Pushkin.

Every year, sixty thousand people in the United States and two million people around the world die because of blood loss.

They get in a car accident, or they get shot and they bleed to death.

These people tend to be relatively young and healthy, and a lot of them could be saved if they were quickly given blood.

But outside the body, blood doesn't travel well.

It's bulky.

You have to keep it cold, and as a result, it's hard to get blood to patience when they urgently need it.

Ambulances don't tend to carry it.

Field medics don't typically have it in combat, and so there's long been this dream.

What if we could come up with a way to make blood easier to store and transport.

What if we could have blood ready to go every time an ambulance gets to a car accident and a medic gets to a wounded soldier.

If we could do that, we could save millions of lives.

I'm Jacob Goldstein and this is What's Your Problem, the show where I talk to people who are trying to make technological progress.

My guest today is Alan Doctor.

He's the co founder and chief scientific officer at Kalasite.

Alan's problem is this, can you make something like freeze dried blood that can be rehydrated and given to patients when and where they need it.

Alan didn't start out wanting to found a company.

He was a doctor taking care of kids in the hospital.

So the type of medicine I do is intensive care of medicine.

So this is and for children, looking after children in the hospital who have severe infections or major injuries and they're critically ill, and most of them are in something a condition we call shock.

And the problem with shock is that you're not effectively getting blood and oxygen where it's needed.

Okay, so people get sick and die.

Even though we fix the underlying problem, so we can cure the infection, we repair the hole in the blood vessel, and people still we lose them because their circulatory system is failing.

You know.

That was frustrating, and I was interested in that problem and I was trying to understand why that happened.

And what we were able to learn is there's a traffic control system in our circulatory system that routes blood where it needs to go, and red blood cells are the traffic lights, so they turn green and they open up the blood vessels or they turn red and close them, and it's very coordinated.

It's a very exquisitely tuned system.

And I was studying that, huh, that's governed by the way hemoglobin interacts with other chemicals in our blood stream.

And it turns out it's highly relevant for shock and fixing shock.

But it turns out it's also relevant for transfusion.

And that's when this story started.

So you're studying red blood cells and hemoglobin, which are obviously hemoglobin are the molecules that transport oxygen, right, that do that key function of blood.

That is the thing in particular that you want to replace when somebody gets shot or gets in a car accident.

Right, of all the things in your blood, the thing you need urgently that minute is hemoglobin to deliver the oxygen right.

Right.

People had known that part for a long time and had tried to develop blood substitutes in particular to solve this acute kind of trauma setting problem.

But it had gone badly right, So tell me about the history up until that point of people trying to come up with ways to you know, get hemoglobin to people in emergencies, do sort of hemoglobin replacements.

Well, they did the first obvious thing.

So the problem is you have to make the bloodshelf stable in order to use it outside of hospitals, So you have to get rid of the cold chain.

The reason we need the cold chain is the hemoglobin's inside a red blood cell.

The red blood cell's alive, and it needs glucose, it needs all kinds of things, and it has to be kept colder.

It goes bad, sort of like the way milk has to be kept colder.

It goes bad, and you can't leave it outside the fridge too long or you can't drink it.

The same thing with blood.

So they say, okay, if we just take the hemoglobin out of the red cell, will it still capture and release oxygen?

Yes, okay it will.

So far, so good, So far, so good.

Does it need to be kept cold in order to work, No, it doesn't, So it's shelf stable.

Doesn't work if we put it inside animals.

Pretty much it does, and so everybody's like, okay, let's try this.

Yeah.

And it was a catastrophe, so it wasn't just ineffective.

It was harmful, so it was more harmful than the controls.

So it caused heart attacks and strokes and death in the people that got the blood.

Why is it bad to give people hemoglobin?

That is a surprising outcome, right, It's not like it's some novel molecule.

It's our bodies are full of hemoglobin, all right.

So what it meant was we didn't understand something.

It turns out hemoglobin does more than just interact with oxygen.

It interacts with other chemicals in the blood stream.

So the hemoglobin has to be sheathed inside a membrane, and it sequesters the hemoglobin from everything else in the blood stream, from the blood vessels, the cells that line the blood vessel, from the chemicals in the bloodstream where it won't do things it's not supposed to do.

And it turns out that when hemoglobin is free in the bloodstream, the blood vessels don't know whether they're to open or close, and what they end up doing is mostly closing.

Uh huh.

So that's why people who got just naked hemoglobin had heart attacks.

Basically exactly, yeah, exactly, got it.

So okay, So this is the context, right, So clear bad idea to just give people hemoglobin.

Alas well, it was a good idea.

It seemed like a good idea, but it became clear that it had been a bad idea.

It's scary in fact, right, it scary like so many things we've all done.

Yeah, yeah, no, no, no shade on the people who tried it.

It's just a it's a terrible outcome that nobody would have wanted.

So you meanwhile, are studying hemoglobin and then a chemical engineer comes to you with an idea, Right, tell me about that.

Twenty ten what happened?

Yeah, I'm just studying regular red blood cells and this routing problem, right, which I understood.

That's why you know a lot of these blood substitutes, what we call the unencapsulated hemoglobins failed.

People started to understand that, but I wasn't thinking like, oh, I know how to solve that problem.

I was minding my own business doing something completely different.

The chemical engineer, the bioengineer was making special particles, nanoparticles for imaging.

So there's a new form of medicines and therapies where you make little fat droplets and you can decorate them with all kinds of molecules that either home to different parts of your body, and you can see them on X ray.

You can put drugs inside, you can do all kinds of things with them.

Well, just to be clear, these fat droplets, as you're describing them, like, they were the technology used to encapsulate the COVID vaccines, right, that's RNA covid vaccines were in what lipid NAO particle is?

That is the jargon, right, although I like exactly I appreciate that.

Yeah, so yeah, liposomas was used for or a fat droplet was used for the covid vaccine, and it's used for other things too.

So what doctor pan Depongen Pans a brilliant chemical engineer.

So he was making particles so that you could see specific things.

So you want to be able to see breast cancer, You want to be able to see a blood clot.

You want to see, you know, a particular type of cell.

Then you put something on a fat droplet that finds that cell, and you put a little metal in the droplet that you can see with a special CT scan and then say suddenly I see very small and tiny, hard to detect cancers and so on.

So he was making these particles, and he was doing them in a way he wanted to make a lot of surface area, and he ended up making particle that looked like red blood.

Cells just by happenstance.

He just looked at it one and said, hey, I know what that looks like a red blood cell.

So red blood cells are also trying to have a lot of surface area because they exchange gas, and he was trying to create a lot of surface area for a different reason, so he could decorate the particles with these proteins, and then you get.

Red blood cells, said trying to think of what they look like, and I thought of bali, which is kind of a niche a niche analogy, right, like a bagel, but with a thin doe part in where the hole would be.

Do you have a go to description of a red blood cell?

That's what we used.

They're called Nanobiali's no kidding, yes, or the other word people say a biconcave disc Yeah.

That's less or less?

Uh that's cool?

Yes, okay, So does he come to you with this, right, So what happens He's like, Oh, that looks like a red blood cell.

What does he do?

So he thought, Hey, I want wonder if I could put hemoglobin inside.

And he was loosely familiar with the problems with auction carriers and he says, I wonder if I could just put hemoglobin inside, and he figured out how to do that, and then he's like, I don't know how to tell if this works or not.

So so we're both at wash YOU and wash You has this collaboration website where you can google or it's.

Like googling, but it's just at WashU the university.

Interesting like an internal like an engine.

Yeah, so he searched red blood cell physiology and I popped up.

And so he called me and told me the story and said, you know, why don't you come over to my lab and and I'd like to show you what we're doing and see if this works, and maybe.

We could figure out how to collaborate.

Well it didn't work, huh, But but wait, what do you mean it didn't work?

I was all ready for a to work.

What didn't Well, it's a little more to it than just putting hemoglobein inside a fat droplet.

So what I realized is conceptually this would solve the problem that the unencapsulated hemoglobins were plagued by this were like little red blood cells.

And if we could figure out the chemistry to make this capture and release oxygen that maybe this would you know, make things safe and and you can freeze dry these things so they could be you know, shelf stable and very lightweight.

So it's like instant coffee, but for red blood cells.

That's the dream.

Yeah, yeah, exactly.

So initially it doesn't work, but you realize that the idea is fundamentally plausible.

So like one of the things you have to sort of figure out make work for this.

Torque a number of things from the inside out.

OK.

So, first of all, you've got a droplet that has hemoglobin inside it.

Hemoglobin the reason red blood cells work.

There are a lot more than just bags of hemoglobin.

They have lots of other functions.

And so we had to decide what are we going to keep and what do we get rid of?

Huh, Because you can't build the whole red blood cell.

We don't know how to do that.

It's nice.

You want to do as little as you can get away with.

Right, right, You want the stripped down yeah, basic thing, and so it just has to transport oxygen and then it has to not do a bunch of other things.

Yeah, we don't want it to cause trouble either.

Well and subtly suddenly when you say transport oxygen.

It has to know when to pick up oxygen from the lungs and has to know when to release oxygen to whatever tissue needs it.

Right, Like that part seems hard from the outside, right, Well they're opposites.

Yeah, yeah, and it has to do it at the right time, right, it has to do in the yes, at the right speed.

So yeah, it's all very finely tuned inside our body.

So we had to try to imitate the behavior of a real red cell, and the real red cell has people understand like, Okay, there are these other molecules inside red cells that modify the way the hemoglobin interacts with aucygen that causes it to capture oxygen effectively in the lung and then let go when it gets out in tissue and the red cells responding.

Red cell doesn't know, oh I'm in the lung, Oh I'm in the lip, I'm in the muscle.

So it's looking for cues.

So it doesn't have a map, but it can almost smell where it is because of the chemicals that are different in the lung.

Than in exercising muscle.

And it's primarily responding to the amount of acid and the amount of carbon oxide that's in the blood.

And so what we did is we created responsive elements that would work like red cells, but in a different way, so that they would change their shape or change their ability to interact with other molecules in response to those two signals carbon dioxide and acid.

So then the artificial red cell quote knows it's in the lung or knows it's in the muscle.

So we call that wetwear.

So it's like a thousand little thermostats inside each little particle, and it's telling the hemoglobin what to do.

I'm sure there are a lot of hard parts, but that sounds like the hard part.

Well that was, Yeah, that was one of the hard right.

Then we have to make it silent to the immune system so our body doesn't recognize it.

We have to make sure that it doesn't alter the viscosity of blood so it doesn't get too thick or too thin, and then we have to make sure it doesn't interact with the blood clotting system, it doesn't cause blood clots or interfere with blood clots.

And then we have to make it freeze dry, and then you know, we have to make it circulate for a long time.

We have to evade the body system for clearing things that shouldn't be in our blood out of our blood.

And so once we solve all those.

Things, you know, then you know now it's working in an animal model.

And that's why the very first one didn't work because while doctor Pan had already figured out how to get hemoglobin inside the fat droplet, it didn't do any of these other things yet.

So is there a moment when you decide, oh, we should start a company.

Yes, and so we started the company when we had first demonstrated proof of concept that we could create art official red cell.

At that point we have a different task.

So the original academic task was can we design an artificial cell?

Can we prove that it works.

Once we've done that, we now have a development commercial development task, which is can we make it reliably?

Can we make it over and over again?

Can we make a lot of it?

Can we make sure that it passes all the safety and efficacy criteria FDA.

So that task we need a company for.

It's very different than a university task, and that's when we formed Kalasite in.

Order to do those things.

We'll be back in just a minute.

Right that in twenty twenty three, you've got a forty six million dollars DARPA grant we're part of that.

Tell me about that.

That seems like a big moment in the history of this project.

That was the moment.

Yeah, So we had been working on in a reasonably successful way developing the red blood cells, artificial red cells.

But what DARPA wanted.

DARPA wanted everything.

They wanted all the function of blood, so the ability to clot.

So for a soldier, i'd basically, if you need artificial red cells.

It's because you're bleeding.

By definition, If you just replace the red cells and you don't replace the clotting factor, then it's like pouring blood into a sieve.

It just falls back out again.

It's ineffective.

So they realize that we need to be able to replace everything, and to do that at the point of injury, you need freeze tride plasma, you need freeze stride platelets, you need free stride red cells, and it has to be scalable, and you know, there are a lot of logistic concerns.

So what they put out a call for applications for teams to form from the people who are working on each of those components, and everybody had just been working on them separately to come together and form a consortium that would figure out how to make all these different components compatible and equivalent.

To stored blood.

So we built a consortium to do that and we completed effectively to win that award.

What is the status of the would you call it artificial whole blood?

What do you call the whole package?

Unfortunately, we don't have a very sexy name for it yet.

We call it the whole blood analog.

So you know, it's not completely artificial because it's a biologically derived PLASMI.

It's just regular plasma that's been freeze stride.

The platelets are fully synthetic, so they help, you know, form blood clots to stop the bleeding, to stop the bleeding, which is you know, that's why they're getting this material.

And so we sort of have two threads going now, right, there's how is it going on your artificial red blood cells?

And then how is the whole blood analog project going?

So let's just take those in order, like, what is the status of the like, are you testing the artificial red blood cell on its own?

In oh?

Yes, in clinical trials.

Is that part of the plan to do that by itself or do you does it need to be the whole package.

Well, it has to be tested by itself first, and so as a standalone element.

And so we are still in what's called pre clinical testing.

So we're testing in animal models and in parallel we're developing the combined product which will be sequentially administered plasma two, carrier and platelet, and that's also in pre clinical testing.

Two is the red blood cell is the red blood cell, that's right, and plasma and platelet and that is expected that will follow.

So we have to first test each element by itself before we start mixing cocktails.

That's so hard, Like I feel like the way fractional probabilities work.

If a bunch of things have to work separately and there's some you know, the fractions multiply, right, so it gets less and less likely that'll work just probabilistically, right.

But what we have the ability to do is adapt to what we find, and that's what we've had to do.

So we took these components, and of course they didn't automatically work altogether, so we weren't able to just take the red blood cells and the plasma and the platelets and just put them in a blender and get blood.

So we've had to tune.

We're actually now on version four zero point one point two of the starting with version zero of the System of the.

Whole Blood of the whole Blood analog.

Yes, yeah, okay.

And is it right that there are other groups?

Is there a group in Japan working on something similar?

Tell me about that, and tell me about the field more broadly, other similar projects.

Sure.

The other main encapsulated program is in Japan, led by a really successful scientists named Romi Sakai.

He's been working on this for over a decade, developing another's It's.

Essentially the same concept.

It's a liposome with hemoglobin on the inside, a fat droplet, A fat droplet, Yeah right, it's a fat droplet, and it's a little different.

It doesn't have that wetwear system that we talked about.

He's adjusted the auction affinity to be sort of in the middle, so it's pretty good at capturing auction in the lung and pretty good at letting it go and tissue.

It doesn't shift up and down depending on where it is, so it's good enough.

It works and he's already begun to test its safety in humans.

Now it's it's not freeze drive.

It's still in water, and they are not working on combining it with plasma and platelets.

It's just the two carrier.

How do you think it's going that the Japanese version?

Great, They're they're out in front, so they've they've tested in humans and they had some minor issues that I think have been probably been addressed in and it's incredibly exciting.

We're all benefiting from doctor Sakai's leadership.

So to return to your own work and the work of the consortium that you're part of, what's the happy story?

Like how long in the future do you think about and what do you think about when you think about it going well?

Uh So, if you think about it going well, I guess there's a presumption baked into that question.

Mostly I think about, you know, how it's not going to go well?

Okay, Well, how might it not go well?

I mean I guess that one's easier to imagine in some ways, but how might it not go well?

I Mean, what I'm really worried about is the things I can't imagine, So the things we imagine we're constantly trying to think.

Of how it won't go well, and we try.

To anticipate a solution to the problem and fix it.

The things that we can't plan for, of course, are the things that we don't yet understand.

The drums felled in unknowns.

Yeah you beat me to it.

Yeah yeah, so and that happens monthly, where it's like, uh, oh, we didn't think of that.

Now we have to solve a new problem because we're off the map, you know, we don't really nobody's been.

Here before, so we have to figure those things out.

Does it seem impossibly hard?

Like, frankly, this one, this project just seems so hard, right, It is hard.

If it were easy, it'd be done already.

But the wonderful thing is that I think that we have all the tools that we need to solve the problem.

So the advances in synthetic chemistry are impossible to overstate.

The advances in nanomedicine and nanofabrication are allowing us to respond in very quick ways.

The ability to use machine learning and artificial intelligence to improve our design is reducing the need to do thousands and thousands of experiments, so we can use the computers to tell us the likely things to work, and it reduces the empiric burden.

And we've got great resources because the NIH and Department of Defense DARPA put a lot of resources in our hands.

So we're very fortunate that we can very quickly respond to the problems that we encounter.

So it works very effectively in the models that we have.

But now we also have to make this scale.

So that's another huge challenge.

So we have to go from making what you might call craft beer to Budweiser.

And just to be clear, it's made from real blood, right, Like the humoglobin in your lipid nanoparticles is hemoglobin from people, right, It's not synthesized.

So that is a scale challenge right there, Right, that's impossible.

Right, So we can't synthesize hemoglobin from amino acids.

That is beyond our current capability, but we can program other organisms to make it for.

Us, like yeast.

Ideally yeast right put it in a fact is that the yeah, we're going to brew it.

So we have a Yeast project where we are training yeast to make human hemoglobin and to secrete it, and that will eventually be our source.

So okay, So take thirty seconds off of thinking about all the things that can go wrong and that you have to figure out, and just tell me if some you or the people who come after you even respectfully figure out how to do all the things you're trying to do, what will it look like?

What will it look like?

Right?

Well, we actually believe it or not have done that.

We have a prototype of the delivery system.

We've been simultaneously trying to work with the people who would be using it so that we don't end up with an end product.

And they say, but did you think about X?

And we just like, uh, So.

A person gets in a car accident or a soldier gets shot on the battlefield, what happens in this future where the thing you're working on works.

So what they'll have is a kit, and in the kit will be three components, the two carrier, the plasma, and the platelet.

All of them will be dry powders.

Okay, So the instructions that we got from the Department of Defense were it has to work in the dark, in a ditch, under fire, and it has to be usable by somebody who has basically known medical training.

So that's basically you know, not a sophisticated nurse or a scientist.

Basically, they want you to make instant coffee, but for blood.

But for blood, but also it's instant coffee.

It's too complicated.

You've got to heat the water, you've got to dispense it from a jar into a cup.

And pour the water.

You can't do any of that.

So what we have is a system that has a split bag with a dry side and a wet side and something called a weak weld.

So when it's folded over, you can stand on it and it won't open.

But when you unfold it, you squeeze it and it pops and the water migrates from one side to the other and hydrates the dry material, and then it slashes around in there for about a minute, and then you hang it and you can use it just like a unit of blood.

Right, you hang it like a like a ba that goes into your arm on an.

Iterate, And there's one like that for the plasma and the platelet's a little different because it's a much smaller volume.

That eventually will be what's called an autoinjector.

Everybody's seen EpiPens, so it'll be like an EpiPen.

Now there's an additional problem.

Damn yes, there's two other problems really.

So one is for it to be shelf stable, it can't interact with oxygen in the air.

So water and iron and oxygen equals rust.

Yeah, when you think about hemoglobin, it seems like rust, right, hemoglobin.

It's iron in the hemoglobin that is binding to the oxygen.

Right, And I'm like, wait, is hemoglobin just rusting all the time?

In my blood?

Is going?

In fact, right now your hemoglobin is rusting about ten percent of it is rusting constantly.

But you have a rust remover inside your red blood cells.

That is, every time it goes around, there's a little molecule in there that's scrubbing the rust and demolishing the polishing the iron.

So we have to we have to prevent that from happening during storage.

And to do that, we have to have a plastic soft plastic, but that has glass like properties, so it doesn't allow water or oxygen through it.

And so that's a very.

Novel film that we are applying for the first time to blood storage.

The other problem is it can't be cold.

So I don't know if you've ever tried to hydrate freez strike coffee with tapwater, it just makes clumps.

It doesn't it doesn't hydrate, so we actually have to warm it.

So we have to.

Build a heater into the bag system.

So this is another layer of plastic that has a little circuit inside, and the circuit, when you turn it on, it will warm the liquid and then it will turn color and then the medic will know, okay, I can squeeze it.

And all the medic has to do is tear it open, unfold the bag, wait for it to change color, squeeze it, slash it a bit, and then hang it.

And that's the way it will work.

That's the user manual version of how it will work.

What's the like thirty thousand foot version of like just at a macro level, somebody who didn't know what was going on, Like what would they see and how would the world be different if this works?

Well, first of all, every soldier would carry this in their cargo pants, so they would have their own blood instead of a blood tag that like now it just says i'm typo, I'm type whatever.

They actually have what they need in their pants, so if they go down, a medic can come up, take it out, and you know, put it, you know, start resustinating somebody.

It will be in every ambulance so that if somebody goes to the scene of an accident somebody's bleeding, they'll be able to give them blood right away, just like they can of oxygen or CPR.

It will be stored in depots for mass casualty incidents.

So many people don't know at the say, for example, at the Boston Marathon bombing, they actually were running out of blood there, and unfortunately those incidents haven't stopped.

So there will be depots around the country where there's warehouse shell stable blood.

It will be on cruise ships.

It will be in resource limited countries like sub Saharan Africa.

It will be on the space station.

It will be on the mission to Mars.

It will be wherever it's hard to get blood.

We'll be back in a minute with the lightning round.

Okay, lightning round.

What's your second favorite type of blood cell?

Nice as opposed to red blood I'm assuming I'm presuming that red blood cells are your favorite, right, Yeah, the juvenile red blood cells, the red cell, the cells that make red blood cells.

Okay, third favorite, third favorite?

Yeah, sorry, well i'd say platelets are pretty important and they're far more complicated than red blood cells.

But no platelets and we just bleed to death.

So plate is very important and fascinating the whole.

Like clotting cascade things seems wild, right because you want the blood to clot when it needs to clot, but you really don't want it to clot when it's not supposed to clot, right, Like, that's such a high stakes equilibrium.

It's an amazing system and amazing that it works when it does.

But yes, clotting system is incredible and very very complicated.

What's one thing you wish we understood about blood that is still a mystery why we have to keep remaking it?

So the you know, we have to renew red blood cells every three months.

They don't last very long.

We live with the neurons that we started with as a baby, but the red cells you had in the spring, they're all gone, Every last one of them is gone.

So you turn over all of your red blood cells.

And it's incredible that we actually do that because it's a huge part of our quote budget in terms of energy and nutrition.

It would be a huge evolutionary advantage in a world of scarce food, presumably, so there must be some reason that it doesn't work, right, Yeah, but we don't know.

What's one common misconception that lay people have about blood that it's not alive.

It's as alive as your brain.

People forget your blood is a living tissue.

Is just a liquid organ, and it's alive, and it's constantly doing things.

It's very very sensitive.

It responds perfectly to you know, when you need to increase oxygen delivery or reduce it.

It can clot, it can fight infection.

It has a lot of functions.

And people just think, well, it's just you know, like motor oil.

But it's it's very sophisticated.

What's your view on nominative determinism?

Nominative determinatism?

So are we what we call ourselves?

Is that?

Yes, I'm frankly surprised that you have not heard that phrase.

I'll be honest with you.

Yeah.

So my last name, so, I fought it for a long time.

In fact, wanted to become a marine biologist.

I Jacques Cousteau was my idol when I was growing up, and but you know, I succumbed and went to medical school.

I'm actually quite happy that I did.

Doctor Alan Doctor is a professor of pediatrics and bioengineering at the University of Maryland and he's the co founder and chief scientific officer of Kalosite.

Please email us at problem at pushkin dot fm.

We are always looking for new guests for the show.

Today's show was produced by Trinomanino and Gabriel Hunter Chang.

It was edited by Alexander Garretson and engineered by Sarah Brugueir.

I'm Jacob Goldstein and we'll be back next week with another episode of What's Your Problem.