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Reinventing Blood · What's Your Problem?

• 0:15
  Speaker 1: Pushkin. Every year, sixty thousand people in the United States
• 0:23
  Speaker 1: and two million people around the world die because of
• 0:27
  Speaker 1: blood loss. They get in a car accident, or they
• 0:31
  Speaker 1: get shot and they bleed to death. These people tend
• 0:35
  Speaker 1: to be relatively young and healthy, and a lot of
• 0:38
  Speaker 1: them could be saved if they were quickly given blood.
• 0:41
  Speaker 1: But outside the body, blood doesn't travel well. It's bulky.
• 0:46
  Speaker 1: You have to keep it cold, and as a result,
• 0:48
  Speaker 1: it's hard to get blood to patience when they urgently
• 0:52
  Speaker 1: need it. Ambulances don't tend to carry it. Field medics
• 0:56
  Speaker 1: don't typically have it in combat, and so there's long
• 0:59
  Speaker 1: been this dream. What if we could come up with
• 1:02
  Speaker 1: a way to make blood easier to store and transport.
• 1:07
  Speaker 1: What if we could have blood ready to go every
• 1:09
  Speaker 1: time an ambulance gets to a car accident and a
• 1:12
  Speaker 1: medic gets to a wounded soldier. If we could do that,
• 1:16
  Speaker 1: we could save millions of lives. I'm Jacob Goldstein and
• 1:25
  Speaker 1: this is What's Your Problem, the show where I talk
• 1:27
  Speaker 1: to people who are trying to make technological progress. My
• 1:31
  Speaker 1: guest today is Alan Doctor. He's the co founder and
• 1:34
  Speaker 1: chief scientific officer at Kalasite. Alan's problem is this, can
• 1:39
  Speaker 1: you make something like freeze dried blood that can be
• 1:43
  Speaker 1: rehydrated and given to patients when and where they need it.
• 1:47
  Speaker 1: Alan didn't start out wanting to found a company. He
• 1:50
  Speaker 1: was a doctor taking care of kids in the hospital.
• 1:53
  Speaker 2: So the type of medicine I do is intensive care
• 1:55
  Speaker 2: of medicine. So this is and for children, looking after
• 2:00
  Speaker 2: children in the hospital who have severe infections or major
• 2:04
  Speaker 2: injuries and they're critically ill, and most of them are
• 2:08
  Speaker 2: in something a condition we call shock. And the problem
• 2:12
  Speaker 2: with shock is that you're not effectively getting blood and
• 2:17
  Speaker 2: oxygen where it's needed. Okay, so people get sick and die.
• 2:22
  Speaker 2: Even though we fix the underlying problem, so we can
• 2:25
  Speaker 2: cure the infection, we repair the hole in the blood vessel,
• 2:30
  Speaker 2: and people still we lose them because their circulatory system
• 2:34
  Speaker 2: is failing.
• 2:35
  Speaker 1: You know.
• 2:36
  Speaker 2: That was frustrating, and I was interested in that problem
• 2:38
  Speaker 2: and I was trying to understand why that happened. And
• 2:41
  Speaker 2: what we were able to learn is there's a traffic
• 2:45
  Speaker 2: control system in our circulatory system that routes blood where
• 2:50
  Speaker 2: it needs to go, and red blood cells are the
• 2:54
  Speaker 2: traffic lights, so they turn green and they open up
• 2:59
  Speaker 2: the blood vessels or they turn red and close them,
• 3:01
  Speaker 2: and it's very coordinated. It's a very exquisitely tuned system.
• 3:07
  Speaker 2: And I was studying that, huh, that's governed by the
• 3:11
  Speaker 2: way hemoglobin interacts with other chemicals in our blood stream.
• 3:17
  Speaker 2: And it turns out it's highly relevant for shock and
• 3:20
  Speaker 2: fixing shock. But it turns out it's also relevant for transfusion.
• 3:25
  Speaker 2: And that's when this story started.
• 3:27
  Speaker 1: So you're studying red blood cells and hemoglobin, which are
• 3:31
  Speaker 1: obviously hemoglobin are the molecules that transport oxygen, right, that
• 3:35
  Speaker 1: do that key function of blood. That is the thing
• 3:40
  Speaker 1: in particular that you want to replace when somebody gets
• 3:43
  Speaker 1: shot or gets in a car accident. Right, of all
• 3:45
  Speaker 1: the things in your blood, the thing you need urgently
• 3:47
  Speaker 1: that minute is hemoglobin to deliver the oxygen right. Right.
• 3:51
  Speaker 1: People had known that part for a long time and
• 3:53
  Speaker 1: had tried to develop blood substitutes in particular to solve
• 3:58
  Speaker 1: this acute kind of trauma setting problem. But it had
• 4:01
  Speaker 1: gone badly right, So tell me about the history up
• 4:05
  Speaker 1: until that point of people trying to come up with
• 4:09
  Speaker 1: ways to you know, get hemoglobin to people in emergencies,
• 4:12
  Speaker 1: do sort of hemoglobin replacements.
• 4:15
  Speaker 2: Well, they did the first obvious thing. So the problem
• 4:18
  Speaker 2: is you have to make the bloodshelf stable in order
• 4:21
  Speaker 2: to use it outside of hospitals, So you have to
• 4:25
  Speaker 2: get rid of the cold chain. The reason we need
• 4:29
  Speaker 2: the cold chain is the hemoglobin's inside a red blood cell.
• 4:32
  Speaker 2: The red blood cell's alive, and it needs glucose, it
• 4:37
  Speaker 2: needs all kinds of things, and it has to be
• 4:40
  Speaker 2: kept colder. It goes bad, sort of like the way
• 4:43
  Speaker 2: milk has to be kept colder. It goes bad, and
• 4:46
  Speaker 2: you can't leave it outside the fridge too long or
• 4:49
  Speaker 2: you can't drink it.
• 4:50
  Speaker 1: The same thing with blood.
• 4:52
  Speaker 2: So they say, okay, if we just take the hemoglobin
• 4:55
  Speaker 2: out of the red cell, will it still capture and
• 4:58
  Speaker 2: release oxygen?
• 4:59
  Speaker 1: Yes, okay it will. So far, so good, So far,
• 5:02
  Speaker 1: so good.
• 5:03
  Speaker 2: Does it need to be kept cold in order to work, No,
• 5:08
  Speaker 2: it doesn't, So it's shelf stable. Doesn't work if we
• 5:13
  Speaker 2: put it inside animals. Pretty much it does, and so
• 5:18
  Speaker 2: everybody's like, okay, let's try this.
• 5:20
  Speaker 1: Yeah.
• 5:21
  Speaker 2: And it was a catastrophe, so it wasn't just ineffective.
• 5:25
  Speaker 2: It was harmful, so it was more harmful than the controls.
• 5:29
  Speaker 2: So it caused heart attacks and strokes and death in
• 5:33
  Speaker 2: the people that got the blood.
• 5:34
  Speaker 1: Why is it bad to give people hemoglobin? That is
• 5:37
  Speaker 1: a surprising outcome, right, It's not like it's some novel molecule.
• 5:42
  Speaker 1: It's our bodies are full of hemoglobin, all right.
• 5:44
  Speaker 2: So what it meant was we didn't understand something. It
• 5:47
  Speaker 2: turns out hemoglobin does more than just interact with oxygen.
• 5:52
  Speaker 2: It interacts with other chemicals in the blood stream. So
• 5:57
  Speaker 2: the hemoglobin has to be sheathed inside a membrane, and
• 6:00
  Speaker 2: it sequesters the hemoglobin from everything else in the blood stream,
• 6:05
  Speaker 2: from the blood vessels, the cells that line the blood vessel,
• 6:08
  Speaker 2: from the chemicals in the bloodstream where it won't do
• 6:13
  Speaker 2: things it's not supposed to do. And it turns out
• 6:17
  Speaker 2: that when hemoglobin is free in the bloodstream, the blood
• 6:20
  Speaker 2: vessels don't know whether they're to open or close, and
• 6:23
  Speaker 2: what they end up doing is mostly closing.
• 6:25
  Speaker 1: Uh huh. So that's why people who got just naked
• 6:29
  Speaker 1: hemoglobin had heart attacks. Basically exactly, yeah, exactly, got it.
• 6:33
  Speaker 1: So okay, So this is the context, right, So clear
• 6:37
  Speaker 1: bad idea to just give people hemoglobin. Alas well, it
• 6:41
  Speaker 1: was a good idea. It seemed like a good idea,
• 6:43
  Speaker 1: but it became clear that it had been a bad idea.
• 6:45
  Speaker 1: It's scary in fact, right, it scary like so many
• 6:48
  Speaker 1: things we've all done. Yeah, yeah, no, no, no shade
• 6:51
  Speaker 1: on the people who tried it. It's just a it's
• 6:54
  Speaker 1: a terrible outcome that nobody would have wanted. So you meanwhile,
• 6:58
  Speaker 1: are studying hemoglobin and then a chemical engineer comes to
• 7:04
  Speaker 1: you with an idea, Right, tell me about that. Twenty
• 7:07
  Speaker 1: ten what happened?
• 7:07
  Speaker 2: Yeah, I'm just studying regular red blood cells and this
• 7:12
  Speaker 2: routing problem, right, which I understood. That's why you know
• 7:16
  Speaker 2: a lot of these blood substitutes, what we call the
• 7:19
  Speaker 2: unencapsulated hemoglobins failed. People started to understand that, but I
• 7:24
  Speaker 2: wasn't thinking like, oh, I know how to solve that problem.
• 7:26
  Speaker 2: I was minding my own business doing something completely different.
• 7:30
  Speaker 2: The chemical engineer, the bioengineer was making special particles, nanoparticles
• 7:37
  Speaker 2: for imaging. So there's a new form of medicines and
• 7:42
  Speaker 2: therapies where you make little fat droplets and you can
• 7:47
  Speaker 2: decorate them with all kinds of molecules that either home
• 7:52
  Speaker 2: to different parts of your body, and you can see
• 7:54
  Speaker 2: them on X ray. You can put drugs inside, you
• 7:56
  Speaker 2: can do all kinds of things with them.
• 7:58
  Speaker 1: Well, just to be clear, these fat droplets, as you're
• 8:00
  Speaker 1: describing them, like, they were the technology used to encapsulate
• 8:05
  Speaker 1: the COVID vaccines, right, that's RNA covid vaccines were in
• 8:10
  Speaker 1: what lipid NAO particle is? That is the jargon, right,
• 8:12
  Speaker 1: although I like exactly I appreciate that.
• 8:14
  Speaker 2: Yeah, so yeah, liposomas was used for or a fat
• 8:18
  Speaker 2: droplet was used for the covid vaccine, and it's used
• 8:21
  Speaker 2: for other things too. So what doctor pan Depongen Pans
• 8:26
  Speaker 2: a brilliant chemical engineer. So he was making particles so
• 8:32
  Speaker 2: that you could see specific things. So you want to
• 8:36
  Speaker 2: be able to see breast cancer, You want to be
• 8:38
  Speaker 2: able to see a blood clot. You want to see,
• 8:41
  Speaker 2: you know, a particular type of cell. Then you put
• 8:43
  Speaker 2: something on a fat droplet that finds that cell, and
• 8:47
  Speaker 2: you put a little metal in the droplet that you
• 8:50
  Speaker 2: can see with a special CT scan and then say
• 8:55
  Speaker 2: suddenly I see very small and tiny, hard to detect
• 8:59
  Speaker 2: cancers and so on. So he was making these particles,
• 9:03
  Speaker 2: and he was doing them in a way he wanted
• 9:05
  Speaker 2: to make a lot of surface area, and he ended
• 9:08
  Speaker 2: up making particle that looked like red blood.
• 9:11
  Speaker 1: Cells just by happenstance. He just looked at it one
• 9:14
  Speaker 1: and said, hey, I know what that looks like a
• 9:17
  Speaker 1: red blood cell.
• 9:18
  Speaker 2: So red blood cells are also trying to have a
• 9:21
  Speaker 2: lot of surface area because they exchange gas, and he
• 9:24
  Speaker 2: was trying to create a lot of surface area for
• 9:26
  Speaker 2: a different reason, so he could decorate the particles with
• 9:30
  Speaker 2: these proteins, and then you get.
• 9:32
  Speaker 1: Red blood cells, said trying to think of what they
• 9:34
  Speaker 1: look like, and I thought of bali, which is kind
• 9:36
  Speaker 1: of a niche a niche analogy, right, like a bagel,
• 9:41
  Speaker 1: but with a thin doe part in where the hole
• 9:43
  Speaker 1: would be. Do you have a go to description of
• 9:45
  Speaker 1: a red blood cell? That's what we used.
• 9:47
  Speaker 2: They're called Nanobiali's no kidding, yes, or the other word
• 9:52
  Speaker 2: people say a biconcave disc Yeah.
• 9:55
  Speaker 1: That's less or less? Uh that's cool? Yes, okay, So
• 9:59
  Speaker 1: does he come to you with this, right, So what
• 10:03
  Speaker 1: happens He's like, Oh, that looks like a red blood cell.
• 10:05
  Speaker 1: What does he do?
• 10:06
  Speaker 2: So he thought, Hey, I want wonder if I could
• 10:09
  Speaker 2: put hemoglobin inside. And he was loosely familiar with the
• 10:14
  Speaker 2: problems with auction carriers and he says, I wonder if
• 10:18
  Speaker 2: I could just put hemoglobin inside, and he figured out
• 10:22
  Speaker 2: how to do that, and then he's like, I don't
• 10:25
  Speaker 2: know how to tell if this works or not. So so
• 10:28
  Speaker 2: we're both at wash YOU and wash You has this
• 10:31
  Speaker 2: collaboration website where you can google or it's.
• 10:34
  Speaker 1: Like googling, but it's just at WashU the university. Interesting
• 10:38
  Speaker 1: like an internal like an engine.
• 10:40
  Speaker 2: Yeah, so he searched red blood cell physiology and I
• 10:46
  Speaker 2: popped up. And so he called me and told me
• 10:49
  Speaker 2: the story and said, you know, why don't you come
• 10:52
  Speaker 2: over to my lab and and I'd like to show
• 10:55
  Speaker 2: you what we're doing and see if this works, and maybe.
• 10:58
  Speaker 1: We could figure out how to collaborate. Well it didn't work, huh,
• 11:03
  Speaker 1: But but wait, what do you mean it didn't work?
• 11:05
  Speaker 1: I was all ready for a to work.
• 11:07
  Speaker 2: What didn't Well, it's a little more to it than
• 11:11
  Speaker 2: just putting hemoglobein inside a fat droplet. So what I
• 11:15
  Speaker 2: realized is conceptually this would solve the problem that the
• 11:21
  Speaker 2: unencapsulated hemoglobins were plagued by this were like little red
• 11:26
  Speaker 2: blood cells. And if we could figure out the chemistry
• 11:29
  Speaker 2: to make this capture and release oxygen that maybe this
• 11:33
  Speaker 2: would you know, make things safe and and you can
• 11:36
  Speaker 2: freeze dry these things so they could be you know,
• 11:40
  Speaker 2: shelf stable and very lightweight.
• 11:42
  Speaker 1: So it's like instant coffee, but for red blood cells.
• 11:46
  Speaker 1: That's the dream. Yeah, yeah, exactly. So initially it doesn't work,
• 11:51
  Speaker 1: but you realize that the idea is fundamentally plausible. So
• 11:56
  Speaker 1: like one of the things you have to sort of
• 12:00
  Speaker 1: figure out make work for this.
• 12:02
  Speaker 2: Torque a number of things from the inside out.
• 12:07
  Speaker 1: OK.
• 12:07
  Speaker 2: So, first of all, you've got a droplet that has
• 12:11
  Speaker 2: hemoglobin inside it. Hemoglobin the reason red blood cells work.
• 12:16
  Speaker 2: There are a lot more than just bags of hemoglobin.
• 12:19
  Speaker 2: They have lots of other functions. And so we had
• 12:24
  Speaker 2: to decide what are we going to keep and what
• 12:27
  Speaker 2: do we get rid of?
• 12:28
  Speaker 1: Huh, Because you can't build the whole red blood cell.
• 12:30
  Speaker 1: We don't know how to do that. It's nice. You
• 12:33
  Speaker 1: want to do as little as you can get away with.
• 12:35
  Speaker 2: Right, right, You want the stripped down yeah, basic thing,
• 12:40
  Speaker 2: and so it just has to transport oxygen and then
• 12:44
  Speaker 2: it has to not do a bunch of other things.
• 12:46
  Speaker 1: Yeah, we don't want it to cause trouble either. Well
• 12:49
  Speaker 1: and subtly suddenly when you say transport oxygen. It has
• 12:52
  Speaker 1: to know when to pick up oxygen from the lungs
• 12:55
  Speaker 1: and has to know when to release oxygen to whatever
• 12:58
  Speaker 1: tissue needs it. Right, Like that part seems hard from
• 13:02
  Speaker 1: the outside, right, Well they're opposites. Yeah, yeah, and it
• 13:06
  Speaker 1: has to do it at the right time, right, it
• 13:08
  Speaker 1: has to do in the yes, at the right speed.
• 13:12
  Speaker 2: So yeah, it's all very finely tuned inside our body.
• 13:16
  Speaker 2: So we had to try to imitate the behavior of
• 13:19
  Speaker 2: a real red cell, and the real red cell has
• 13:24
  Speaker 2: people understand like, Okay, there are these other molecules inside
• 13:28
  Speaker 2: red cells that modify the way the hemoglobin interacts with
• 13:32
  Speaker 2: aucygen that causes it to capture oxygen effectively in the
• 13:37
  Speaker 2: lung and then let go when it gets out in
• 13:40
  Speaker 2: tissue and the red cells responding. Red cell doesn't know,
• 13:44
  Speaker 2: oh I'm in the lung, Oh I'm in the lip,
• 13:47
  Speaker 2: I'm in the muscle. So it's looking for cues. So
• 13:55
  Speaker 2: it doesn't have a map, but it can almost smell
• 13:58
  Speaker 2: where it is because of the chemicals that are different
• 14:01
  Speaker 2: in the lung.
• 14:02
  Speaker 1: Than in exercising muscle.
• 14:04
  Speaker 2: And it's primarily responding to the amount of acid and
• 14:08
  Speaker 2: the amount of carbon oxide that's in the blood. And
• 14:12
  Speaker 2: so what we did is we created responsive elements that
• 14:18
  Speaker 2: would work like red cells, but in a different way,
• 14:22
  Speaker 2: so that they would change their shape or change their
• 14:27
  Speaker 2: ability to interact with other molecules in response to those
• 14:31
  Speaker 2: two signals carbon dioxide and acid. So then the artificial
• 14:37
  Speaker 2: red cell quote knows it's in the lung or knows
• 14:40
  Speaker 2: it's in the muscle. So we call that wetwear. So
• 14:44
  Speaker 2: it's like a thousand little thermostats inside each little particle,
• 14:51
  Speaker 2: and it's telling the hemoglobin what to do.
• 14:53
  Speaker 1: I'm sure there are a lot of hard parts, but
• 14:55
  Speaker 1: that sounds like the hard part.
• 14:57
  Speaker 2: Well that was, Yeah, that was one of the hard right.
• 15:00
  Speaker 2: Then we have to make it silent to the immune
• 15:03
  Speaker 2: system so our body doesn't recognize it. We have to
• 15:08
  Speaker 2: make sure that it doesn't alter the viscosity of blood
• 15:12
  Speaker 2: so it doesn't get too thick or too thin, and
• 15:15
  Speaker 2: then we have to make sure it doesn't interact with
• 15:17
  Speaker 2: the blood clotting system, it doesn't cause blood clots or
• 15:21
  Speaker 2: interfere with blood clots. And then we have to make
• 15:24
  Speaker 2: it freeze dry, and then you know, we have to
• 15:29
  Speaker 2: make it circulate for a long time. We have to
• 15:33
  Speaker 2: evade the body system for clearing things that shouldn't be
• 15:37
  Speaker 2: in our blood out of our blood.
• 15:38
  Speaker 1: And so once we solve all those.
• 15:40
  Speaker 2: Things, you know, then you know now it's working in
• 15:43
  Speaker 2: an animal model. And that's why the very first one
• 15:46
  Speaker 2: didn't work because while doctor Pan had already figured out
• 15:50
  Speaker 2: how to get hemoglobin inside the fat droplet, it didn't
• 15:53
  Speaker 2: do any of these other things yet.
• 15:55
  Speaker 1: So is there a moment when you decide, oh, we
• 15:58
  Speaker 1: should start a company.
• 15:59
  Speaker 2: Yes, and so we started the company when we had
• 16:03
  Speaker 2: first demonstrated proof of concept that we could create art
• 16:09
  Speaker 2: official red cell. At that point we have a different task.
• 16:12
  Speaker 2: So the original academic task was can we design an
• 16:18
  Speaker 2: artificial cell? Can we prove that it works. Once we've
• 16:22
  Speaker 2: done that, we now have a development commercial development task,
• 16:27
  Speaker 2: which is can we make it reliably? Can we make
• 16:30
  Speaker 2: it over and over again? Can we make a lot
• 16:32
  Speaker 2: of it? Can we make sure that it passes all
• 16:36
  Speaker 2: the safety and efficacy criteria FDA.
• 16:40
  Speaker 1: So that task we need a company for.
• 16:42
  Speaker 2: It's very different than a university task, and that's when
• 16:45
  Speaker 2: we formed Kalasite in.
• 16:46
  Speaker 1: Order to do those things. We'll be back in just
• 16:53
  Speaker 1: a minute. Right that in twenty twenty three, you've got
• 17:07
  Speaker 1: a forty six million dollars DARPA grant we're part of that.
• 17:11
  Speaker 1: Tell me about that. That seems like a big moment
• 17:13
  Speaker 1: in the history of this project. That was the moment. Yeah,
• 17:19
  Speaker 1: So we had been working on in a reasonably successful
• 17:22
  Speaker 1: way developing the red blood cells, artificial red cells.
• 17:26
  Speaker 2: But what DARPA wanted. DARPA wanted everything. They wanted all
• 17:31
  Speaker 2: the function of blood, so the ability to clot. So
• 17:36
  Speaker 2: for a soldier, i'd basically, if you need artificial red cells.
• 17:41
  Speaker 1: It's because you're bleeding.
• 17:42
  Speaker 2: By definition, If you just replace the red cells and
• 17:47
  Speaker 2: you don't replace the clotting factor, then it's like pouring
• 17:53
  Speaker 2: blood into a sieve. It just falls back out again.
• 17:57
  Speaker 2: It's ineffective. So they realize that we need to be
• 18:00
  Speaker 2: able to replace everything, and to do that at the
• 18:04
  Speaker 2: point of injury, you need freeze tride plasma, you need
• 18:07
  Speaker 2: freeze stride platelets, you need free stride red cells, and
• 18:11
  Speaker 2: it has to be scalable, and you know, there are
• 18:13
  Speaker 2: a lot of logistic concerns. So what they put out
• 18:16
  Speaker 2: a call for applications for teams to form from the
• 18:22
  Speaker 2: people who are working on each of those components, and
• 18:25
  Speaker 2: everybody had just been working on them separately to come
• 18:28
  Speaker 2: together and form a consortium that would figure out how
• 18:32
  Speaker 2: to make all these different components compatible and equivalent.
• 18:37
  Speaker 1: To stored blood. So we built a consortium to do
• 18:41
  Speaker 1: that and we completed effectively to win that award. What
• 18:45
  Speaker 1: is the status of the would you call it artificial
• 18:48
  Speaker 1: whole blood? What do you call the whole package?
• 18:50
  Speaker 2: Unfortunately, we don't have a very sexy name for it yet.
• 18:53
  Speaker 2: We call it the whole blood analog. So you know,
• 18:56
  Speaker 2: it's not completely artificial because it's a biologically derived PLASMI.
• 19:01
  Speaker 2: It's just regular plasma that's been freeze stride. The platelets
• 19:05
  Speaker 2: are fully synthetic, so they help, you know, form blood
• 19:09
  Speaker 2: clots to stop the bleeding, to stop the bleeding, which
• 19:12
  Speaker 2: is you know, that's why they're getting this material.
• 19:16
  Speaker 1: And so we sort of have two threads going now, right,
• 19:19
  Speaker 1: there's how is it going on your artificial red blood cells?
• 19:22
  Speaker 1: And then how is the whole blood analog project going?
• 19:25
  Speaker 1: So let's just take those in order, like, what is
• 19:27
  Speaker 1: the status of the like, are you testing the artificial
• 19:30
  Speaker 1: red blood cell on its own? In oh? Yes, in
• 19:33
  Speaker 1: clinical trials. Is that part of the plan to do
• 19:35
  Speaker 1: that by itself or do you does it need to
• 19:37
  Speaker 1: be the whole package.
• 19:39
  Speaker 2: Well, it has to be tested by itself first, and
• 19:43
  Speaker 2: so as a standalone element. And so we are still
• 19:48
  Speaker 2: in what's called pre clinical testing. So we're testing in
• 19:52
  Speaker 2: animal models and in parallel we're developing the combined product
• 19:59
  Speaker 2: which will be sequentially administered plasma two, carrier and platelet,
• 20:06
  Speaker 2: and that's also in pre clinical testing.
• 20:08
  Speaker 1: Two is the red blood cell is the red blood cell,
• 20:11
  Speaker 1: that's right, and plasma and platelet and that is expected
• 20:16
  Speaker 1: that will follow. So we have to first test each
• 20:19
  Speaker 1: element by itself before we start mixing cocktails. That's so hard,
• 20:25
  Speaker 1: Like I feel like the way fractional probabilities work. If
• 20:28
  Speaker 1: a bunch of things have to work separately and there's
• 20:31
  Speaker 1: some you know, the fractions multiply, right, so it gets
• 20:35
  Speaker 1: less and less likely that'll work just probabilistically, right. But
• 20:39
  Speaker 1: what we have the ability to do is adapt to
• 20:42
  Speaker 1: what we find, and that's what we've had to do.
• 20:45
  Speaker 1: So we took these components, and of course they didn't
• 20:48
  Speaker 1: automatically work altogether, so we weren't able to just take
• 20:51
  Speaker 1: the red blood cells and the plasma and the platelets
• 20:54
  Speaker 1: and just put them in a blender and get blood.
• 20:57
  Speaker 2: So we've had to tune. We're actually now on version
• 21:01
  Speaker 2: four zero point one point two of the starting with
• 21:04
  Speaker 2: version zero of the System of the.
• 21:08
  Speaker 1: Whole Blood of the whole Blood analog. Yes, yeah, okay.
• 21:12
  Speaker 1: And is it right that there are other groups? Is
• 21:14
  Speaker 1: there a group in Japan working on something similar? Tell
• 21:17
  Speaker 1: me about that, and tell me about the field more broadly,
• 21:19
  Speaker 1: other similar projects. Sure.
• 21:21
  Speaker 2: The other main encapsulated program is in Japan, led by
• 21:29
  Speaker 2: a really successful scientists named Romi Sakai.
• 21:34
  Speaker 1: He's been working on this for over a decade, developing
• 21:38
  Speaker 1: another's It's.
• 21:41
  Speaker 2: Essentially the same concept. It's a liposome with hemoglobin on
• 21:46
  Speaker 2: the inside, a fat droplet, A fat droplet, Yeah right,
• 21:49
  Speaker 2: it's a fat droplet, and it's a little different. It
• 21:52
  Speaker 2: doesn't have that wetwear system that we talked about. He's
• 21:57
  Speaker 2: adjusted the auction affinity to be sort of in the middle,
• 22:01
  Speaker 2: so it's pretty good at capturing auction in the lung
• 22:04
  Speaker 2: and pretty good at letting it go and tissue. It
• 22:07
  Speaker 2: doesn't shift up and down depending on where it is,
• 22:10
  Speaker 2: so it's good enough. It works and he's already begun
• 22:14
  Speaker 2: to test its safety in humans. Now it's it's not
• 22:17
  Speaker 2: freeze drive. It's still in water, and they are not
• 22:22
  Speaker 2: working on combining it with plasma and platelets.
• 22:25
  Speaker 1: It's just the two carrier. How do you think it's
• 22:28
  Speaker 1: going that the Japanese version?
• 22:30
  Speaker 2: Great, They're they're out in front, so they've they've tested
• 22:34
  Speaker 2: in humans and they had some minor issues that I
• 22:37
  Speaker 2: think have been probably been addressed in and it's incredibly exciting.
• 22:42
  Speaker 2: We're all benefiting from doctor Sakai's leadership.
• 22:45
  Speaker 1: So to return to your own work and the work
• 22:48
  Speaker 1: of the consortium that you're part of, what's the happy story?
• 22:51
  Speaker 1: Like how long in the future do you think about
• 22:54
  Speaker 1: and what do you think about when you think about
• 22:55
  Speaker 1: it going well? Uh So, if you think about it
• 23:02
  Speaker 1: going well, I guess there's a presumption baked into that question.
• 23:05
  Speaker 1: Mostly I think about, you know, how it's not going
• 23:07
  Speaker 1: to go well? Okay, Well, how might it not go well?
• 23:10
  Speaker 1: I mean I guess that one's easier to imagine in
• 23:12
  Speaker 1: some ways, but how might it not go well?
• 23:14
  Speaker 2: I Mean, what I'm really worried about is the things
• 23:17
  Speaker 2: I can't imagine, So the things we imagine we're constantly
• 23:20
  Speaker 2: trying to think.
• 23:21
  Speaker 1: Of how it won't go well, and we try.
• 23:22
  Speaker 2: To anticipate a solution to the problem and fix it.
• 23:26
  Speaker 2: The things that we can't plan for, of course, are
• 23:29
  Speaker 2: the things that we don't yet understand.
• 23:31
  Speaker 1: The drums felled in unknowns. Yeah you beat me to it.
• 23:35
  Speaker 2: Yeah yeah, so and that happens monthly, where it's like, uh, oh,
• 23:40
  Speaker 2: we didn't think of that. Now we have to solve
• 23:43
  Speaker 2: a new problem because we're off the map, you know,
• 23:46
  Speaker 2: we don't really nobody's been.
• 23:48
  Speaker 1: Here before, so we have to figure those things out.
• 23:52
  Speaker 1: Does it seem impossibly hard? Like, frankly, this one, this
• 23:56
  Speaker 1: project just seems so hard, right, It is hard. If
• 24:01
  Speaker 1: it were easy, it'd be done already.
• 24:03
  Speaker 2: But the wonderful thing is that I think that we
• 24:06
  Speaker 2: have all the tools that we need to solve the problem.
• 24:09
  Speaker 2: So the advances in synthetic chemistry are impossible to overstate.
• 24:15
  Speaker 2: The advances in nanomedicine and nanofabrication are allowing us to
• 24:21
  Speaker 2: respond in very quick ways. The ability to use machine
• 24:25
  Speaker 2: learning and artificial intelligence to improve our design is reducing
• 24:30
  Speaker 2: the need to do thousands and thousands of experiments, so
• 24:34
  Speaker 2: we can use the computers to tell us the likely
• 24:38
  Speaker 2: things to work, and it reduces the empiric burden. And
• 24:44
  Speaker 2: we've got great resources because the NIH and Department of
• 24:49
  Speaker 2: Defense DARPA put a lot of resources in our hands.
• 24:54
  Speaker 2: So we're very fortunate that we can very quickly respond
• 25:00
  Speaker 2: to the problems that we encounter. So it works very
• 25:04
  Speaker 2: effectively in the models that we have. But now we
• 25:07
  Speaker 2: also have to make this scale. So that's another huge challenge.
• 25:13
  Speaker 2: So we have to go from making what you might
• 25:15
  Speaker 2: call craft beer to Budweiser.
• 25:18
  Speaker 1: And just to be clear, it's made from real blood, right,
• 25:22
  Speaker 1: Like the humoglobin in your lipid nanoparticles is hemoglobin from people, right,
• 25:27
  Speaker 1: It's not synthesized. So that is a scale challenge right there, Right,
• 25:32
  Speaker 1: that's impossible.
• 25:33
  Speaker 2: Right, So we can't synthesize hemoglobin from amino acids. That
• 25:38
  Speaker 2: is beyond our current capability, but we can program other
• 25:43
  Speaker 2: organisms to make it for.
• 25:44
  Speaker 1: Us, like yeast. Ideally yeast right put it in a
• 25:48
  Speaker 1: fact is that the yeah, we're going to brew it.
• 25:51
  Speaker 2: So we have a Yeast project where we are training
• 25:55
  Speaker 2: yeast to make human hemoglobin and to secrete it, and
• 25:59
  Speaker 2: that will eventually be our source.
• 26:02
  Speaker 1: So okay, So take thirty seconds off of thinking about
• 26:05
  Speaker 1: all the things that can go wrong and that you
• 26:06
  Speaker 1: have to figure out, and just tell me if some
• 26:09
  Speaker 1: you or the people who come after you even respectfully
• 26:13
  Speaker 1: figure out how to do all the things you're trying
• 26:15
  Speaker 1: to do, what will it look like? What will it
• 26:17
  Speaker 1: look like? Right?
• 26:18
  Speaker 2: Well, we actually believe it or not have done that.
• 26:21
  Speaker 2: We have a prototype of the delivery system. We've been
• 26:25
  Speaker 2: simultaneously trying to work with the people who would be
• 26:29
  Speaker 2: using it so that we don't end up with an
• 26:32
  Speaker 2: end product. And they say, but did you think about X?
• 26:34
  Speaker 2: And we just like, uh, So.
• 26:37
  Speaker 1: A person gets in a car accident or a soldier
• 26:39
  Speaker 1: gets shot on the battlefield, what happens in this future
• 26:44
  Speaker 1: where the thing you're working on works.
• 26:46
  Speaker 2: So what they'll have is a kit, and in the
• 26:49
  Speaker 2: kit will be three components, the two carrier, the plasma,
• 26:53
  Speaker 2: and the platelet. All of them will be dry powders. Okay,
• 26:57
  Speaker 2: So the instructions that we got from the Department of
• 27:00
  Speaker 2: Defense were it has to work in the dark, in
• 27:03
  Speaker 2: a ditch, under fire, and it has to be usable
• 27:07
  Speaker 2: by somebody who has basically known medical training. So that's
• 27:11
  Speaker 2: basically you know, not a sophisticated nurse or a scientist.
• 27:16
  Speaker 1: Basically, they want you to make instant coffee, but for blood.
• 27:18
  Speaker 2: But for blood, but also it's instant coffee. It's too complicated.
• 27:23
  Speaker 2: You've got to heat the water, you've got to dispense
• 27:26
  Speaker 2: it from a jar into a cup.
• 27:29
  Speaker 1: And pour the water. You can't do any of that.
• 27:32
  Speaker 2: So what we have is a system that has a
• 27:37
  Speaker 2: split bag with a dry side and a wet side
• 27:40
  Speaker 2: and something called a weak weld. So when it's folded over,
• 27:44
  Speaker 2: you can stand on it and it won't open. But
• 27:47
  Speaker 2: when you unfold it, you squeeze it and it pops
• 27:51
  Speaker 2: and the water migrates from one side to the other
• 27:55
  Speaker 2: and hydrates the dry material, and then it slashes around
• 28:01
  Speaker 2: in there for about a minute, and then you hang
• 28:03
  Speaker 2: it and you can use it just like a unit
• 28:07
  Speaker 2: of blood.
• 28:07
  Speaker 1: Right, you hang it like a like a ba that
• 28:09
  Speaker 1: goes into your arm on an.
• 28:10
  Speaker 2: Iterate, And there's one like that for the plasma and
• 28:14
  Speaker 2: the platelet's a little different because it's a much smaller volume.
• 28:17
  Speaker 2: That eventually will be what's called an autoinjector. Everybody's seen EpiPens,
• 28:22
  Speaker 2: so it'll be like an EpiPen. Now there's an additional problem.
• 28:26
  Speaker 2: Damn yes, there's two other problems really. So one is
• 28:32
  Speaker 2: for it to be shelf stable, it can't interact with
• 28:37
  Speaker 2: oxygen in the air. So water and iron and oxygen
• 28:43
  Speaker 2: equals rust.
• 28:44
  Speaker 1: Yeah, when you think about hemoglobin, it seems like rust, right, hemoglobin.
• 28:48
  Speaker 1: It's iron in the hemoglobin that is binding to the oxygen. Right,
• 28:51
  Speaker 1: And I'm like, wait, is hemoglobin just rusting all the time?
• 28:54
  Speaker 1: In my blood? Is going?
• 28:55
  Speaker 2: In fact, right now your hemoglobin is rusting about ten
• 28:59
  Speaker 2: percent of it is rusting constantly. But you have a
• 29:04
  Speaker 2: rust remover inside your red blood cells. That is, every
• 29:08
  Speaker 2: time it goes around, there's a little molecule in there
• 29:11
  Speaker 2: that's scrubbing the rust and demolishing the polishing the iron.
• 29:16
  Speaker 2: So we have to we have to prevent that from
• 29:18
  Speaker 2: happening during storage. And to do that, we have to
• 29:21
  Speaker 2: have a plastic soft plastic, but that has glass like properties,
• 29:26
  Speaker 2: so it doesn't allow water or oxygen through it.
• 29:29
  Speaker 1: And so that's a very.
• 29:30
  Speaker 2: Novel film that we are applying for the first time
• 29:34
  Speaker 2: to blood storage. The other problem is it can't be cold.
• 29:40
  Speaker 2: So I don't know if you've ever tried to hydrate
• 29:44
  Speaker 2: freez strike coffee with tapwater, it just makes clumps. It
• 29:48
  Speaker 2: doesn't it doesn't hydrate, so we actually have to warm it.
• 29:52
  Speaker 1: So we have to.
• 29:53
  Speaker 2: Build a heater into the bag system. So this is
• 29:56
  Speaker 2: another layer of plastic that has a little circuit inside,
• 30:01
  Speaker 2: and the circuit, when you turn it on, it will
• 30:04
  Speaker 2: warm the liquid and then it will turn color and
• 30:08
  Speaker 2: then the medic will know, okay, I can squeeze it.
• 30:11
  Speaker 2: And all the medic has to do is tear it open,
• 30:13
  Speaker 2: unfold the bag, wait for it to change color, squeeze it,
• 30:17
  Speaker 2: slash it a bit, and then hang it.
• 30:19
  Speaker 1: And that's the way it will work. That's the user
• 30:22
  Speaker 1: manual version of how it will work. What's the like
• 30:26
  Speaker 1: thirty thousand foot version of like just at a macro level,
• 30:30
  Speaker 1: somebody who didn't know what was going on, Like what
• 30:31
  Speaker 1: would they see and how would the world be different
• 30:33
  Speaker 1: if this works?
• 30:35
  Speaker 2: Well, first of all, every soldier would carry this in
• 30:37
  Speaker 2: their cargo pants, so they would have their own blood
• 30:42
  Speaker 2: instead of a blood tag that like now it just
• 30:45
  Speaker 2: says i'm typo, I'm type whatever. They actually have what
• 30:48
  Speaker 2: they need in their pants, so if they go down,
• 30:52
  Speaker 2: a medic can come up, take it out, and you know,
• 30:56
  Speaker 2: put it, you know, start resustinating somebody. It will be
• 31:00
  Speaker 2: in every ambulance so that if somebody goes to the
• 31:04
  Speaker 2: scene of an accident somebody's bleeding, they'll be able to
• 31:07
  Speaker 2: give them blood right away, just like they can of
• 31:09
  Speaker 2: oxygen or CPR. It will be stored in depots for
• 31:15
  Speaker 2: mass casualty incidents. So many people don't know at the say,
• 31:19
  Speaker 2: for example, at the Boston Marathon bombing, they actually were
• 31:22
  Speaker 2: running out of blood there, and unfortunately those incidents haven't stopped.
• 31:28
  Speaker 2: So there will be depots around the country where there's
• 31:33
  Speaker 2: warehouse shell stable blood. It will be on cruise ships.
• 31:38
  Speaker 2: It will be in resource limited countries like sub Saharan Africa.
• 31:41
  Speaker 2: It will be on the space station. It will be
• 31:44
  Speaker 2: on the mission to Mars. It will be wherever it's
• 31:48
  Speaker 2: hard to get blood. We'll be back in a minute
• 31:53
  Speaker 2: with the lightning round.
• 32:05
  Speaker 1: Okay, lightning round. What's your second favorite type of blood cell?
• 32:09
  Speaker 1: Nice as opposed to red blood I'm assuming I'm presuming
• 32:13
  Speaker 1: that red blood cells are your favorite, right, Yeah, the
• 32:17
  Speaker 1: juvenile red blood cells, the red cell, the cells that
• 32:20
  Speaker 1: make red blood cells. Okay, third favorite, third favorite? Yeah, sorry,
• 32:24
  Speaker 1: well i'd say platelets are pretty important and they're far
• 32:27
  Speaker 1: more complicated than red blood cells. But no platelets and
• 32:31
  Speaker 1: we just bleed to death. So plate is very important
• 32:35
  Speaker 1: and fascinating the whole. Like clotting cascade things seems wild,
• 32:39
  Speaker 1: right because you want the blood to clot when it
• 32:40
  Speaker 1: needs to clot, but you really don't want it to
• 32:43
  Speaker 1: clot when it's not supposed to clot, right, Like, that's
• 32:46
  Speaker 1: such a high stakes equilibrium.
• 32:49
  Speaker 2: It's an amazing system and amazing that it works when
• 32:52
  Speaker 2: it does. But yes, clotting system is incredible and very
• 32:57
  Speaker 2: very complicated.
• 32:58
  Speaker 1: What's one thing you wish we understood about blood that
• 33:01
  Speaker 1: is still a mystery why we have to keep remaking it?
• 33:05
  Speaker 2: So the you know, we have to renew red blood
• 33:08
  Speaker 2: cells every three months. They don't last very long. We
• 33:13
  Speaker 2: live with the neurons that we started with as a baby,
• 33:17
  Speaker 2: but the red cells you had in the spring, they're
• 33:20
  Speaker 2: all gone, Every last one of them is gone. So
• 33:24
  Speaker 2: you turn over all of your red blood cells. And
• 33:27
  Speaker 2: it's incredible that we actually do that because it's a
• 33:32
  Speaker 2: huge part of our quote budget in terms of energy
• 33:36
  Speaker 2: and nutrition.
• 33:37
  Speaker 1: It would be a huge evolutionary advantage in a world
• 33:39
  Speaker 1: of scarce food, presumably, so there must be some reason
• 33:43
  Speaker 1: that it doesn't work, right, Yeah, but we don't know.
• 33:46
  Speaker 1: What's one common misconception that lay people have about blood
• 33:53
  Speaker 1: that it's not alive. It's as alive as your brain.
• 33:58
  Speaker 1: People forget your blood is a living tissue.
• 34:01
  Speaker 2: Is just a liquid organ, and it's alive, and it's
• 34:06
  Speaker 2: constantly doing things.
• 34:08
  Speaker 1: It's very very sensitive.
• 34:10
  Speaker 2: It responds perfectly to you know, when you need to
• 34:15
  Speaker 2: increase oxygen delivery or reduce it. It can clot, it
• 34:19
  Speaker 2: can fight infection. It has a lot of functions. And
• 34:23
  Speaker 2: people just think, well, it's just you know, like motor oil.
• 34:27
  Speaker 2: But it's it's very sophisticated.
• 34:32
  Speaker 1: What's your view on nominative determinism? Nominative determinatism? So are
• 34:39
  Speaker 1: we what we call ourselves? Is that? Yes, I'm frankly
• 34:43
  Speaker 1: surprised that you have not heard that phrase. I'll be
• 34:44
  Speaker 1: honest with you. Yeah.
• 34:45
  Speaker 2: So my last name, so, I fought it for a
• 34:49
  Speaker 2: long time. In fact, wanted to become a marine biologist.
• 34:52
  Speaker 1: I Jacques Cousteau was my idol when I was growing up,
• 34:55
  Speaker 1: and but you know, I succumbed and went to medical school.
• 35:01
  Speaker 1: I'm actually quite happy that I did. Doctor Alan Doctor
• 35:11
  Speaker 1: is a professor of pediatrics and bioengineering at the University
• 35:14
  Speaker 1: of Maryland and he's the co founder and chief scientific
• 35:18
  Speaker 1: officer of Kalosite. Please email us at problem at pushkin
• 35:23
  Speaker 1: dot fm. We are always looking for new guests for
• 35:26
  Speaker 1: the show. Today's show was produced by Trinomanino and Gabriel
• 35:31
  Speaker 1: Hunter Chang. It was edited by Alexander Garretson and engineered
• 35:35
  Speaker 1: by Sarah Brugueir. I'm Jacob Goldstein and we'll be back
• 35:38
  Speaker 1: next week with another episode of What's Your Problem.