be improved. It's not that we can take the cells from this worm and have our bodies get better, it's that just understanding how the machine of this worm works can give us inspirations on how to fix some of the problems in our machine, which is, maybe we'll find that these cells in these worms have some trick that holds their genome in a more flexible state, and we could maybe find a way to make ourselves a little bit more flexible to turn these induced pluripotent stem cells into better stem cells, let's say. I would say this would be a sort of longer-term benefit, but mostly I think that work in my lab is about understanding this phenomenal, beautiful process that lots and lots of animals do out there.

 

Jennifer Berglund 26:21

So it's just a piece to the puzzle of understanding ourselves, but more than anything, it's to develop a better understanding about the tree of life.

 

Mansi Srivastava 26:32

Right. Because animals have just explored so many, many different ways of living, and this is one way of living that we see in many different animal phyla. So, I think it's very important to understanding the capacities that animals have at large.

 

Jennifer Berglund 26:56

As a child, you grew up in Delhi, India. And unlike a lot of other curators out there, you didn't grow up collecting critters in your backyard. Describe your upbringing and how your childhood did or did not influence your career trajectory.

 

Mansi Srivastava 27:18

Thank you for bringing that up. You know, I think for a while I questioned whether I belonged in evolutionary biology because I grew up in a concrete building, and my experience of ornithology was pigeons, crows and sparrows. And my experience of the arthropod world was cockroaches as you get in any big city in the world. So yeah, I was not exposed to a lot of biodiversity around me. I grew up in a middle-class household, but I think a huge influence may have been my mother who was a biology teacher, and so I was always surrounded by thinking about biology. I would help my mother grade exams and quizzes, even when I was quite young. It's hard to pinpoint, you know, how it happened, but I just always was very naturally attracted to biology. So, most people are grossed-out by cockroaches. One time, playing under our dining table, I discovered a cockroach nymph, and I thought it was beautiful. My friends did not agree with me. So, there's no one incident, but I would say that a series of inspiring women who were biology-oriented, were key. So my mother was a biology teacher, and my best friend's mother was a botany professor. And so, you know, she would bring out peas of all kinds to start explaining Mendelian genetics to me when I was 10 years old, and I thought that was incredible, so that's how it started, and growing up in India, in the socioeconomic group that I belonged to, you are presented with two option, well actually one option. So, if you were a boy, you had to become an engineer. If you're a girl, you had to become a doctor, and I always knew that I did not want to go into a medical profession, but I knew I loved biology, and so I was very fortunate in that I came to the US as an undergraduate to a small college, which really encouraged curiosity and thinking deeply about things, and actually, that's where my love of regeneration started.

 

Jennifer Berglund 29:28

So describe that. Where did you first learn about it, and what was your first exposure?

 

Mansi Srivastava 29:34

Yeah, so one of the most formative experiences for me in this trajectory towards becoming a biologist was I went to college, took biology my first year, and then learned that there was this Howard Hughes Medical Institute-sponsored summer program at our college where 10 students get to stay on campus over the summer, and they get to do research in a few different labs, and one really awesome aspect of that experience was that they would take us for a weekend to the Marine Biological Laboratory at Woods Hole, which, of course, is sort of the birthplace of American developmental biology. A lot of amazing work was done there at the turn of the previous century, and continuing to this day. We, you know, spent a day going on the Gemma, which is the boat to get on the trawls the floor, and you bring in all kinds of marine life, and then we got to look at them, figure out what they were, do some experiments on them, and that night at dinner, one of my professors asked me what I was interested in, and I said, "well, I really like developmental biology," because, of course, what we had found that day on the boat were embryos of all kinds of species, ranging from squid to annelids, and then I said, "I also really love evolution, and I wish there was some way to combine that." And then my professor told me that, "oh, there's this field called evolutionary developmental biology." And so from that day onward, that's the field within the context of which I have been doing my research, which seeks to compare biological processes across species to understand how life has diversified.

 

Jennifer Berglund 31:18

Thinking about your childhood and your trajectory, where you ultimately ended up. What would you have told yourself as a child interested in biology?

 

Mansi Srivastava 31:30

I would say to worry less about what's expected of me, and feel more sure about following where my interests take me.

 

Jennifer Berglund 31:41

I think that's very sound advice. Mansi, thank you so much for doing this has been wonderful.

 

Mansi Srivastava 31:50

Thank you so much. I really enjoyed this conversation.

 

Jennifer Berglund 31:59

Today's HMSC Connects! Podcast was produced by me, Jennifer Berglund, and the Harvard Museums of Science and Culture. Special thanks to Mansi Srivastava, and the Museum of Comparative Zoology for their wisdom and expertise. And thank you so much for listening. If you'd like today's podcast, please subscribe on Apple Podcasts, Spotify, Podbean, or wherever you get your podcasts. See in a couple of weeks!