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They are really beautiful creatures.
They have a really simple body plan and two googly eyes.
They stare deep into your soul.
You know, they’re great, cute little worms.
They don’t need a lot of work to be maintained.
You just cut them and every little fragment that you cut will make a new worm.
There is a whole host of biodiversity out there that we don’t know about because we
don’t study the organisms that show that biodiversity.
So by studying planarians, we can find out about biology that we could potentially
apply to humans one day.
In Peter Reddien’s lab at Whitehead Institute, flatworms called planarians allow researchers
to explore the mysteries of regeneration.
We’re very interested in what it takes to regenerate, what are the minimal components
you need to explain how an animal can regenerate something missing — using this organism
as sort of an experimental tool to probe the unknown.
But we’re also interested in generalizable principles.
Peter had been working on planaria for a long time, and he was interested in whether
or not all these facets of regeneration we see in planaria are weird quirks of planaria
or if they are actually necessary for the regeneration of many organisms.
Reddien’s lab explores how a planarian creates a map of its anatomy, a system of molecular
signposts that tells a cell where it is in the body.
The genes that encode these signals are called position control genes.
The researchers had previously found something intriguing:
muscle cells express the position control genes,
and that gene expression then guides the regeneration of body parts in planarians.
They wanted to know if other animals worked the same.
And the best way to get at this question is to go to something that regenerates but is
really, really, really different.
The researchers found a species that fit the bill: a marine worm called Hofstenia,
also known as the three-banded panther worm.
Both worms, so you might think that they’re very similar. Actually they are incredibly different.
We are more related to planaria than Hofstenia are.
Hofstenia are as far away as you can get on the evolutionary tree of animals before hitting
jellyfish.
Planaria and Hofstenia had a common ancestor 550 million years ago.
It’s also the common ancestor of all animals with bodies that have two-sided symmetry,
including humans.
This shared ancestry far back in evolutionary history means that if Hoftsenia also expressed
position control genes in muscle, that could indicate that many other animals do so as well.
The researchers observed gene activity in Hofstenia, looking to see which cell type
expressed the genes for positional control.
And what was that cell type?
Muscle.
In Hofstenia, as well, muscle cells are also responsible for saying this is head and this
is tail — and tell the stem cells where they are so they can make head tissue
or tail tissue.
So that was very exciting to us, because
if this similarity reflects common ancestry as an explanation for the similarity, then
it points to a role for muscle in controlling regeneration and positional information in
adult tissues dating back over 550 million years ago.
If that’s true, then it might be widespread in animals today.
But planarians have more than one type of muscle.
You have what we call longitudinal fibers that are basically muscle fibers that go from
the head to the tail of the worm.
And then you have circular fibers that go around the worm.
And then you have diagonal fibers.
By feeding the worms RNA molecules that knocked out genes needed to make a particular muscle type,
the researchers produced worms that lacked either longitudinal or circular muscle
as a tool to then ask: what are the roles of those muscle fibers in regeneration?
We can inhibit the gene, the muscle fibers slowly start going away, and then we can cut
the animal and look at what happens.
So what we found there was very surprising.
Different subsets have different roles during regeneration.
Longitudinal muscles have a particularly crucial role.
Longitudinal fibers actually express a certain amount of genes once you cut the animal that
are essential to regenerate.
So they require these genes in order to regenerate.
So when we inhibited the ability of these longitudinal muscle fibers to be maintained,
they slowly went away. We cut the animals — the animals completely failed to regenerate.
So why don’t they regenerate?
Well, what we found was after cutting them, the animals failed to reset positional information.
There’s a position control gene called notum expressed in the longitudinal fibers that
tells a cell whether it’s in the head or the tail.
Based on the expression of this gene, the cells in the animals know which is the anterior.
So where to regenerate the head, versus where to regenerate the tail.
And this suggests that the resetting of positional information after injury, to now re-specify
the positional coordinates for the missing cell types, is a driver of regeneration.
So the fact that they couldn’t reset positional information means they didn't regenerate
because they didn’t know anything was missing.
Now when we turn to the circular muscle fibers, again running from side to side, what happens when
we cause those fibers to be lost from the animal?
Animals that don’t have those fibers — they start duplicating the head.
It’s pretty amazing to see.
We found that it’s most likely because an anterior organizer that these animals have
has been duplicated.
We hypothesize that these circular fibers are required to constrict, somehow, that organizer.
So it indicated these different roles for different muscle fibers in controlling
attributes of how regeneration occurs.
But ultimately it’s the stem cells that build new tissue, replace missing heads and
tails cell by cell.
What rules did those stem cells use to decide where to form new structures?
So I’m very fascinated with the concept of self-organization, which is the emergence
of structure and function out of local interactions between the elements of an initially
disordered system.
The researchers asked if stem cells have self-assembling properties.
They focused on how specialized stem cells called eye progenitors rebuild the eye, which
was a small, discrete organ they could study in isolation.
If this is true for the eye progenitors it’s likely true
for many progenitors for many tissue types.
The style of the experiments they used was a throwback to the classic planarian experiments
from centuries past.
A lot of the experiments in this work could have been done with a razor blade and a magnifying glass.
It was really the concepts that were sophisticated.
The researchers wanted to figure out how stem cells respond to the positional information
that muscle cells provide.
When there’s an injury, position control genes in muscle create a map that’s a scaled-down
version of the original body map.
But in some uneven injuries, the recreated map is shifted relative to the remaining body parts.
The researchers predicted that this mismatch could produce an animal with three eyes
if the animal was decapitated, cut down the side,
and one of the eyes was removed during head regeneration.
I remember the day we drew that shape on the board.
We asked ourselves, can this really happen?
And we did this experiment nearly on the same day.
They cut the planarians down the side and decapitated them.
While the head was growing back, they removed one eye, and waited a few more days.
Then the moment we saw these three-eyed animals was the most amazing moment.
The results showed the researchers that eye progenitors did self-assemble.
They weren’t solely relying on the body’s positional map, they could form structures
because they attract each other.
So self-organization allows the eye to basically serve as an attractor, stabilizing the function,
basically, and the position of the eye while the animal is restoring its correct proportions.
So that’s the first feature.
Two other features help explain why the stem cells formed three eyes instead of two.
The second feature is the target zone created by the positional map.
Eye progenitors or any kind of progenitors basically read out this map to go and find
where they should nucleate and start growing.
A third feature puts the first two together.
It’s is called the targetable zone, which is the broad area in the body where organ
progenitors hang out, ready to respond and rebuild structures in case of injury.
It’s a wide area so that if an animal loses its whole head, it still has progenitors
for organs in the head.
If you imagine a small targetable zone right around the eye, upon decapitation we would
lose all of it.
When you have a broad targetable zone, this allows the existing anatomy to have access
to these progenitors while the new tissues are being regenerated
Even if that organ is out of place with the coordinates guiding the placement of new tissues
that were missing.
So the features of self-organization, the target zone, and the broad targetable zone
let the researchers explain why they’re able to produce these three-eyed worms.
What we’re able to find is a small set of principles that we think explain how tissue
architecture is maintained and organized during the process of regeneration.
A lot of our findings have necessarily focused on different pieces to the puzzle, different modules.
But what’s been exciting is to see how some of these modules fit together.
I particularly enjoy solving some small puzzles.
I enjoy just the plain discovery of finding things and trying to understand how they’re
connected to each other, how they’re working with each other.
I think that’s the fun of basic science—trying to put the pieces together in the big puzzle.
The reason we can’t fix a broken spinal cord today is that we are missing certain
fundamental answers regarding the biology.
So that’s why basic biology is incredibly important.
So looking at these animals that are incredibly proficient in their regenerative capacity,
I think we can uncover a lot of fundamental rules.
One of the reasons that if we cut of your arm it can’t regenerate, is that we can
no longer set the positional information that says: I’m going to be a finger.
And so if we could figure out what tissue could give this information,
then maybe we could find a way to unlock that holy grail of regenerative medicine.
We have a draft explanatory model for how an animal could regenerate.
Now there’s lots of holes in that model, lots of things we don’t know, we don’t
have explanations for.
But still — you can start to see how it might work.
And that is very exciting.
And you know, we’ve been pretty focused on trying to explain the logic of how regeneration
works in planarians for many years.
And it’s satisfying to feel like you’re starting to see
how some key pieces to the puzzle work.