What's new in the world of synthetic blood, and how a bacterium evolves into a killer

This episode delves into groundbreaking research on synthetic blood substitutes and the evolutionary journey of a deadly bacterium, providing insights into medical advancements and challenges.

1. Erythrimur represents a significant step towards developing universal, shelf-stable blood substitutes that could potentially save lives in emergency situations without the need for specific blood type matches.
2. The episode highlights the historical challenges and scientific milestones in the development of blood substitutes, reflecting on past failures and the potential of new technologies.
3. Pseudomonas aeruginosa has evolved into a significant health threat, with particular implications for individuals with cystic fibrosis and hospital patients, showcasing the bacterium's ability to develop resistance and adapt to human hosts.
4. Genetic studies of the bacterium reveal specific adaptations that have enabled it to thrive in human environments, underscoring the role of genetic factors in pathogenicity.
5. The discussion on both topics illustrates the intersection of historical research, modern scientific techniques, and the ongoing need for innovative solutions in medical science.

1. Introduction to Synthetic Blood

Focuses on the development of synthetic blood substitutes, particularly erythrimur, and its potential impacts on medical practice. Discusses historical attempts and recent advancements. Kevin McLean: "So, synthetic blood, what are the components and why is it needed?" Andrew Zaleski: "It's critical due to the decline in blood donors and the necessity for universal blood types in emergencies."

2. The Evolutionary Path of Pseudomonas Aeruginosa

Explores the transformation of Pseudomonas aeruginosa from an environmental bacterium to a critical pathogen, highlighting its impact on public health. Erin Wyman: "We've traced the bacterium's adaptation to humans, pinpointing genes that have given it a survival advantage." Zakiya Whatley: "Understanding its evolution is crucial for developing targeted treatments."

1. Consider the importance of universal donor blood substitutes in emergency preparedness plans.
2. Stay informed about the latest advancements in medical research to understand potential impacts on healthcare.
3. Support scientific research that aims to tackle global health challenges, such as antimicrobial resistance.
4. Educate about the significance of genetic diversity in medical research to enhance treatment strategies.
5. Advocate for increased funding and support for medical innovations that can bridge critical gaps in healthcare services.

First up this week, guest host Kevin McLean talks to freelance writer Andrew Zaleski about recent advancements in the world of synthetic blood. They discuss some of the failed attempts over the past century that led many to abandon the cause altogether, and a promising new option in the works called ErythroMer that is both shelf stable and can work on any blood type.

Next on the episode, producer Zakiya Whatley talks to Aaron Weimann from the University of Cambridge about the evolutionary history of the deadly bacterial pathogen Pseudomonas aeruginosa. They discuss how more than a century’s worth of samples from all over the world contributed to new insights on the emergence and expansion of the pathogen known for its ability to develop antimicrobial resistance.

People

Kevin McLean, Andrew Zaleski, Erin Wyman, Zakiya Whatley

Companies

• None

Books

"Nine Pints" by Rose George

Guest Name(s):

Andrew Zaleski, Erin Wyman

Content Warnings:

None

A
This podcast is supported by the Icon School of Medicine at Mount Sinai, one of America's leading research medical schools. Icon Mount Sinai is the academic arm of the eight hospital Mount Sinai health System in New York City. It's consistently among the top recipients of NIH funding. Researchers at Icon Mount Sinai have made breakthrough discoveries in many fields vital to advancing the health of patients, including cancer, Covid and long Covid, cardiology, neuroscience, and artificial intelligence. The Icahn School of Medicine at Mount Sinai we find a way.

B
This is the science podcast for July 5, 2024. I'm Kevin McLean, filling in for Sarah Crespi. First up this week, freelance writer Andrew Zaleski joins me to talk about recent advancements in creating synthetic blood. We discussed some of the failed attempts over the past century and how a new shelf stable candidate called erythrimur could be a critical emergency substitute for any blood type. Next, producer Zakiya Whatley talks with Erin Wyman from the University of Cambridge about the evolutionary history of a bacteria known for its ability to develop antimicrobial resistance. They discuss how over a century's worth of samples from all over the world helped piece together the emergence of an expansion of the pathogen pseudomonas aeruginosa.

Blood transfusions are a life saving option for patients with a severe injury or illnesses like leukemia or others with chronic blood disorders. But that blood has to come from a donor, a person who has given their time and fluids to help others, and it has to be compatible with that recipient.

It's a generous thing to do, but when an important resource relies on generosity, supply can be tricky. In fact, earlier this year the Red Cross declared an emergency blood shortage. This week in science, freelance writer Andrew Zeleski wrote about the long and surprising journey that researchers have been on to find substitutes for donated blood. Turns out there have been a number of dead ends and abandoned efforts.

C
But.

B
But he spoke to some scientists who have been making some promising headway. Hi Andrew. Welcome to the science podcast.

C
Hi Kevin. Thanks for having me.

B
Sure. In reading your story, you know, it really made me think about what blood really is, like all the components and what they do, and I do want to get to that. But first, I was really fascinated to read about the history of replacing blood.

C
So that's, there's this weird I history around blood transfusion from roughly the early 18 hundreds for about a century until we really did figure out blood types was various doctors tried different ways to replace blood loss during surgery or some sort of procedure. There were attempts to transfuse the blood of dogs into humans. In the 1870s, there were doctors in the US trying to use milk as a transfusable substance.

B
Oh, my gosh.

C
So, yeah, it's a good thing that we don't do things like this anymore and that people figured out blood types and how to actually transfuse human blood into other humans when necessary.

B
Yeah, absolutely. So, I mean, I guess with that in mind, we've worked out how to do blood transfusions. They work really well now. So why is it so important to figure out a substitute for blood?

C
I mean, some of it is just that there are few and fewer blood donors. There isnt enough o negative, which is the universal donor type. So you can put that in anyone, do a transfusion?

B
Anyone.

C
There just isnt enough of that blood around.

Think about rural America. Average ambulance wait times in rural America, about 45 minutes. Thats a long time to wait, especially if theres some sort of severe hemorrhaging incident going on. You need blood very long time away. So if you had something that could keep someone going, then you could locate the blood that you need to do a proper transfusion. And then the military has always been fascinating, something like this, I mean, dating all the way back to, you know, world War two, this idea that, okay, if blood is at a premium on the battlefield and someone needs to get to a field hospital before they can get a real hospital, how do we make sure that we, we keep wounded soldiers alive?

B
We don't have to get into, like, a super lengthy biology lesson. But what are these sort of basic components of blood that we have to have to be able to think about in order to find a replacement.

C
Right, okay, so when we talk about transfusions themselves, every red blood cell in the body is coated in a web of proteins, and that determines the type. So we've all heard of, you know, a B O Abdez, but then there are antibodies in your plasma. They carry something called a rhesus factor, which determines whether someone is positive or negative. So if you're a positive, you need blood from either a universal donor or you need a positive blood. Hemoglobin is one of the other components of blood. So red blood cells are what actually hold hemoglobin, which are these globular proteins that ferry oxygen around the body to your organs. They're encased in these red blood cells, so there's a membrane around them, because if they're flying around in the blood, not in case they can be toxic to various tissues. So think about if you're going to create something that mimics its oxygen carrying capacity. You obviously don't want anything toxic happening to your tissues or your blood vessels.

B
Yeah, definitely not. So you kind of have to have this balance between not having too much oxygen, but carrying enough for it to be useful. And it sounded like one of the challenges in coming up with blood substitutes earlier on had something to do with that. Right.

C
So the earlier generations of artificial oxygen carriers, these things that have forms of. Of hemoglobin bound together in some way and then put into the bloodstream to help carry around oxygen, what began happening, at least to some degree, not every single time, was doctors were noticing that these free hemoglobin that composed some of these earlier generation of artificial oxygen carriers would gobble up nitric oxide in. In the bloodstream. Nitric oxide is released by the endothelial lining of your blood vessels, and it basically controls vasoconstriction and vasodilation. If you gobble up a bunch of nitric oxide, the thinking was there was a one to one causal connection between free hemoglobin taking in too much nitric oxide and then causing vasoconstriction. In 2008, there was a very controversial meta analysis published in the Journal of the American Medical association that essentially looked at five of the earliest artificial oxygen carriers and said, all of these things are toxic to the heart and we shouldn't use them because of this vasoconstriction issue, basically shut down the whole field for a little while. But more and more, there are plenty of clinicians out there who say that meta analysis is way too broad. When you create an artificial oxygen carrier, you're really just trying to keep someone alive until they can get a blood transfusion. When we call them blood substitutes, which in some, you know, these terms get used interchangeably, but it's nice to be precise.

Like, a hemoglobin based oxygen carrier is not a blood substitute. It's literally not like new blood. It's. It's something where hemoglobin is taking oxygen around, keeping you alive until you can get to a hospital and get a transfusion of packed red blood cells.

B
Got it. Okay, so now, in your story, you focused a lot on the work of a particular researcher and the rest of his team. Alan, doctor, maybe. You visited his lab in Baltimore, right?

C
Yes.

B
What was that experience like? Yeah.

C
So doctor doctors lab, which is just. What a name. So, in his lab, Alan doctor is working on hemoglobin based oxygen carrier that he calls erythrimir. And it's still in preclinical trials. It's in animal studies, what they're trying to do is basically mimic a red blood cell. So they have hemoglobin molecules, but it's surrounded by a lipid membrane that acts similarly to how a red blood cell, they say, would act. And at least in their trial so far, it seems to be doing so. They are surmising that if you wrap the hemoglobin in something that mimics a red blood cell, we think we can get around this issue of vasoconstriction and basically have a product that is maybe safer in the long run.

B
They're doing sort of artificial encasing of hemoglobin. Does that mean that the proteins that would be on the surface of red blood cells that cause the compatibility issues are not a problem as well? Like, we wouldn't need to have a specific donor?

C
Exactly. Theoretically speaking, universal donor. That's the idea, too.

B
Okay. I'm just trying to picture this. The erythromer. What does this stuff actually look like?

C
Right. So erythromere, before it's. It's in any sort of form you put in the body, it's a freeze dried powder.

B
Okay.

C
It's sort of this freeze dried, pinkish reddish powder, maybe think of the consistency of. Of baby powder. And then you mix it with saline, you reconstitute it in saline solution, and then it becomes liquid that you can then inject intravenously.

B
Okay. And so that's. That's also part of what the advantage of the. Of trying to develop something like this would be, is to. To make something that could be more like shelf stable, I guess. Is that right?

D
Right.

C
Lots of the work done in general about hemoglobin based oxygen carriers focuses on the fact that, look, stored blood is good for about 42 days, and then it goes bad. You can't use it beyond that. So if you have some sort of artificial oxygen you carry, presumably you could have it sitting on a shelf for a long time. In erythromeres case, the time period they're going for is about two years. And you can think about how useful this might be. You can have blood on the battlefield, where real packed red blood cells are at a premium, but in this way, you could actually save soldiers lives because you would be able to keep them alive, keep their organs alive until they could get to a hospital that had real blood to transfuse into them.

B
Right. Okay. There was another example that you had talked about as well. Hemopure. What was, what was that one?

C
Hemopure has been around for quite some time. It was developed in the nineties. It is available in the United States for compassionate use. There are many doctors who have used this to great effect. They've kept people alive. Chemipure is made from purified bovine hemoglobin. Cow's blood. The issue with Hemopur was it was one of those hemoglobin based oxygen carriers mentioned in that 2008 study. Now, I mean, let's be very clear. There's a side effect profile associated with it, but it's not toxic. And there are doctors around the country who use this. There's a doctor at University of Pittsburgh Medical center who uses this, and as a matter of fact, said to me, you know, I can probably think of at least ten patients who would be dead if not for hemopyre. There's a doctor, University of Minnesota, who use this on one patient who came in with critically low hemoglobin levels. Put ten units of hemopur into this patient, and she woke up, she's fine. So hemopure is out there, but it's only available as an investigational new drug. It's something that its creator, Zaf Zephyr Ellis, has been trying to get approved by the FDA for years, but just hasn't been able to.

B
I mean, it sounds like there have been some hurdles, maybe some skeptics in this field. What are some of those hurdles? Is it still just the legacy of that one meta analysis, or what has been so difficult about developing products like this?

C
I think it's some of that probably, maybe some after effects of that meta analysis. Funding. You need adequate funding. There are people who are skeptics of this who just think that artificial oxygen carriers do more harm than good, and for that reason, just should probably not be attempted, be created. But there are plenty of other clinicians who say, no.

Getting enough blood is a highly unmet medical need. So we need these artificial oxygen carriers. Development should continue.

We know enough now. We know how to make them safe. We know how to make sure things such as vasoconstriction don't happen. If we get the appropriate funding, we can definitely get one of these to market, get one of these with FDA approval. I mean, the other thing to think about is also products have to go through clinical trials, human clinical trials, and you got to think about how. I mean, it'd be completely unethical to design a trial where you have patients in anemia and you say, okay, some of you are going to get this artificial oxygen carrier, and others of you are just going to get saline solution or you know, some of you are going to get packed, red blood cells, conventional transfusion, and others are going to get this artificial oxygen carrier, because if someone's in anemia, they need blood. So, I mean, some of that is just trying to figure out how you would actually set up the trials. Some of it is just funding.

B
I know you've been working on this story for quite a while. Did, did working on it sort of make you think differently at all about blood or anything like that?

C
I'm just sort of fascinated at just how complex blood is. I think, you know, we just, you get a little cut on your arm or something, I put a band aid on it, and you don't really think about it. And in just writing about it, the amount of stuff I had to try to cram into my head about what blood is, what blood is made up of, the history of trying to figure out exactly how transfusions work. You know, some of the crazy stuff just about doctors in the past thinking, oh, yeah, you can just take blood from an animal and put it into someone. Or just the very idea that for centuries, people thought it was the lungs that pumped your blood and not the heart. All of these little fascinations along the way in sort of figuring it out.

B
Yeah, it's so interesting to hear about all those sort of incremental discoveries that teach us about something that we kind of take for granted.

C
Yeah. I should shout out a great book. It's called nine pints by Rose George, and the title is kind of like a subtle nod. The average person has between like nine and twelve pints of blood in their body. It's a great book, a great resource just to learn about the history and blood itself. If any of you are looking for a beach, read. Hey, nine pints.

B
Great. You're great. Well, thank you so much, Andrew. It was great to talk with you.

D
Sure.

C
Thank you, Kevin.

B
Andrew Zaleski is a freelance writer based near Washington, DC. You can find a link to the story we discussed@science.org. podcasts stay tuned for Zakiya Whatleys conversation about the evolution of a deadly pathogen.

A
A deeper understanding of genetic diversity is essential to ensuring robust, equitable healthcare for all. The all of us project led by the National Institutes of Health is making great strides towards this goal by sequencing the genomes of over a million diverse individuals, including previously underrepresented populations. To ensure high quality sequencing data, the NIH used Roche's Kappa Hyperprep library prep kits. Learn more about this study and Kappa Hyperprep kits by visiting go dot roche.com hyperprep this week's episode is brought to you in part by science careers.

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E
It's no secret that our bodies are colonized by a multitude of microorganisms. So that includes bacteria and fungi. And while most of these tiny little microbes are harmless, some of them can be quite harmful.

Pseudomonas aeruginosa is a bacterium that's commonly found in the environment, but it becomes a serious threat when it infects humans, so much so that the World Health Organization has listed it as a critical pathogen. Today, I'm speaking with Aaron Wyman about his work to understand the evolution of pseudomonas aeruginosa. How did these environmental microbes become such dangerous pathogens?

And how do pseudomonas aeruginosa samples that are over 200 years old tell us about the pseudomonas aeruginosa we're encountering today?

F
Erin, thank you for joining me today.

D
Hi, Sakia. It's great to be on the show.

F
So let's start with pseudomonas. I think maybe if you know someone with cystic fibrosis or you've had a.

E
Stent or family member has had a.

F
Stent in the hospital, you may have heard of pseudomonas aeruginosa, but it wasnt always a pathogen. Is that correct?

D
Yeah, thats absolutely right. Historically, people thought of pseudomonas more of a bacteria thats just occasionally making its way into humans. People thought its more of an environmental bacteria that just occasionally caused infections. But nowadays, its, as you were already saying, causing massive problems. For example, people with cystic fibrosis, where it can cause lung infections that last decades and are very hard to eradicate and cause a lot of suffering as well. It's a massive problem in hospitals. It's causing a big number of deaths, a huge burden to a lot of people. We don't really have a good idea of how this bacteria evolved to become such a dangerous pathogen. And that's something we addressed in this work and found some really exciting stuff.

E
When I was looking at your work, I was really excited because you looked at pseudomonas aeruginosa samples from a very large time period, and you're trying to make sense of them, to understand pseudomonas as we knew it then. So in the early 19 hundreds to pseudomonas as we know it now, just as recent as a few years ago, you had samples that were from strains collected, I think, as late as 2018. So tell me a little bit about this collection of pseudomonas aeruginosa you used for this study.

D
That's maybe a contribution that's a little bit understated in the paper of just how much work it was to put this collection together. This is definitely the biggest collection of pseudomonas anyone in the world has. And we went through a lot of effort to put this together. So we reached out to people all over the world. Some of the samples were available publicly. Those were easy, but some of them were really hard to get. For instance, there was this global surveillance study, and the lead on this, this was done at a pharmaceutical company. We finally managed to track him down on LinkedIn.

We had to purchase premium because that's the only way you can actually message someone you're not connected to. And he got back to us and was all excited about our project and that we're doing this kind of work. He got in touch with the data lead. They still had the data from back in the days, and we were able to share it with that's. Which was really an amazing experience.

E
Yeah, that's incredible.

F
That's also an interesting touch. You know, when we think about experimental costs, we don't often think of LinkedIn premium. Right. As being something that's absolutely vital to your work. Your earlier samples, were those from the public collections, or were they really hard to track down as well?

D
So again, we were lucky. We got in touch with the so called international pseudomonas consortium, and they run this database, which already had quite a large number of strains and genomes in them. A lot of those were historical samples. The oldest ones were 120 years old, which is really rare. They were sleeping in this historical strain collections, and no one had touched them in a very long time. And these kind of samples are just very crucial if you want to pin down the time when pseudomonas emerged. Reconstruct the history of it.

E
Yes.

F
So walk us through it. Once you have this huge collection, what are you finding?

D
First, I think it's important to mention that there are lots of different kinds of pseudomonas or strains. Maybe people know variants in Covid, so that makes it a bit easier to explain. We often refer to them as clones, and we realized when we analyzed our data, there were hundreds of different clones.

But when we looked at the number of infections every clone caused, there was really just a few, 21, that were responsible for the majority of the infection. We then focused our efforts on these epidemic clones because we realized they had spread globally. Most of them we found in all continents.

And we then got interested in when might they have first emerged in the human population.

F
So it sounds like you started with 9800 samples. You were able to whittle those down to 21 clones that you saw were. I don't know if drivers is the right word, but that were responsible for most of the human infection that you saw?

D
Yeah, I think drivers is the right word. So these epidemic clones caused really the majority of the infections. So we think they are most relevant, at least medically to us.

F
What was different about these clones?

D
We were exactly wondering what set them apart from the sporadic clones that we only see occasionally. And we could identify specific genes that had been acquired in that evolutionary history of the clones that we think has given them an edge to take off in the human population.

E
When we consider the emergence of these clones, what genes did they acquire that allowed them to exist in the human body?

D
We found that actually in the epidemic clones, compared to the sporadic clones, there were specifically genes affecting gene expression in those epidemic clones, which might suggest that they had quite drastic impact on the ability of the clones to adapt to humans. So that might have been what's given them the edge, really.

F
I'm curious, is that what you expected? Did you expect genes that were related to gene expression?

D
I think to a certain degree, yes, because that's probably one of the easiest way how you can rewire yourself. Sure, you can take up other genes, but actually, in terms of the fitness cost, there's always a cost to something newly acquired in a bacterial strain, but through gene expression, that's a quick change for the bacteria. So easy enough to reach. It's much easier to get in a new, say, transcriptional regulator that then downstream, completely rewires how high isobacteria interact with the environment, the human environment.

F
Okay, you said, all right, we see these changes that are related to gene expression, and we see that this is related to these epidemic clones that we have. But then you took it a step further and said, now, what advantage does this give these clones, and what does this look like? If we think about our ideal environment, which is a human host.

D
So it turned out that some of the clones are really frequently seen causing infections with people cf. Other clones were only seen in on CF and other sorts of patient groups. And so we started wondering about why that might be case, because this was really striking. We then realized that this didn't seem to be just an accident.

Again, we saw gene expression as a theme coming up here. Also, transcriptionally, the strains from patients with CF cluster together and strains from patients with non CF. And it turned out one of the main drivers of this was this gene, DkSA one, which is a transcriptional regulator related to the bacterial stress response. So when the bacteria is under stress, for example, so when it doesn't have enough food, then this might be turned on.

E
So when you look at all of your samples, you say, okay, the samples that were taken from patients that had cystic fibrosis or your CF samples, the transcriptional profile there looks different than the samples that are taken from patients that didn't have CF. You're saying the cause of that, or a large part of that is DkSA one expression. But how do you prove that? How do you then test that? It's real.

D
To test the importance of this transcription regulator, we infected zebrafish with the CF mutation and the biotype as zebrafish. In the zebrafish that had this CF mutation, we found that pseudomonas that didn't have this transcription regulator was less able to survive and replicate, suggesting really that this gene was important for survival in cf. Compared to wild type. Zebrafish is a really great infection model for pseudomonas and other bacteria, just because the larvae of the zebrafish are translucent. So you can actually see what's going on in the zebra fish. It's just so cool that you can see it in the fish and you have this transparent lever, you can really tell what's going on there.

F
The transparency of zebrafish definitely makes it top tier model organism.

Yeah, I'm sure that must have been so rewarding and exciting to be able to visually see it.

D
Yeah, we have some cool images in the paper.

E
Yes, you do. So let's go back to the clones.

What else did you find or see that was exciting?

D
When we look more at the sort of more recent history of the clones, we see lots of dangers in these epidemic clones. So regions in the genomes that are commonly mutated, and a lot of these genes turned out to be important for antimicrobial resistance, which makes sense because pseudomonas is one of these really drug resistant bacteria that's causing a big part of the problem. Then, quite excitingly this, what we call signature of adaptation to humans, was actually not the same for people with CF and people without CF. So we could clearly tell strains apart from CF and non CF. Even more interesting, you also don't see any or very little potential transmission between people with CF and non CF, which we think is because you have this specific adaptation to different human patient groups. So the bacteria adapts, finds its niche, and then doesn't make it out of this niche anymore, which, of course, is very exciting or is irrelevant for clinical practice.

F
This is really medically relevant, and it closes the gap. There may have been small pieces and, oh, we found this thing here or there, but without these kind of historical collections that allow you to go back in time and that are also geographically rich, it's hard to tell these types of stories. So this feels like everything kind of falling in place. I wonder what's next after this work. I'm curious about what you'd like to see expanded on and how you think this work can be used to inform others.

D
I think that was one of the coolest thing, to be actually able to go back in time and see what epidemic clone emerged when. And, yeah, you could almost call it a hidden epidemic that's been going on for all this time. People just hadn't really realized. And this shows you just how important surveillance is, because we are missing out on a lot of this. There might be the next epidemic clone already emerging, but we have no idea because it's in a part of the world that has very poor surveillance, most of the world, actually. So that's the unfortunate reality. I think there needs to be a reason. We need to ramp up surveillance both as global as possible, but also more targeted for those patient groups that are most vulnerable.

F
Absolutely. Tell me a little bit about the team that you worked with.

D
It was an incredible team effort. In our lab itself, there are people who are doing the cell line, the macrophage experiments. We also shout out to our collaborators in Montpierre who have done the animal model, the zebrafish. There was an incredible amount of work as well. It was almost hard to find a stop to our work. It was all quite exciting.

E
I can imagine how exciting it was to be a part of it, because it's been great to read it.

Erin Wyman is a postdoctoral researcher at the University of Cambridge. You can find a link to the paper we discussed@science.org.

podcast.

B
And that concludes this edition of the Science Podcast. If you have any comments or suggestions, write us at Sciencepodcast AAA's Dot dot to find us on podcast apps, search for Science magazine, or you can listen on our website, science.org podcast. This show was edited by Sarah Crespi, Megan Cantwell, Zakiya Whatley, and me, Kevin McLean. We also had production help from Megan Tuck at Prodigy. Our music is by Jeffrey Cook and Wen Khoi Wen on behalf of Science and its publisher, AAa's. Thanks for joining us.