Harnessing the Power of Proteins

What comes to mind when you hear the word "protein"?

Maybe food?

Or exercise?

Proteins are responsible for nearly all body parts and biological functions.

From firing neurons, to digesting food, they carry out the genetic blueprints for life.

There are said to be over 100,000 kinds of proteins in the human body.

A technology developed in Japan allows almost any human or plant protein to be synthesized at will.

This is a revolution in Life Sciences.

We can now synthesize around
28,000 different proteins.

I think it's a great asset to humanity.

Especially in medicine, where it allows for the development of new drugs.

What's more, proteins from mosquitos could be used to detect early-stage cancers.

On today's Science View, we'll see how proteins are being artificially produced and repurposed to shape our future.

And recently, an underwater volcano erupted near Japan, suddenly spewing countless light porous rocks that floated up and washed in,

clogging up the coastal waters.

A novel device was used to help remove these floating rocks.

Later in the program, we'll learn about this device from the Japanese innovator behind it.

Hi, I'm Tomoko Tina Kimura.

Welcome to Science View.

Today, we'll be talking about how the proteins that comprise our bodies can now be produced in the lab.

And joining as our guest commentator is David Hajime Kornhauser.

He is the Director of Global Communications at Kyoto University, where he shares Japanese science and technology with the world.

Thank you for joining us today.

Thank you for having me.

Now, the idea of artificially making the proteins we rely on for so many bodily functions that seems like research with tremendous potential.

Yes, it is.

Protein engineering could be a whole new way of creating and altering the basic components that make human life possible.

We're still in the basic research phase.

But in engineering, basic research often leads to indispensable inventions like cars, skyscrapers, and mobile phones.

And artificially synthesizing proteins will likely prove similarly innovative.

Applying what we learn from this research could allow us to produce and create new proteins to better our lives.

So, to get us started, we'll take a look at how the proteins of the body are being created in the process known as "synthesis."

Matsuyama City, Ehime Prefecture.

Here, Professor Tatsuya Sawasaki is experimenting with the stuff of life.

He synthesizes proteins by transferring the genes that create them into a special culturing medium.

His results are stored in this freezer.

This contains 384 kinds of human proteins.

They're kept in this container.

Each of these small openings is home to a different protein with its own form and function.

The university has filled 75 of these containers with 28,000 kinds of artificially synthesized proteins.

Covering most of the major human proteins, this is a "world first" accomplishment.

Their greatest promise lies in the development of new drugs.

Medicine and proteins go hand in hand.

Here's an example.

This is a protein called "pepsin."

It's a digestive enzyme found in the stomach.

It breaks apart food proteins entering this grooved area like a pair of scissors.

But, if it inadvertently breaks down the lining of the stomach, it can lead to gastric ulcers.

So, what can be done to limit pepsin's function?

Here's a drug with a shape that just fits into the groove in the pepsin.

With the groove blocked, the pepsin's function is suppressed.

Drugs like this one can fit into a protein like a key into a keyhole.

The drug takes effect by occupying the open space in the targeted protein.

But drugs can inadvertently attach to other proteins, ones with important and desirable functions, and prevent them from working.

This is what we call a "side effect."

For the past several years, Sawasaki has been using the 28,000 proteins he synthesized to study the side effects of the drug "thalidomide."

In the 1950s, thalidomide was marketed as a sleep aid.

When taken during pregnancy, however, it was found to cause birth defects, impairing the development of children's arms and legs.

It's said to have caused around 6,000 cases of these birth defects worldwide.

Although it was later found to be promisingly effective against some blood-related cancers, for years, no one knew which proteins thalidomide was binding to when causing its harmful side effects.

We didn't know which proteins were involved.

I wanted to figure that out, and maybe create
a similar drug without the harmful side effects.

Here's what was known about the side effects when Sawasaki began his research.

When thalidomide enters the body...

...it attaches to an opening in a protein known as "cereblon."

Cereblon serves as a janitor inside cells, getting rid of unwanted items.

When an object attaches to this opening, the cereblon usually recognizes it as unwanted, and breaks it down.

But, it ignores desirable proteins that don't fit into the binding space.

But, when thalidomide fits in and attaches to the binding site, the shape of the opening changes.

Desired proteins can now inadvertently attach, be misidentified as unwanted, and be broken down.

In the thalidomide side effect, the misidentified and destroyed proteins were needed for limb development.

But, we didn't know which proteins were likely to bond to cereblon with thalidomide present and lead to side effects.

So, Sawasaki identified over 1,100 questionable proteins from those he'd synthesized, and tested their bonding affinities, one by one.

Here are the results.

The higher the number, the stronger that protein's tendency to bond to the opening in the cereblon.

The analysis showed that proteins "SALL4" and "PLZF" were likely candidates worthy of testing.

This experiment tested the absence of the PLZF protein on the development of limbs in baby chicks.

It confirmed that the legs were underdeveloped.

Sawasaki had successfully identified a particular protein involved in the side effects of thalidomide.

There were many patients around the world
who really suffered from those side effects.

We were happy to solve one piece of the puzzle.

I can see this is work that requires perseverance.

And thalidomide is effective against some blood-related cancers.

Have they been able to completely eliminate the side effects?

They say that work is moving forward.

But the properties of molecular compounds can change significantly with just a slight modification.

Let's look at thalidomide.

Here is its molecular structure.

The right part attaches to cereblon, the janitor protein that cleans up the insides of cells.

And the left part attaches to other proteins, like SALL4 and PLZF, which are needed for arms and legs to grow properly.

Sawasaki hopes to change the left side of the thalidomide enough so that it doesn't attach to needed proteins, but it still functions as a drug.

Yes. But if they change the left structure even a little, it could allow other needed proteins to attach there, causing other side effects, no?

Yes, that's certainly a challenge.

But, Sawasaki's "secret weapon" is his team's ability to make 28,000 different proteins to experiment with.

So, he's in a strong position to make the attempt.

It's sort of like having all the biological machinery at your disposal.

But amassing that arsenal of proteins wasn't easy.

There was a lot of hard work involved.

And also, some surprising "behind the scenes" stories.

Let's take a look.

Research on artificial proteins was given an enormous boost by the Human Genome Project.

By 2003, the project had decoded all the genes of the human body.

The genes contain the DNA instructions for producing all the proteins that occupy the human body.

But until we actually produced the proteins, we didn't really know much about them.

At the time, live E. coli bacteria were used to synthesize proteins.

Human genes were incorporated to the E. coli, which read the DNA instructions and produced the proteins.

But, if a protein created is harmful to the E. coli, upon completion the E. coli starts breaking it down.

So, we could only produce about 30% of all the human proteins there are.

This obstacle was overcome by Sawasaki's mentor, Professor Yaeta Endo.

Endo sought a way that was completely different than using live E. coli.

With E. coli, we couldn't produce important
proteins that are fundamental to life.

Endo turned his attention to wheat.

It's actually the wheat germ that's important, the "embryo" of the seed that grows into a plant.

Wheat germ comes equipped with mechanisms to produce all kinds of proteins for when
the plant begins sprouting in the spring.

Half of its proteins are there
for making other proteins.

Inside the wheat germ cells, biological machines known as "ribosomes" build the proteins.

They work in pairs, one large and one small.

Inside the cell, the ribosomes attach to strands of messenger RNA and read the genetic information written there.

Following these instructions, they churn out proteins, one after another.

Ribosomes are the crucial protein-building factories in all forms of life.

Endo ground up the wheat germ and extracted the ribosomes.

Then, he added the genetic blueprints for the desired proteins.

This allowed him to synthesize a series of proteins that couldn't be done with E. coli.

But he ran into a major hurdle.

For some reason, the ribosomes extracted from the wheat germ stopped functioning after about 15 minutes.

For four years, Endo tried everything he could think of to make the ribosomes work longer.

I was disappointed in myself.

I thought, "if this doesn't work,
there's no way it can be done."

Those were really tough days.

Just when he was about to give up, he tried one more thing...

...rinsing the wheat germ in water.

I figured we could just try rinsing it in tap water.

This is how he did it.

He wrapped the wheat germ in gauze.

Then, rinsing it in tap water, the wheat germ released a white substance.

He found it was something inside this white substance that was impeding the ribosomes.

That was surely a shock for him.

A simple process that people do every day was the solution to the problem he couldn't solve for years.

Fifteen minutes isn't enough time to produce many proteins.

So, what exactly happened when he rinsed the wheat germ that made it work?

The white substance that rinsed off with water is the part we call "flour."

It contains a protein called "tritin," which impedes the functioning of ribosomes.

Tritin is a substance that shuts down the protein-building ribosomes inside cells.

It sits outside the cell walls of the plant.

Without tritin, a damaged cell wall could allow viruses to enter the cell, take over the ribosomes, and multiply, potentially killing the entire plant.

That's where tritin comes to the rescue.

It protects the plant from viruses by quickly entering damaged cells and deactivating their ribosomes.

Washing away the tritin extended the time that wheat germ can be used for artificial synthesis from 15 minutes to about 10 days.

Wow. That's a tremendous improvement.

And that's what made it possible for them to produce 28,000 different proteins.

Exactly.

Such a simple solution must've surprised researchers all around the world.

And now, protein synthesis is booming.

We've entered a period where exceptional proteins from not only humans, but other animals and plants are easily produced and put to new uses, as in this next story.

This device uses biological proteins in an unexpected way.

It's an odor sensor that uses a
cell membrane protein from mosquitos.

It detects cancer-related
odorants in exhaled breath.

How can proteins from a mosquito detect cancer?

The mouth section of a mosquito has highly sensitive cells that can detect the smell of human sweat, even from a distance.

If even a single molecule of an odorous substance called "octenol" comes in contact, the biological switch is engaged and the mosquito smells dinner.

It's this protein that alerts blood-thirsty mosquitoes to humans nearby.

If we can harness the abilities
of other living things, I believe we can create
a whole new class of sensors.

Researcher Toshihisa Osaki and his colleagues knew that liver cancer patients have higher levels of octenol in their sweat, and also in their breath.

They thought a synthesized version of this mosquito protein might be useable for the early detection of cancers.

The mosquito protein is placed in these compartments in the center of the sensor.

If ions are detected in the internal chamber...

...it indicates the presence of gate-opening octenol, which is associated with cancer.

In this experiment, an otherwise undetectably small amount of octenol is mixed in with exhaled human breath.

When this mixture is fed into the device...

...the waveform changes!

The octenol was successfully detected.

Osaki believes this sensor can help detect liver cancer at a very early stage, because it can detect even trace amounts of octenol.

The extreme sensitivity is a big advantage.

I think it'll start a whole new class of sensors.

Incorporating the amazing abilities of living organisms into machines, an era of early detection of diseases may be just around the corner.

That seems like very promising research.

In this case, it was liver cancer.

But other cancers might have other substances that are detectable like this, right?

It seems so.

Recent research findings are identifying more and more components in human breath.

Apparently, there are many, including some associated with cancers.

So, it becomes a matter of creating new sensors to detect each target substance.

That's right.

And if it's a substance that appears in the early stages of that cancer, it should allow early detection.

And they also expect that similar sensors can be made for diseases other than cancer.

If doctors could perform health checks with such a non-invasive procedure as just measuring a person's breath, that'd be very welcome.

Next, an innovative machine to remove floating volcanic rocks from coastal waters, and the creator behind it.

October 2021.

The coastal waters of Okinawa and Amami region were filled with floating gray objects.

Rocks made of pumice.

These porous low-density stones were emitted two months earlier from an underwater volcano eruption in the Ogasawara Islands, over 1000 km east of here.

When these floating stones get sucked into a ship's engine, they can damage it beyond use.

This was a serious threat, especially for fishing boats.

The removal process took several months, using mostly heavy equipment and manual labor.

Just then, people noticed a little device floating in the sea of pumice.

It's called a "floating oil skimmer."

Originally designed to collect waste oil from factories, it can remove pumice stones easily, collecting this many in just 15 minutes.

Let's meet the developer of this still-evolving device.

We visited an industrial complex in Joso City, Ibaraki Prefecture.

Toru Ebihara worked on the floating skimmer at this fluid machinery factory.

This is a standard floating oil skimmer.

These yellow parts provide buoyancy
to keep the whole device floating.

The surface oil falls into this cylindrical part.

This discharge port is connected by a hose to a
separation tank. It's very simple design.

This is a standard oil skimmer.

But the pumice stone skimmer required a redesign.

Which meant a lot of trial and error.

Let's see an oil skimmer in action.

This mini-skimmer removes the red oil floating on the water.

When the device is turned on, oil and water are sucked in together and divided with a separation tank.

If too much water is sucked in, the separation tank fills up quickly, hampering performance.

The objective is to take in the oil with minimal water.

To do this, the intake opening needs to be kept just below the surface of the water.

This was an important issue in the design.

But, the conventional models had a critical weakness.

Waves.

The design worked well enough on placid waters.

But when hit by waves, the water poured in, driving the intake part of the floating device deeper underwater.

The problem was that the entire device floated as a single unit.

While sucking in matter from the water surface, the device also takes in a certain amount of air.

This gives the hose connected to the main body buoyancy.

But, when waves come in, they fill the inside of the device with water, not air.

The buoyancy drops and the entire device sinks.

Incompatible with ocean waves, it's of limited use.

This was a challenge for Ebihara.

He tried different shapes, but couldn't get around the buoyancy problem.

Then one day, a member of his team saw something that triggered a breakthrough.

They saw a child in an inflatable swim ring.

The child floated on the waves without
touching anything. That gave us the idea.

Like the child, if the water intake part floats independently, it can move up and down with the waves.

This keeps the water intake at the same shallow depth.

Seeing the child gave them the idea for this double float design.

To fix the problem, the main body and intake part float separately.

But it wasn't easy to build.

The intake part moves up and down.

But oils and solids get stuck in the gap
between the inner and outer cylinders.

That gets clogged and won't move. So, we had a
double float, but it wasn't working as we wanted.

Ebihara's team thought that things were clogging up the gap because the surfaces of the cylinders were touching each other.

So, they tried reshaped the inner cylinder to reduce contact with the outer cylinder.

That way, things that got lodged in the gap could come out more easily as the cylinders moved up and down, avoiding the clogging problem.

This is the finished product, a "floating oil skimmer" with a double float structure.

It can also skim off pumice stones.

It even works well with waves.

The intake part doesn't sink, even when deluged with swells of water.

It maintains the optimum positioning.

The latest design adds rotations to break up moss and sludge while skimming.

It can even handle high-viscosity substances, which were also an issue.

It's now being used at food factories to skim solid matter away from wastewater.

This time we skimmed pumice stones in Okinawa.

But if we get asked to skim
something that hasn't been done before, we'd be happy to further refine our
devices in response to that request.

The floating stones were a serious and potentially devastating threat to fishermen and other people who were affected by them.

So, it makes me really happy to know that we can tackle these issues with ingenuity!

I think the design that rotates might be even more useful.

Oil spills can involve other substances, making the oil more difficult to skim off.

I'll bet those rotators would be helpful in cases like that.

Yes.

Our main topic today has been the artificial synthesis of proteins.

Proteins are the building blocks of life, carrying out a variety of tasks throughout the body, like little machines.

Yes, I've heard some specialists refer to proteins as "nanomachines."

Until now, a lot of research has focused on chemistry to produce new substances or materials.

But now that we have technologies to read, interpret, and write DNA instructions, as we saw with some of the coronavirus vaccines,

biology is a growing part of the process.

Mastering proteins might allow us more ways to harness the power of living things when conventional technologies fall short.

I hope new proteins will be found or created for use in medicine, and other fields such as energy production, environmental protection, and space exploration.

Mister Kornhauser, thank you very much for joining us today.

The pleasure was all mine.