- I hate needles, I hate the idea of watching 500 milliliters of warm red blood leave my body, but I'm here, and Ashley is about to stick me because there are people who need my blood more than I do.

I'm a chemist by training, so while I'm sitting here reverse vampiring, I was wondering, why hasn't chemistry provided us with a better solution than this?

Why don't we have synthetic blood yet?

Now, it turns out there are some new breakthroughs on this, but creating something that just transports oxygen through the nooks and crannies of your circulatory system without killing you, surprisingly difficult.

(upbeat music) Leave it.

(stuttering) Even chemists stumber, stumble, stumble, stumber.

People have been working on this for nearly 400 years.

Early attempts, including things like sticking quills into dogs' veins and transfusing lamb's blood into humans, which did not go well.

But after much kind of grizzly trial and error, for about 115 years now, transfusions have been relatively routine.

Doctors can determine your blood type, find someone else with a matching blood type, and then transfuse blood between the two of you.

Now, having synthetic blood would offer some benefits over getting it from human sources like me, why?

First, today, millions of liters of blood around the world are donated every year and still it's not enough.

There's a constant chronic blood shortage.

Doctors are having to choose who gets blood and who doesn't.

Some hospitals have less than a one-day supply of critical blood types.

Okay, second, we're gonna need more and more blood as the world's population gets older.

For example, many cancer patients need blood platelets just as a standard part of their treatment.

Third, real blood is expensive.

When you factor in all the costs, including making sure the blood is safe, storing it, transporting it, and transfusing it, it can cost up to $2,000 a liter.

Fourth, receiving real blood isn't risk free.

There's the potential for human error in type matching.

There's something called transfusion related acute lung injury, and the very, very low but still possible risk of getting a bloodborne disease like hepatitis C. Synthetic blood would probably have its own set of risks, but there would be no risk of a type match error and no risk of bloodborne diseases.

The extra great thing about synthetic blood is that it doesn't even have to replicate every aspect of real blood to be useful, why?

Well, real blood does one thing that every second of every day prevents you from dying.

That is, it transports oxygen.

If oxygen transport fails catastrophically for whatever reason, and there are many, your brain will soon starve for oxygen, shut down, and the rest of you will follow.

So for synthetic blood to be a game changing medical innovation, it just has to do one simple, little thing, transport oxygen.

Which raises the question, how hard could that really be?

Okay, let's approach this logically.

What is the simplest conceivable solution?

Just use water, right?

I mean, blood is already 55-ish percent water, and patients who've lost a lot of blood often get intravenous saline solution, which is mostly water, to prevent their arteries and veins from collapsing.

Now, water can dissolve about seven milligrams of oxygen in it per liter at body temperature.

Blood is roughly 30,000 times better than water at binding oxygen, which means that if your body used water as an oxygen transport system, your heart would have to beat at the leisurely rate of 1.8 million beats per minute to get enough oxygen to your tissues.

By the way, the fastest heartbeat in all of the animal kingdom is 1,500 BPM.

Adorable.

Unfortunately, despite its many wonderful qualities, water is just not a great candidate for synthetic blood.

Okay, next logical step.

What do millions of years of evolution have to say about it?

(making squawking noises) I'm kidding, they have to say hemoglobin.

Hemoglobin is a protein with four subunits.

Each subunit has a group called a heme group.

Heme is this thing.

And these transition-metal complexes are a motif you see everywhere in nature, in plants, in humans, in spiders, in crustaceans, in worms, everywhere.

Human hemoglobin uses iron complexed to porphyrin, but other creatures use other metals or other scaffolding, so their blood is different colors.

Now, we could do a whole video about how hemoglobin works, but the short version of it is, in the lungs, oxygen binds to the iron in the heme group, then the blood gets pumped far away then releases the oxygen to the tissues that need it.

Then deoxygenated hemoglobin goes back to the lungs and then the cycle starts all over again.

So one of the first things scientists tried in the quest for synthetic blood was purified hemoglobin, but here's the absolutely crucial piece of information, free hemoglobin just floating around in your blood is, somewhat ironically, very toxic.

Heme groups are incredibly redox reactive.

The metal atoms in them, iron in humans, love picking up or giving up electrons, which makes them the biochemical equivalent of a bull in a china shop.

(bull gasps) (bleeped) Let's look at just one thing heme can do.

When an oxygen molecule is bound to the iron in heme, occasionally, instead of shuttling the oxygen around, the iron will just shunt one of its electrons onto the oxygen molecule forming this bad boy, superoxide.

Now, that dot means unpaired electron, which means very reactive, which means it will pretty much indiscriminately react with anything.

Superoxide is one of the many molecules that cells in your immune system called natural killer cells generate on purpose to kill bacteria.

This is not something you want just floating around in your bloodstream.

Now, your red blood cells have a whole system whose sole purpose in life is to undo this process, but when hemoglobin is freely floating around in your blood, it can't access this superoxide reversal system, so the superoxide just floats off and causes a bunch of havoc, and so does the oxidized form of heme.

Heme also picks up and hoards nitric oxide, which is a small signaling molecule your body makes to widen or dilate your blood vessels.

If enough heme is floating around in your bloodstream, it can pick up enough nitric oxide to constrict your blood vessels and raise your blood pressure.

Now, because heme causes all of this havoc and so much more, your body has a heme cleanup mechanism, your kidneys.

This cleanup system works fine on small amounts of heme, but if you're in what's called hemolytic crisis, which is where lots of red blood cells break open and spill out their hemoglobin at the same time, or if you're having hemoglobin directly injected into your blood, it can clog up your kidneys.

If this gets bad enough and you're not treated, you can die.

We know this because in the 1930's and 1940's, animals and then anemic people were given purified hemoglobin.

The transfusions seemed to go well at first, but within a few hours or days, some patients developed kidney problems.

Some even died.

After that, scientists worked hard to figure out what was going on, but that took decades.

Okay, at the same time, the U.S. Navy was experimenting on their own substitute for blood transfusions with a completely different approach that came out of something called liquid breathing.

Look at this scene from the 1989 movie "The Abyss."

- Can I borrow your rat?

- What are you doing?

- This is not CGI or faked in any way.

That is a real rat, that's a real liquid, and that rat is really, and truly breathing this liquid.

Liquid breathing is based on a series of experiments famously performed in 1966 in which scientists submerged mice, and with less success cats, in this same liquid.

The animals were able to breathe somewhat normally for a few hours, and at least with mice, if you properly drain their lungs after you pull them out of the liquid, they're able to live pretty normally for at least a few weeks.

- [Man] All right, warm him up, let him breathe.

- We did it to five rats and five different takes.

They were all fine.

(group applauds) Beany died of natural causes.

about three weeks before the movie opened.

- Now, liquid breathing was developed by the Navy to deal with the issue of rapid surfacing, the bends.

The idea was to fill a diving suit with a liquid and have Navy divers breathe this liquid underwater.

Because if you can breathe a liquid, you can surface as quickly as you want without any decompression sickness.

The explanation for that is a whole other video.

But a liquid that can transport oxygen so well that you can breathe it sounds promising for our synthetic blood search, right?

So what is this magical liquid?

There are a few different specific ones, but the general class is called perfluorocarbons, or PFCs.

PFCs are like alkanes, except all the hydrogens are replaced with fluorenes.

The C-F bond is one of the strongest single bonds in all of chemistry, which means PFCs are super unreactive, so they won't react with your lungs when you inhale them, nor will they react with your blood or your blood vessels when you inject them.

Now, PFCs are also nonpolar, meaning they can dissolve way more oxygen than water can.

The PFC most commonly used in liquid breathing experiments was FC-80, or perfluoro-2-butyltetrahydrofuran, nailed it!

And it can dissolve 16 times more oxygen than water.

The problem is, since PFCs are nonpolar, they don't dissolve in blood.

You don't want a two-phase system in your blood vessels.

What you want is this, nice and emulsified.

So you need to add an emulsifier.

Now, many companies over the past few decades have experimented with PFC-based blood substitutes, but some clinical trials were ended early because of higher rates of stroke and other side effects.

Now, there is a PFC product that's been approved in Russia called Perftoran, and there were plans to rebrand it as Vidaphor or Veedaphor and bring it to the U.S., but the company that was gonna do that folded.

Meanwhile, back in hemoglobin land, scientists had figured out that a big part of the reason free hemoglobin floating around in your blood is toxic is that it splits apart.

Now remember, the original protein is four subunits.

That protein splits up into two, two subunit pieces.

These pieces are small enough that they can sneak through the walls of your blood vessels, and that's when they do most of their damage, particularly all the kidney damage.

Now, if chemistry is good at anything, it's sticking stuff together.

I mean, half of all chemistry is just fancy words for glue.

That's absolutely not true.

Chemistry is a wonderfully varied field.

The central science, as it were.

In fact, that reminds me of a quote from Freud, "From error"- (jazzy music) Can we use chemistry to prevent hemoglobin from splitting up?

Yes we can, and many companies did, but the story is much the same as it is with PFC-based blood substitutes.

There is one hemoglobin based product called Hemopure that's approved in South Africa.

A cousin of Hemopure called Oxyglobin is approved in the U.S., but only for veterinary use.

The FDA does allow Hemopure to be used as part of its expanded access or compassionate use program, which means that doctors can use a technically unapproved product, but only in life-threatening situations when no other treatment is available.

Now, there are also some promising new approaches that are still in the very early phases of lab development, and I'm gonna give you one example.

Now, stick with me, because this is pretty amazing.

Researchers took red blood cells, fixed them with formaldehyde, and then encapsulated them inside a 10-nanometer thick layer of silica, forming exact replicas that preserved the classic red blood cell shape.

Then they coded the replicas with an ultra thin polymer and then treated them with hydrofluoric acid, which I'm sure you remember from "Breaking Bad," to dissolve away all the silica while keeping the polymer layer intact.

So now they've got these soft red blood cell-shaped replicas which they then encapsulated inside membranes that mimic human red blood cell membranes with the same shape and flexibility as real blood cells.

Finally, they filled up these synthetic blood cells with hemoglobin and tested how well they could flow through thin spaces, circulate in animals, and carry oxygen.

And the answer was, pretty damn well.

Now, this was done at a small scale and it's unclear whether it would be feasible, practical, and importantly, cheap enough to make liters of this stuff.

It also has not yet been tested in humans, but still they essentially built a prosthetic red blood cell from scratch.

Blood is chemically and biologically complex, and making a synthetic blood substitute just to carry oxygen without side effects is really hard.

Now, that's actually understandable.

Anytime you're putting half a liter or more of something directly into someone's bloodstream, it's really hard to minimize side effects to an acceptable level.

So the barriers to full FDA approval are very high, and that can be a disincentive for companies, especially small ones, to develop the product.

But if someone does crack this nut, it could create a multi-billion dollar industry, and more importantly, help a lot of people.

For now though, we do have an alternative, relying on the kindness of strangers to donate blood.

If you can donate blood, even if you, like me, don't like to, please do it.

It doesn't take that long and it can literally save someone's life.

And you get free snacks.

Hmm, delectable.