The Secrets of the Newt's Amazing Regenerative Ability

This is the heart of a certain creature.

Part of it is missing.

Yet one month later, it regenerated completely on its own.

And even though this creature has lost a leg...

After about 5 months, it's back to normal with no scarring!

These incredible creatures are newts, a type of amphibian.

Researchers in the field of regenerative medicine

hope to apply this "super" regenerative ability of newts to human medicine.

If we can figure it out, I'm sure
we can apply it to people.

I want to continue my research
believing that day will come.

The latest research has made a major discovery bringing us one step closer to that future.

We named it Newtic1 because it was
the first factor that we had found.

I think it's a very big step.

In this episode, we'll look at the secrets behind the amazing regenerative abilities of newts.

And in our J-Innovators segment,

we'll meet someone who has developed a revolutionary shoe featuring tiny yet high-performance tactile sensors.

Hello and welcome to Science View.

I'm Tomoko Tina Kimura.

Today's topic is the secrets of regeneration in newts.

Together with me here in Tokyo is Mr. David Hajime Kornhauser,

Director of Kyoto University's Office of Global Communications.

Hello, it's great to be here!

When I think of regeneration of body parts,

the first thing that comes to my mind is not newts, but a lizard's tail that regrows.

Yes, some lizards do regenerate their tails after they come off,

but the mechanism is quite different between lizards and newts.

For example, geckos have a special structure so that they can detach their tails in front of an enemy.

Yes, the detached tail wriggles to distract the enemy's attention, giving them time to escape.

Exactly!

And the new tail grows where the old tail had fallen off,

but there is no original bony structure there, and the tail is just supported by cartilage.

You mean, it's different from the original tail?

Yes. Moreover, it's not possible to regenerate the tail many times; generally, only about twice at most.

On the other hand, the newt's body is not designed to shed appendages.

Instead, exactly the same tissue is born anew from a wound.

And there is no limit to the number of times this can happen.

It's not known for sure whether other creatures once possessed this amazing regenerative power,

or whether it was suddenly acquired only by newts during the course of evolution.

However, recent research has uncovered several discoveries that may hold the key to the secrets of their regeneration.

With better understanding of these secrets, we can hope that one day,

it might be possible for humans to restore lost limbs.

There is certainly plenty of potential.

First, let's find out what newt regeneration is all about.

What kind of creature is a newt?

We visited a facility that exhibits newts from all over Japan.

Welcome to the world of the mighty newt!
Newts are truly amazing.

The director, Dr. Naoshi Shinozaki, is an amphibian researcher who loves newts.

His research mind got the better of him and he created this exhibit.

The Japanese fire belly newt
has a beautiful color.

This red-bellied newt is endemic to Japan, and other than Hokkaido and Okinawa, is found across the country.

Newts in each region have their own unique characteristics.

The one from Fukui has an intricate design.

The one from Niigata is particularly red.

They are all stunning.

As amphibians, newts are born from eggs, in water.

This is a juvenile, soon after hatching.

Gills are attached to the side of its face.

It does not have legs yet.

After a month or so, the legs grow...

And after about three or four months, the gills are gone and its lungs take over!

This is how the body dynamically changes, and is a characteristic of the newt.

It's so cute, yet also has tremendous capability,

so much so that none of the same
amphibians can regenerate at this level.

One of the secrets of the newt's strong regenerative power is the stem cells that are actively working in its growing body.

Cells of an organism can be divided from a fertilized egg into skeletal stem cells, muscle stem cells, and so on.

Muscle stem cells are further divided into muscles of the arm, palm and fingertips, etc.

In fact, amphibians besides newts such as frogs and salamanders

are also known to have active stem cells and high regenerative capacity when they are young.

Yet by the time their body is fully formed, the ability of stem cells to regenerate has weakened.

This is the forelimb of an adult frog.

It does indeed regenerate, but the fingers cannot grow back.

Newts, however, can regenerate their bodies many times throughout their lives.

I did not know that newts were so special!

It seems like they have a super power enabling them to regenerate the exact same limb over and over again.

It certainly seems that way.

Since newts can regenerate all parts of their body, they are called the "champion of regeneration."

Why is it that newts can do this, while other animals like us humans, cannot?

Well, let's review the stem cells that hold the key to this process.

Our original cell is the fertilized egg.

The fertilized egg is, so to speak, a pluripotent cell that divides into muscle stem cells, bone stem cells, and so on.

Muscle stem cells are further divided into cells of each muscle.

For example, when making a thigh, they become thigh muscle cells.

This is called "differentiation."

Once a cell becomes a muscle of a specific location in the body, it does not return to become a muscle stem cell again.

I see.

In growing amphibians, these stem cells are active, but as they mature, their function diminishes.

Newt stem cells are no exception; yet newts are still able to regenerate perfectly.

Why do you suppose that is?

Hmm... Their cells must be special...

That's right.

The newts' differentiated cells can change further in a process known as "de-differentiation."

What is happening when a newt has a wound?

Take the muscles in the arm.

When the cells undergo de-differentiation, they revert to cells that look exactly like the muscle stem cells.

It's as if, after differentiating into the muscles unique to the arm,

the cells went back in time and reverted to their previous state.

From here, they can be transformed into any muscle, including fingertip muscles.

These cells, born from de-differentiation, create a miniature model in the immediate vicinity of the wound.

Then the relevant muscle cells go to their respective places...

And the limb regrows!

This is the "de-differentiation" mechanism of regeneration unique to newts.

That is truly amazing.

Is that possible for all parts of the newt's body?

Well, although it has not been proven,

it is believed that de-differentiation is occurring in other areas of the body as well, since they do in fact regenerate.

iPS cells used in regenerative medicine are also created by inducing mature cells back to their pluripotent state, right?

So how does this differ from the mechanism of regeneration in newts?

Well, in the case of iPS cells, the cells return to the egg stage, but this is not the case with newts.

iPS cells are used to artificially create various types of cells in the lab and then return them to the body,

but in the case of newts, all of that work is being done inside their bodies.

I see.

As we just learned, de-differentiation is the key to regeneration in newts.

How this can happen has long been a mystery, but the latest research has revealed the mechanism.

Why are newt cells able to undergo de-differentiation?

Dr. Chikafumi Chiba, who has long studied the regenerative abilities of newts, thought the secret lay in their genes.

He spent six years studying all the genes that work in newts' bodies.

In 2018, Chiba and his team discovered a gene that is unique to newts, which they called "Newtic1."

We named it Newtic1 because it was
the first one that we had found,

and it seemed unique to newts.

Naturally, we hoped that Newtic1
would play a key role in regeneration.

Here are the laser microscopic images of a newt's wound as it regenerates over a one month period.

Look at this photo taken around the end of that month.

There is a red substance in the actively regenerating area...

This is the protein produced by Newtic1.

What is happening?

Using a microscope with even higher magnification,

Chiba observed in three dimensions the areas where the red protein gathers.

The parts in blue are the cell nuclei.

The red Newtic1 protein wraps around the nuclei like rubber bands.

From this, Chiba imagined that the cells in which Newtic1 is working had a flattened and collapsed plate-like structure.

I wondered if the cells
had a special characteristic

of having some kind of strange structure
wrapping around them like a thin belt.

And, to his surprise, what emerged was red blood cells!

This was a discovery that defied common sense in biology.

The black moving objects are red blood cells.

In humans and other mammals, red blood cells are supposed to specialize in carrying oxygen,

and have nothing to do with regeneration.

It's just so out of the ordinary,

that red blood cells are actively secreting
some factor involved in regeneration.

This was more than unexpected;

it's something that no one
had ever imagined before.

A closer examination of newt red blood cells revealed the presence of at least 10 other important proteins

involved in regeneration besides Newtic1.

Further examination of the Newtic1 protein, which looked like a rubber band around the red blood cells,

revealed it to be in small granular form.

Based on these facts, Chiba came up with this scenario.

When red blood cells reach a wound,

the proteins needed for regeneration go into the granules that Newtic1 is making.

These granules act as carriers, so to speak, releasing proteins involved in regeneration,

where needed, outside the red blood cells.

This turns on de-differentiation and supports unparalleled regenerative capacity.

We're just beginning to see some of the amazing regenerative abilities that scientists have been chasing for years!

So if red blood cells trigger de-differentiation,

it means that regeneration is possible anywhere where there are blood vessels.

That's right.

It sure would be nice to have such a mechanism in human blood...

but, that's not the case, is it?

It isn't. Well, these red blood cells in newts, known as erythrocytes, have nuclei,

where they produce various proteins involved in regeneration.

However, in mammalian red blood cells, we do not have nuclei, so they cannot produce such proteins.

That's unfortunate.

It is. But still, there is hope.

Newtic1 itself may be a gene that is unique to newts,

but the substances involved in regeneration that emerge from Newtic1-expressing erythrocytes are, in fact, in our bodies too.

Unfortunately, nothing is in charge of selecting them and delivering them to where they are needed.

So you're saying that if we could manually select and collect the substances involved in this regeneration,

and apply or inject them to the affected area, regeneration might occur?

Essentially, yes.

That sounds like science fiction coming true.

Now, there's also a different approach regarding research on the regenerative ability of newts.

It's the analysis of their genetic information, the so-called genome, which is said to be the blueprint of an organism.

Research on "whole-genome analysis" of newts is underway at Hiroshima University's Amphibian Research Center.

Dr. Toshinori Hayashi studies regenerative biology and has created a unique apparatus as an integral part of his research.

And here's the newt involved!

We call this place the newt farm.

The newt we are raising here
is the future of newt research.

It's the Spanish ribbed newt.

The Spanish ribbed newt is one of the largest newts in the world and is found in Spain and other countries.

It has several advantages for newt research.

Such as the sheer number of eggs.

Spanish ribbed newts produce from 150 to 600 eggs at a time.

They also grow quickly and can reproduce within a short period of time after birth,

making it easy to increase their numbers.

When there is an abundance of uniform eggs, laid by the same parents,

genetic and other studies can be conducted at once.

With a system in place to distribute large quantities to other researchers,

the entire genome was decoded and all the nucleotide sequences were revealed.

What emerged was something called "retrotransposon!"

Retrotransposon is a phenomenon in which a portion of the genome is copied and inserted elsewhere.

This happened so often that the newt genome became enormous,

more than seven times larger than the human genome.

Repetitive parts created by retrotransposon were previously thought to be useless with no particular function.

However...!

People thought the newt's large genome size
was due to a lot of repetitive sequence junk,

and that large genome size is meaningless,

but now we know from other organisms
that the opposite is true.

Repetitive sequences are very important.

For example, the genome of the Mexican salamander,

which has particularly high regenerative ability among salamanders,

also has a very large number of repetitive sequences due to retrotransposon.

By analyzing the entire genome in detail,

Hayashi and his team hope to uncover the secret of their amazing regenerative abilities

by looking for commonalities among these organisms.

That retrotransposon, in which part of the genome is copied and inserted elsewhere, also occurs in the human genome.

However, in such cases, the inserted gene fails to function as it should and can cause diseases such as cancer.

But Hayashi and his team concluded from their analysis that, in the case of newts,

this may play an important role in maintaining life.

So there's still a lot of mystery,

but I guess we can say that detailed genome analysis led to the discovery of something important.

That's right.

This genome is a crucial blueprint for researchers to understand the structure of the organism.

Genome analysis is a very important approach to understanding newt reproduction.

Up next is J-Innovators with Michelle,

who will introduce a person that has developed some rather "groundbreaking" shoes.

Walking and running are basic human movements.

However, until now, to measure the force applied on the movements in detail,

expensive and large-scale measuring equipment was needed.

Today, we will introduce you to an innovator who has created a game-changing tactile sensor technology.

Taito Ward, Tokyo.

This area has long flourished in commerce and industry.

This company specializes in the development of sensors that quantify the sensation that occurs when touching something.

Hello, I'm Michelle Yamamoto.

Hi, I'm Maruyama.

Today's "Takumi," or "innovator," is Maruyama Naoya.

He has been developing some rather unique products.

A musical instrument that emits sounds when it detects fingers tracing or pressing on it.

A controller that detects the gripping force.

And now, he has developed a revolutionary shoe using state-of-the-art tactile sensor technology.

These are our sensor shoes.

Those? At a glance,
they look like ordinary shoes.

The shoes allow us to instantly visualize the mechanical energy hidden in complex foot movements...

Okay, ta-da!

I've tried them on, and they're very comfortable.

I just can't imagine that there are sensors inside.

This screen shows the state of your feet.

The black circle indicates the shift of the center of gravity.

In the green area, the center circle changes from yellow to red when strong vertical force is applied.

The four triangles change color to indicate which direction the force is applied.

With just a pair of shoes and a smartphone,

you can record in real-time how your center of gravity is shifting and where the stress is being placed.

For example, a golf swing involves a twisting motion of the sole, so the corresponding green circles rotate as well.

This kind of movement could not be measured with conventional instruments.

The secret is sensors hidden under the insole.

This black circle is one sensor.

Three sensors are placed inside the shoe.

It is only 9 millimeters square - small enough to fit on a fingertip.

We were shown what kind of movement the sensor detects.

This is a system in which the airplane on the screen moves in conjunction with the force applied to the sensor.

It moves freely, be it vertically,
horizontally, up or down.

Conventional tactile sensors mainly detected pressure, so only vertical motion could be detected.

The Takumi's tactile sensor can measure left, right, up, down, vertical, and even torsion,

allowing more detailed measurement of force changes.

The technology that achieved both this small size and high functionality is found under the black resin.

It is MEMS, a micro mechanical electronic system measuring only 1.5 millimeters square.

It incorporates electrical circuits and a mechanical structure with tiny beams.

Let's take a look at these two beams.

The purple part is a material that does not conduct electricity.

The beam exterior is specially treated to allow electricity to pass through.

In the purple sections, electricity flows down the sides of the beams.

When force is applied from the side, the beams bend.

The side closer to the force will contract, while the side farther away will stretch.

At this time, the contracted side is more conductive and the stretched side is less conductive.

The change in electrical resistance is used to detect the magnitude and direction of the force.

These are beams that measure horizontal and vertical directions.

By placing four of these pairs, it is possible to measure each torsion force

in addition to vertical, lateral, and perpendicular.

And the world's smallest high-sensitivity tactile sensor became possible.

This sensor technology is based on that developed by Dr. Isao Shimoyama of the University of Tokyo,

where advanced technology through industry-academia collaboration is taking place.

The Takumi's shoes can be applied in a variety of ways.

This is a service used to measure walking fitness age for the elderly, created jointly with a university.

Follow the instructions and perform four types of exercises to see how fit you are for your age.

First, normal walking.

Next, stand up from the chair and walk around the mark and return.

Then, get up from the chair five times.

Lastly, stand on one leg.

The four movements were easy.

Okay, let's see the results.

Yes.

For this test, I used the data of a 65-year-old person as the standard age.

74 years old.

You only had full marks
for standing on one leg.

Results for the other ones are too slow.

Maybe I was a bit too cautious.

I'll have to exercise
a little more in the future.

We had a real 65-year-old employee try it out.

The result was...

Perfect. The result is appropriate for your age.

The easy measurement allows the elderly to monitor their physical condition while having fun.

With these shoes, detailed analysis results are also available after measurements are taken.

Six areas, including pushing force and propulsive force can be measured and utilized for research.

The RIKEN Institute of Physical and Chemical Research uses this technology

to see how Parkinson's disease patients walk in order to measure the effect of medication.

And at Keio University, it's being used in sports research,

such as to visualize weight transfer during short-distance running.

These sensor shoes are the starting point
from which new services will be created.

We are manufacturing with the idea
that we can make a change.

The future of tactile sensors is expected to open up a wide range of fields.

Well, that tactile sensor seems to have a great deal of potential in a wide variety of fields,

not only in sports but also medicine and healthcare.

I agree.

Big data is a hot topic these days, and I'm sure that walking data gathered from shoes could become valuable.

It will be neat to see where the Takumi takes this tech.

Looking back at today's main topic, we gained some insight into the secrets of newt regeneration.

How do you suppose this research will progress in the future?

Well, the issue is still how to apply it to medical care.

It's not that easy with only the current research results,

so it will likely take another 10 to 20 years before that becomes a possibility.

There is hope that young researchers will be able to find the best mix

by successfully combining iPS cell-based technology with this newt-type regeneration.

There certainly are many people who could benefit from this technology.

So let's hope it becomes a reality sooner than later!

And that's all for this week's Science View.

Thank you for joining us.

And please come and join us again for the next episode!