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Donated blood saves 4.5 million American lives each year, but has a short shelf life, low portability and must be available for all blood types. Researchers have sought safe and effective blood substitutes for 60 years, and a few viable alternatives are in animal testing.

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  • Dr. Allan Doctor, Professor of Pediatrics and Biochemistry, Washington University in St. Louis, School of Medicine
  • Dr. Jan Frayne, researcher, University of Bristol (UK)

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Blood Substitutes

Reed Pence: Red blood cells are among the smallest cells in the human body. In a single drop of blood there are between a quarter and a half million red cells. Most of us have about 10 pints of blood, but if we’re injured and lose 40% or more of it life is in danger without a transfusion. Donated blood saves around 4.5 million American lives each year, but it has it’s drawbacks and limitations.

Dr. Allan Doctor: Blood cells in our body really last only 3 months and we turn over our blood pretty regularly, in fact you and I are replacing 1% of our red blood cells every day. In fact each second we produce and remove about 1.5 million red blood cells So this is constantly going, in our life time the average person will produce something like 250 kilograms of read blood cells in order to continue to refresh that supply.

Pence: That’s Dr. Allan Doctor, Professor of Pediatrics and Biochemistry at the Washington University in St. Louis School of Medicine.

Doctor: So these red blood cells, in our own body only last three months. If they’re donated it’s not rational to imagine that they can be preserved for an extended period outside the body either. So we can really only keep them viable for about a month outside the body, and even as they begin to approach the limits of their shelf life, there’s some concern that they might lose some of their optimal performance characteristics. But we can only keep them for a month and there also needs to be very careful matching between donor and recipient to avoid transfusion reactions.

Pence: Getting blood where it’s needed and keeping it ready for use are problems too. To be a life saving resource, blood needs to be available in all of the different blood types and kept under refrigeration.

Doctor: Within hospitals, once patients are within in the emergency department or in the hospital resource, then the blood is very available and there really aren’t any problems in getting it to the right patients at the right time. However when people are injured out in, at an accident, and that could be in a rural setting or it could be in the middle of Manhattan, sometimes they’re bleeding so fast that they need blood administered right then and there. And the institute of medicine recently estimated there’s somewhere between 10 and 20,000 preventable deaths due to hemorrhage in the United States alone every year.

Pence: And then Doctor says there’s the military, a setting that’s even more challenging.

Doctor: Sometimes, soldiers who are wounded can’t be evacuated either because it’s too dangerous or the logistic support isn’t available and so in the field, or even in field hospitals medics don’t have access to blood to transfuse trauma victim.

Pence: It’s no wonder then that doctors have tried and failed for 60 years or more in their attempts to create a substitute for our blood – something with a long shelf life that can be given anyone in an emergency without regard to blood type. Doctor’s lab made significant progress towards a blood substitute, and he admits that some of the substances tried over the years by other sound pretty scary to have in your veins. For example the family of chemicals that includes Freon, the refrigerant in your air conditioner.

Doctor: Well, it’s close – there were perflurocarbons, so it sounds a little like Freon. SO it’s very clear liquid, which has a high solubility for oxygen, so a lot of oxygen can be dissolved in it. In fact it was even popularized in a movie called “The Deep” where people were breathing this liquid when they were going pretty far under the ocean. So that same liquid was converted into little droplets with coatings, called an emulsion, and it is used in fact in Russia and people are still trying to figure out how to optimally make it work here in the States. But it has not been approved by the FDA and there’s some performance characteristics that limit its generalized use.

Pence: The quality that’s most important in a blood substitute is the ability to carry oxygen and release it at the right time. Red blood cells have hemoglobin for that and most proposed substitutes use it as well.

Doctor: Carrying oxygen is actually the easy part; it’s letting go of the oxygen that’s the hard part. So, if you think about what red blood cells do, it’s they go through the lung – they capture the oxygen, and then when they go out to the tissues – they let go of it. So that’s the same proteins reacting in an opposite way under similar conditions with the gas. And for that to occur there has to be a rather complex control system in the red blood cells that help that happen. And the more simple blood substitutes that were based on simply purifying the oxygen carrying protein in the blood called hemoglobin didn’t do that very well. They were very good at capturing the oxygen but not as good at letting go. And one of the design challenges we had was to replicate this behavior.

Pence: Blood also carries other components that are important for clotting, immunity, and removing waste products. But most blood substitutes don’t worry much about those qualities. Researchers have their hands full simply with oxygen transports and making sure that a blood substitute is safe.

Doctor: The blood vessels in our body are lined by muscle and there’s a little bit of a tension that maintains the pressure in our circulatory system to push the blood through our organs and the cells that line our blood vessels product a gas called nitric oxide that causes the blood vessels to stay relaxed. Hemoglobin, when it’s outside the red blood cells traps outside gas and causes the blood vessels to constrict or go into spasm and the blood substitutes – that first generations so to speak based on hemoglobin – were capturing the nitric oxide and were believed that this was a problem that led to some outcome concerns and they were associated with heart attacks.

Pence: Doctors says that about 10 years ago the FDA shut down research on naked hemoglobin blood substitutes. That set most scientists down one of two paths.

Doctor: One is to modify the hemoglobin either chemically by cross linking it or changing the protein itself with other chemicals, or to modify it genetically that is to genetically engineer a recombinant hemoglobin that’s produced by another life form like a bacteria or a yeast – and then use those. And that has become a pretty significant challenge because that molecules evolved over millions of years to do something perfectly well and it’s very hard to only change one part of it without disrupting the overall function. The other problem is that the naked molecules tend to leak out of the blood stream and get trapped in tissue, so for the hemoglobin to be effective and safe the blood stream has to be cross-linked. Meaning knitting chemically, multiple molecules together, so they can’t leak out of the blood stream and then by crosslinking you also change the performance characteristics – so this has been difficult.

Pence: The other major approach, the one that Doctor’s pursuing, is to enclose hemoglobin in a membrane. Doctor’s team has developed a synthetic polymer for their product, which they call “Erythromer.” The product can be freeze dried for long term storage and so far in animal experiments, it’s working well.

Doctor: We have tested this in rats first, where we bled them and took away 40% of their blood volume and left them in shock for 20 minutes. This simulate, basically, an accident that might’ve occurred in a developed country like the US and then we resuscitate with the Erythromer.

Pence: Then researchers removed 70% of the blood volume of mice and successfully replaced it with the blood substitute. But with such a critical product Doctor’s going slow – it could be 8-10 years before the first human trials. But if it works, accident victims and deployed military personal would be it’s first patients.

Doctor: The goal is to rescue the people out in the field who would not have otherwise made it to the emergency department. Our goal is not to replace natural transfusions in the hospital, but we’re trying to push transfusion capacity out into the field or into austere environments. Soldiers come to mind but this could be suitable for submarine, cruise ship, or as remote as the space station or even Mars.

Pence: However, you don’t need to leave earth to find people who are in a tough spot if they ever need a transfusion, even if they’re at a hospital. Some people have extremely rare blood types that are hard to match, that’s one reason some researchers are working to get stem-cells to mass produce red blood cells in the lab.

Dr. Jan Frayne: What we’re trying to do is trait what the body makes naturally and so you don’t have some of the problems you have with artificial products – blocking, ending up in places you don’t want them to be, behaving in a way that can be disruptive to the body system – by using something that we naturally have, the body will accept it and it should behave as your normal red blood cells do in the body.

Pence: That’s Dr. Jan Frayne, a researcher at the University of Bristol in the UK.

Frayne: The cells desperately want to mature out the red blood cell pathway to turn into a red blood cell, they don’t divide back many times which means some stem cells you can only make a limited finite number of the resulting blood cells. Which limits the potential of that system at the moment. So we needed a way to make them divide more – so we can more and more cells. And what we’ve done in the recent publication is again, we’ve taken those exact stem cells, some circulation so it’s not an invasive approach, we’ve put them into our culture system to make active a very early red blood cell, what’s called a (inaudible) cell stage where they’re naturally dividing and then what we’ve done is immortalized them at that stage so they keep dividing and dividing, indefinitely until we put them into the next stage of the culture system and then they finish off maturing into a red blood cell.

Pence: When the technology is perfected, theoretically just 1 person per blood type would be needed to produce large amounts of blood for everyone else with that type.

Frayne: Because they divide indefinitely you can just keep them in cultures and keep adding more and more culture medium in to keep them dividing and in the first nine we made we kept them continually dividing, to show you could actually do it. But we didn’t keep increasing the volume; we basically divide the culture, threw half away and kept half of it. Because it just gets expensive to have unnecessarily large volume. So in principle you can just keep them dividing.

Pence: Frayne believes mass produced red blood cells could be ready for a human test within five years. You can find out about all of our guests on our website, RadioHealthJournal.net. You can find archives of our programs there as well and also on iTunes and Stitcher. I’m Reed Pence.

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