There were news stories afoot this week with somewhat breathless headlines that suggested a medical breakthrough was at hand: “In a 1st, two people receive transfusions of lab-grown blood cells.” A headline like that certainly catches the eye, especially as the holidays approach and the inevitable calls for increased blood donations that always seem to happen this time of year as the supply gets pinched. Does a headline like that mean that someone is working on completely artificial blood?

As always with this sort of thing, the answer is a mixed bag. Yes, a team in the UK has transfused two patients with a small amount of lab-grown red blood cells, and it’s the first time that particular procedure has been performed. But while the headline is technically correct, the amount transfused was very small, so the day when lab-grown whole blood transfusions replace donated blood isn’t exactly here yet. But the details of what was done and why it was attempted are the really interesting part here, and it’s worth a deep dive because it does potentially point the way to a future where totally synthetic blood may be a real thing.

Growing Up Red

To understand what’s being done in this trial, which is called “Recovery and survival of stem cell originated red cells”, or RESTORE, we have to look into the process of blood formation in some detail. The journey from a single cell type to whole blood filled with a balance of red blood cells, white blood cells, platelets, and myriad other specialized cells and factors, is called hematopoiesis. It’s an immensely complex and tightly regulated process, but it all begins with the simplest and in some ways the most important cells in the body: stem cells, which are undifferentiated cells that can make an essentially unlimited number of copies of themselves.

Many branches, but one starting point. A simplified view of hematopoiesis. Source: CCCOnline, CC BY-SA 4.0

The stem cell at the root of hematopoiesis is called a hemocytoblast. In adults, hemocytoblasts are located mainly in the bone marrow, particularly in the sternum, the vertebral bodies, the ribs, and the wings of the pelvis bones. In response to the presence or absence of certain growth factors, hemocytoblasts undergo a series of divisions that result in increasingly differentiated cells with specialized functions. While some hemocytoblasts end up going down a branch that leads to the various types of cells that make up our immune system — the leukocytes, or white blood cells — others begin a process of differentiation into cells specialized for the transport of oxygen and carbon dioxide: the red blood cells (RBCs), also called erythrocytes.

In the process of differentiation, or erythropoiesis, the stem cells undergo a dramatic transformation in both size and shape. The developing red blood cells get smaller and start to take on their characteristic biconcave disc shape. Genes that code for heme proteins start to get expressed, and the developing erythrocytes start to turn red as the oxygen-carrying protein hemoglobin accumulates in the cytoplasm. Eventually, the nucleus that was present in the stem cell, which has been shrinking during the whole differentiation process, is ejected from the immature erythrocyte, leaving a small bag of hemoglobin and not much more.

The immature red blood cells at this stage are called reticulocytes. At this point they migrate from the marrow and into circulation, where they mature into erythrocytes in a couple of days. Reticulocytes make up about 1% of the RBCs in a healthy patient at any given time, with the other 99% being a mixed population of ages up to about four months. When they get that old the RBCs are too damaged to do their job, so they are removed from circulation and recycled by the spleen, with the elemental iron from their hemoglobin recycled for the next round of erythropoiesis.

Baby Blood Cells

In a healthy adult, erythropoiesis is a prodigiously productive process; even though it takes three weeks to go from stem cell to reticulocyte, the marrow puts something like 200 billion new RBCs into circulation every day. This ability to quickly rebuild our stock of RBCs is the key to blood donation; typically, blood donors completely recover from the donation of half a liter of whole blood within 20 days or so. As a result of this rapid recycling, blood donation has become an absolutely critical life-saving tool, used to treat a huge range of diseases and disorders.

Photomicrograph of erythrocytes. Source: by Drs. Noguchi, Rodgers, and Schechter of NIDDK, National Institutes of Health. Public domain.

But, as life-saving as whole blood transfusions may be, there can be complications. Red blood cells carry protein factors on their surface — the familiar “ABO” groupings — that can, even when carefully typed and cross-matched, eventually raise an immune reaction in the recipient. This tends to be most prevalent in frequent blood recipients, particularly in those with anemias like sickle cell anemia or thalassemia, or with clotting disorders like hemophilia.

One way to potentially get around the issue of developing what essentially amounts to a “blood allergy” is to increase the time between transfusions, and that’s exactly what the RESTORE trial is looking at. Rather than transfusing whole blood containing RBCs with a wide range of ages, they want to be able to transfuse patients with blood where every RBC is exactly the same age and brand new. That way, hypothetically at least, the transfused RBCs would survive for their full 120-day lifespan, rather than being retired continuously starting from nearly the moment of transfusion.

The first step in exploring how useful lab-grown blood is in treating diseases is to make some blood. While there hasn’t been a paper published from the RESTORE trial yet, in vitro erythropoiesis has been a pretty standard lab procedure for decades. Methods vary, but from the description given by the RESTORE team, it’s likely that they’re isolating and amplifying the small number of hematopoietic stem cells that circulate in the blood along with mature cells. These cells have antibodies on their surface that mature red blood cells lack, and that fact can be used to isolate them from the rest of the cells. A small population of stem cells can then be grown up in the appropriate growth medium.

To turn the stem cells into RBCs, the culture can be treated with erythropoietin, a protein that’s normally secreted by the kidneys. Erythropoietin, or EPO, is secreted when the body senses low blood oxygen; the body responds by stimulating the differentiation of stem cells into RBCs, to increase the oxygen-carrying capacity of the blood. EPO gained fame in the 1990s as a performance-enhancing drug when used by athletes, particularly cyclists, to increase the oxygen-carrying capacity of their blood.

For the RESTORE study, whole blood is obtained from healthy donors, stem cells are purified from the whole blood, and RBCs are cultured. Some of the whole blood is also set aside as a control. Both batches of blood are then labeled with a mildly radioactive tracer. On the donor side, healthy volunteers are given a very small transfusion — just a few milliliters — of the cultured blood. They’ll be followed over the next four months, with samples of their blood being analyzed to see how many of the cultured RBCs remain. After all the cultured blood has been cleared out, the experiment is repeated with the donated blood.

If all goes well, the RESTORE team will transfuse a total of ten volunteers. They expect that the cultured RBCs will last longer in circulation than the whole blood transfusion; if so, this may open the door to improved therapies for patients in need of frequent blood transfusions. There’s a lot of ground to cover before that, of course, not least of which is scaling up a method that can currently produce enough cultured RBCs for one person.

The Future of Synthetic Blood

But could a similar process one day result in completely lab-grown whole blood? Possibly, but whole blood is far more complex than just RBCs, and learning to grow large quantities of it is likely to be orders of magnitude more difficult. What would make this possible is the initial stem cell: the hemocytoblast. Since every cell in whole blood descends from that one cell type, it should be possible to grow whole blood completely in vitro. This doesn’t mean that the process would be entirely synthetic, of course. Those stem cells have to come from somewhere, and the most obvious source would be human donors. That begs the question of why you’d bother with the in vitro steps at all; if you’ve got to get a donation, just get whole blood and be done with it, right?

While that’s true, there would be significant benefits to turning donated stem cells into artificial whole blood. The main advantage is that since stem cells are essentially immortal, a single donation could potentially generate an unlimited amount of whole blood. This could be of great benefit anywhere the pool of potential blood donors is limited, but there still may be demand for blood in an emergency — think space travel. And even if generating whole blood from a stem cell culture never proves to be possible, being able to scale up erythrocyte production and mix it with donated plasma could be tremendously valuable — thanks to plasmapheresis, plasma can be donated much more often than whole blood.

The day when human whole blood donations are no longer needed will probably never come, and if it does it’s a long way off. But the fact that the RESTORE trial has managed to grow even the few milliliters of blood needed to do their initial experiments is exciting news. Not only might this trial result in tangible benefits to patients in need right now, but it may also open the door to unlimited whole blood on demand.

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