Could Stem Cells Breathe New Life into the Field of Blood Substitution?

 

Immature cells' regenerative prowess injects new excitement into the field

Mar 17, 2014 |By Dina Fine Maron

Image: CDC

More than a century after scientists embarked on the quest to find an alternative to the blood coursing through our veins, the dream still will not die. Not after a major study dealt a seemingly fatal blow to the field—determining that the top synthetic blood candidates at the time were all more likely to kill you than to save your life. Not after billions of dollars in public and private investments dried up. And not after multiple companies ran aground.
Starting in 2011, however, the moribund field received yet another revival, this time from a group of French researchers with a new approach to boosting blood supplies. Their principal insight: don’t try to re-create millions of years of evolution. Instead, they proposed to piggyback off of what nature already made by coaxing stem cells into taking on the job.
The appeal of creating blood alternatives is obvious. Certainly after a battlefield trauma or a car accident a ready transfusion of artificial blood that could theoretically work with any blood type and not require refrigeration would be a welcome medical tool. A synthetic product outlasting the typical 42-day shelf life of red blood cells and sidestepping even the miniscule risk of transmitting a blood-borne disease would also be high on the medical wish list. But such a product has not yet been created and proved safe in humans.

It’s not for lack of trying. Although blood cells serve multiple roles in the body and have complex interactions with other cellular materials, most synthetic blood products have aimed to just stick to the bare basics—shuttling oxygen from the lungs to different vital organs and then bringing carbon dioxide back to the lungs to be exhaled. When the red cell count gets low, bodily organs may not get the oxygen they need, making a person weak and eventually resulting in serious health problems. The most popular approach taken to replicate that function has been to create artificial hemoglobin-based oxygen carriers, tapping proteins in red blood cells called hemoglobin that act as oxygen’s transport service, and chemically modifying them to increase oxygen-carrying capacity.
But the new idea is to get the body to grow its own substitute—a product that would not be the same as whole blood but could fit the bill in a pinch.

A Paris-based research group, headed up by Luc Douay, professor of hematology at University Pierre and Marie Curie Faculty of Medicine, has already had some success. They culled stemlike cells from blood circulating through a patient’s body and manipulated them into becoming red blood cells nearly identical to those that normally transport oxygen in the body. The team injected two milliliters of the stem-cell derived blood cells back into the patient—an amount far smaller than would be needed in a typical transfusion. The creations had stored well at refrigerated temperatures and circulated in the body with survival time on par with that of original red cells.
Jackpot. In short, the work—albeit on one person, tapping cells from his own body—proved that it could be done. “It’s a promising approach,” says Harvey Klein, chief of the Department of Transfusion Medicine at the National Institutes of Health. “There is a school of pessimists who believe that because of costs it will never materialize on a practice level, but I’ve heard that all my life about different areas of medicine including bone marrow transplants in the ‘60s.” Still, he and others caution that the field is far from being able to forgo the need for blood donors for day-to-day care. In fact, the market for artificial blood products would likely be limited to people with rare blood types and those who, due to blood diseases, require new transfusions, perhaps every couple months.

It’s an encouraging step forward for a field littered with odd and sometimes cringe-worthy efforts to get at the lifesaving power of blood. Animal to human blood transfusions received a short-lived audition in 1667. But the first human-to-human blood transfusion was not performed until 1818—before we learned about blood types and how and when the body rejects certain transfusions. Blood-product research also included attempts in the late 1800s to hook up ailing patients to infusions of fresh cow’s milk. Milk, like blood, had fats that emulsify in fluid, the reasoning went. Plus, milk would be safer than blood because it would not clot. When patients died, physicians figured it was due to other complications. Needless to say, milk injections, like those from animal blood, never really took off.
In the U.S. there is no shortage of blood products available for most patients, thanks to blood donors. After a healthy person donates blood that fluid is typically whirred in a centrifuge and separated out into several parts. Most commonly, patients receive transfusions of red blood cells, the component of blood that shuttles oxygen to tissues throughout the body. (Patients may also receive infusions of white cells that help fight infection or platelets, the small, colorless cell fragments that help stanch bleeding by clotting.)

Although most people only get transfusions once or twice in their lives (if at all), individuals with conditions like sickle-cell anemia require consistent blood transfusions of red cells. But with each infusion there’s a small risk that the body could develop an infection, reject the foreign blood or form antibodies that will lead to the body rejecting and destroying certain bloods in the future. A key threat, however, is that each transfusion contributes to the risk of iron overload in the body. All red blood cells contain iron, but after the body takes what it needs it has no easy way to dispose of the excess. It gets stored, instead, in organs including the heart, liver and pancreas. That buildup of increased iron with each transfusion can damage the organs and eventually prove fatal.
The French researchers hope that using freshly created blood cells made from stem cells could help alleviate those iron buildup concerns. “We think it could be transfused at least three to five times less each year because of the efficiency of the transfusion,” Douay says.

The secret lies in the age of the red blood cells derived from stem cells. Although red cells from donors have a typical shelf life of 42 days, they are a mix of older and newer cells, which means a number of them may not last long in the body. With stem cell–derived options all of the blood product would be new, which could theoretically give patients more bang for each infusion. The only thing that would appear different to a patient receiving the transfusions, ideally, is that he would be receiving them less often. “If you have brand-new cells, you should be able to increase the intervals between transfusions so you can make it longer, says David Anstee, director of the International Blood Group Reference Laboratory in England. “You might be able to improve the quality of life in those situations.” It’s not a perfect fix because it would likely add months, not years, between transfusions, but it could be a start.
Also, researchers could carefully select which blood types to culture with each batch of stem cells, creating stockpiles of needed blood products for people with extremely rare blood types whose blood cell makeup makes it challenging to find good blood matches for transfusions because they would reject most other types of blood. But so far all this remains theoretical—since that initial breakthrough no new blood product has inched close to regulatory approval in the U.S. or Europe.

The greatest hurdles are arguably more monetary than technical, but the monetary obstacles are massive. To match the current prices of high-quality blood products the process would have to become at least fivefold more cost-effective, Douay notes in a recent study published in Biotechnology Journal. Although the current price tag for an average hospital to create one unit of red blood cells from donor blood comes in at about $225, more expensive, unique stockpiles of red cells, kept for individuals with rare blood needs, can cost anywhere from $700 to $1,200 per unit. By comparison, with Douay’s method the price for equivalent amounts of blood cells (assuming that much product could be made successfully) would likely be around $8,330. It could even cost up to $15,000 per unit if all does not go according to plan, Douay estimates.
Moreover, the idea of using Douay’s earlier process, which involved growing the cells in culture, at a larger scale would be “delusional,” he says. To make just one unit of blood—roughly a pint—it would require growing cells in about 400 flasks that were about 30 centimeters by 20 centimeters, he says. But even with endless space for those flasks it would still be impossible because the constant pH and temperature controls that would be needed would be impossible to maintain. What would be needed, he says, is an automated, stirred large-scale bioreactor (something his team hopes to one day produce themselves). “Even something as seemingly simple as red blood cells that don’t have a nucleus evolved a structure and a function that is much more complicated than we can perceive by looking under the microscope,” says Jason Acker, associate director of development for Canadian Blood Services.
Douay, for his part, is not surprised it has taken more than a century for science to get even to this point, where the future of subbing in stem cells for blood products still remains little more than a reverie. “For years,” he says, “we tried to replace nature and do as well as nature does.” The regenerative powers of stem cells may just yet inject new options into the field.