ALEJANDRO SANCHEZ ALVARADO: Imagine
that somebody came and told you that there were animals
whose heads could be decapitated,
and that, in the span of a short period of time,
these heads would begin to grow again from the animal that
has just lost his head.
I would say, yeah, that's great science fiction.
But then, it turns out that many animals out there can actually
do this.
My lab has been studying planarians, a type of flatworm,
since 1998.
These warms have an amazing ability
to regenerate lost body parts.
My lab is studying them because we
hope to understand the fundamental rules
of this process, which could be important for our own health.
Our lives depend on the ability of our tissues,
like our skin, gut, and blood, to regenerate.
But unlike planarians, we can't regenerate
a new head or half our body.
How do planarians do this?
Planarians are everywhere.
And the best way to find them is to go to a clean body of water,
fresh water, a stream or a pond, and get your hand in the water,
grab a rock, lift it, turn it upside down,
and expose it to the sunlight.
And what you'll see on that rock is this little blob
beginning to stretch out.
They just glide.
They're very beautiful, very elegant.
And it's going to have these cockeyes on their head.
That's a flatworm.
Planaria, humans, and every other animal
have to make new tissues at some points in their lives,
like during development or to heal a wound.
Understanding how the process works in one group,
such as planaria, can give us important clues
about how it might work in other species, including humans.
So what is the key to planarian regeneration?
They have in their body plan a large number
of these adult stem cells.
Human embryos also have lots of stem cells.
They're needed during development
to produce different types of differentiated cells,
such as skin, brain, muscle, and liver cells.
But stem cells become more rare as we age.
Planaria, on the other hand, have abundant stem cells
throughout their lives.
Up to a fifth of their adult body cells are stem cells.
When we cut a planarian, these stem
cells multiply and differentiate into all the cell types needed
to replace the missing parts.
But how do stem cells know what kind of cells
they need to produce to regenerate the correct body
part?
The stem cells are not swimming in vacuum.
They're in contact with differentiated cells,
which are already specialized to perform particular functions.
These differentiated cells can make
molecules that signal to the stem cells
to also start differentiating and become specialized.
Inside of cells, the molecular signals
are transmitted like dominoes, where
the action of one molecule affects
the function of the next, ultimately steering the stem
cells into rebuilding a missing body part.
One way to understand this complicated process
is to eliminate one player at a time
and see what happens to planarian regeneration.
Dr. Alicce Accorsi, a postdoctoral scientist training
in my lab, is working with me on this quest
using a technique called RNA interference,
or RNAi for short.
DNA is the template for making messenger RNA, which
in turn is a template to make a particular protein.
RNAi use uses a molecule of double stranded RNA
that is complementary to specific messenger RNA.
The double stranded RNA causes the destruction
of the matching messenger RNA, blocking
the production of the protein and deleting its function
in the cell.
In humans, a protein called beta-catenin
is important during embryonic development.
It acts like a master switch that turns on many genes.
We wondered whether the planarian
version of beta-catenin might be important for regeneration.
What we did was to take advantage of RNA interference
to test the function of this protein during regeneration.
So we made a double stranded RNA,
complementary to beta-catenin messenger RNA,
to block beta-catenin protein production
and see if regeneration was affected.
But first, we needed to introduce this double stranded
RNA into planarian cells.
So what you're seeing here is a gourmet top drawer
feed for planarians.
This is actually made from organic beef liver.
We prepared a double standard RNA, mixed it with the liver.
We take a little bit of that mixture, put it in a Petri dish
where the planarians are, and they will now
congregate towards the food.
To eat, planarians stick out two black structures
called pharynges on the underside of their body.
At the end of these tubes is the mouth.
As they ingest the food, it gets irrigated
throughout the anatomy of the animal,
guaranteeing essentially that every single cell in the animal
will receive a dose of double standard RNA.
Normally, when you amputate a planarian's head and tail,
the animal will regenerate both head and tail
in the right positions.
But when we did this procedure with the animals that
were treated by RNAi, we got an amazing result.
So this is a worm that was treated with beta-catenin RNAi.
In the absence of beta-catenin, what you see essentially
is that the head regenerates where it should regenerate.
But if you now look at the tail, where
it should have grown a tail, you're
actually now growing a head.
If removing in beta-catenin results in two-headed worms,
what would happen if there is too much beta-catenin?
We knew that the levels of bet-catenin
are normally turned down in cells by the action
of another protein called APC.
So to increase beta-catenin, we needed to remove APC.
To do that, we made double stranded
RNA complementary to APC messenger RNA
to block the production of APC protein
and see if regeneration was affected.
And so if we now introduce RNAi against APC,
now you're going to get a huge amount of beta-catenin inside
of the cell.
We feed them RNAi against APC.
We cut the animals.
And now we look at the trunk pieces.
And we look at both ends.
And to our surprise, what we found
was that instead of regenerating a head and a tail,
it regenerated tail and tail.
This research shows that beta-catenin and APC
are part of the line of molecular dominoes
that direct stem cells to regenerate
either a head or a tail.
By removing beta-catenin, we manipulated the normal process
of regeneration, signaling to stem cells
on both sides of the body to regenerate a head,
while removing APC caused beta-catenin to accumulate
throughout the planarian body, we
signaled to stem cells on both sides of the body
to regenerate a tail.
We've repeated these experiments many times.
And together with research from other scientists,
they suggest that heads normally regenerate
where they're supposed to because beta-catenin activity
is naturally low in tissues at the front of the animal,
while tails regenerate at the back of the animal,
because beta-catenin activity is naturally
high in those tissues.
We now know that beta-catenin and APC
are two important proteins for regeneration.
But there are undoubtedly many more.
Using RNAi and other techniques, we
hope to identify all the major players.
Humans have versions of many, if not all, of these molecules.
So these planarian experiments can
guide us to further understand the biology
of human regeneration.
And while regeneration is probably
one of the last wild frontiers of biology,
it's not very difficult to tell people
when we work on regeneration for them
to see why this is important.
What would happen if we could harness the power of planarian
regeneration?
Wouldn't that be a good thing for humans.