What's Stopping Scientists from Making Viable Synthetic Blood?
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(Inside Science) -- Back in the 1600s, lacking an alternative, doctors tried transfusing milk and wine into the bloodstreams of their hemorrhaging patients. When that failed, they moved on to sheep's blood. It wasn't long before it became clear that these treatments were killing people, not saving them. Thankfully, we now know that human blood, donated by someone with a compatible blood type, is the way to go. That blood is then refined, separated into its components and screened for bloodborne diseases such as HIV.
Yet the current system is not perfect. Some countries' health care systems lack the infrastructure needed to safely collect, store and deliver blood to patients in need. Even in countries with those kinds of resources, there are communities with rare blood types for whom it can be challenging to find a match in the blood bank. Often people in these communities are ethnic minorities.
Simply put, severe bleeding requires medical care. The problem is especially acute in dangerous and remote locations such as war zones. That's why, following World War II, military scientists began to ask themselves if it might be possible to manufacture blood. Civilian researchers soon followed and so began the modern quest for artificial blood.
While scientists have not yet created a viable artificial blood product, they have achieved some advances. Instead of trying to reproduce the complexity of whole blood and master how its various contents interact with each other, scientists are focused on making blood's individual components. This includes red blood cells, which carry oxygen around the body; white blood cells, which fight infections; platelets, which clot to heal cuts; and plasma, which carries substances like proteins. In most countries, transfusions are usually given in this way too -- it's rare for patients to be given whole blood. Depending on a patient's clinical needs, they will be given either one blood product or a combination. A relatively small bleed may require only red blood cells, whereas substantial blood loss may call for red blood cells along with platelets and plasma.
The pursuit of these lab-made blood products has branched into two main areas of research. The first is focused on producing entirely synthetic substances to carry out the same functions as blood's constituent parts, and the second seeks to exploit stem cells to generate cells and substances that are biologically identical to those found in natural blood. Each approach comes with its own set of pros and cons, but experts are predicting that some of these products could be rolled out within the next 10 years, should clinical trials prove successful.
"Blood donations have fallen considerably during the pandemic as people stay at home," said Koji Eto, a stem cell biologist at Kyoto University. "That's why these efforts to manufacture blood products are so important, to make sure we have a stable blood supply as we anticipate future pandemics."
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Red blood cells contain a protein called hemoglobin, which captures oxygen in the lungs and distributes it to other organs. Oxygen delivery is a critical function of blood, so it's always been an important feature in any artificial blood research. The first experiments that launched the hopes of a synthetic route toward manufacturable blood took place during the 1950s and they used pure hemoglobin, which scientists isolated from human or animal blood. The hope was that hemoglobin, even without the rest of the red blood cell's architecture, would still be able to carry oxygen. If that had been the case, scientists would have then moved on to synthesizing hemoglobin in the lab.
Hemoglobin, however, does not work well outside of the red blood cell. Instead, it degrades into smaller portions, which accumulate in the liver and kidneys, causing damage. In the decades that followed, scientists modified the chemistry of hemoglobin proteins so that they bind to each other, making it harder for them to break down. This technique was eventually shelved after a 2008 review of 16 studies with a combined 3,700 patients revealed that heart attacks were more common and that treating patients in this way increased their risk of death by 30%.
One possible explanation for the increased risk of heart attacks is that hemoglobin doesn't bind to only oxygen -- it also has a high affinity for nitric oxide, which regulates how open or closed blood vessels are. Introducing cell-free hemoglobin disrupts this process, which could restrict blood from reaching organs such as the heart.
"You've messed with the body's ability to regulate where blood goes," said Michael Reade, professor of military surgery and medicine at the University of Queensland, in Australia. "It got taken off the table for obvious reasons and ever since the focus has been on packaging hemoglobin, so it doesn't bind to nitric oxide." It's not yet clear whether this approach will work.
Progress has been slow on the synthetics front partly because blood is so difficult to study, said Lt. Col. Matthew Armstrong, who studies the fluid dynamics of blood as a chemical engineer at the U.S. Military Academy at West Point. "As soon as it's out of the body, it starts to age," he said. "A reproducible experiment is also tough because your blood changes during the day based on whether you've exercised or what you've eaten."
Scientists are working on ways to boost the shelf life of platelets, for example, and freeze-drying them is one proposal, but difficulties begin to emerge when they're resuspended in fluid.
"The army invested millions in producing a blood replicant to be used for causalities in the battlefield, but it has so far come to naught," he said. "I don't think they've adequately accounted for the mechanical properties of blood."
Carefully understanding the viscosity of synthetic blood products, the mechanics of how they move within fluid, and whether they correspond well with the real deal may be important, Armstrong said.
Since making viable artificial blood has been so challenging, researchers have begun to try a different approach: manipulating stem cells to become blood products.
If scientists can bioengineer blood products such as red blood cells or platelets in this way, then they circumvent the issues of compatibility that are so fraught in synthetic blood products.
Scientists can take a particular type of stem cell known as hematopoietic cells from a donor. These cells are already capable of turning into any kind of blood cell; researchers use certain signaling molecules to then coax the stem cells into the specific blood product they want. This process is well understood and has been practiced with success for many years. In fact, Eto from the University of Kyoto said he has successfully given platelets produced from stem cells to a 52-year-old female patient -- something he called a world first.
"The sticking point is scaling up," said Rebecca Griffiths, a senior research fellow at the Australian Red Cross Lifeblood research team, since one stem cell can yield only a limited number of red blood cells. Scientists are working to iron out this kink. In a 2017 paper, Griffiths and colleagues described a process known as "cell immortalization," in which they inoculated cells with the human papillomavirus when they were in an early stage of their transformation from stem cell to red blood cell. "The HPV stops them from maturing any further, which means the cells can still replicate," said Griffiths. Theoretically, this provides a sustainable source of red blood cells that doesn't rely on regular stem cell donations.
Yet this method isn't without flaws. Red blood cells don't contain a nucleus, which ensures they remain flexible enough to squeeze through tiny blood vessels without causing clots. When the immortalized stem cells shed their nuclei as they develop into red blood cells, this gets rid of the otherwise potentially harmful HPV. Some of the red blood cells created in this way, however, don't properly lose their nuclei. Researchers are therefore trying to improve immortalization strategies to correct this fault.
The clinical trial quandary
Compared to synthetics, stem cell blood products have the upper hand when it comes to clinical trials, said Reade. It's debatable whether scientists can even ethically gain consent from patients to forgo donor blood, which is proven to work well. Why should a patient opt for the synthetic alternative when some of the products tested thus far come with an increased risk of heart attacks?
But there are many situations in real life where donor blood isn't an option. For a wounded soldier on a remote battlefield, for example, it doesn't matter if a synthetic blood product isn't as effective as donated blood, because it's impossible to offer such a transfusion. In such a circumstance, the better question is whether synthetic products are more effective than nothing. Yet that's a scientifically difficult question to interrogate, said Reade. "In environments where we can't do a normal blood transfusion, it's also tough to do a clinical trial," he said.
It would be possible to do a retrospective study comparing the survival rates of those given the artificial blood in an emergency setting to those who weren't, but that comes with bias limitations. Those receiving such an artificial blood product would have also initially survived their injury and might have lived anyway. Those who suffer extreme trauma and die instantly wouldn't be a candidate for artificial blood, so it's possible that a study would overestimate the benefit of an artificial blood product.
But if these issues of experimental design can be solved, there are a number of treatments on the horizon that look promising, Reade said. Either way, these efforts are testament to how far modern medicine has progressed since the days of transfusing milk and wine.