Red Blood Cells
In 1873, Dr. Joseph Howe of New York City injected 1.5 ounces of goat’s milk into a tuberculosis patient’s vein.
Vertigo, chest pain, and uncontrollable eye movement soon racked Howe’s milk-infused patient. Naturally, the physician doubled the dose. “I am of the opinion it had no effect,” Howe noted in an 1875 account of the procedure. The patient promptly died.
Surprisingly, Howe was not the first to conduct milk transfusions—years earlier, in the midst of a cholera epidemic, two doctors brought a cow to a Toronto hospital and pumped the animal’s milk into their own patients. Howe, though, was a far more persistent advocate of the procedure.
Despite his first patient succumbing to the treatment, the New York physician continued his experiments on dogs (bleeding seven of them to near death and attempting to revive the hounds with milk) and as a live show (audiences watched as a goat was brought into the operating room and milked before their very eyes). In 1880, testing a hypothesis about the superiority of injecting humans with human milk, Howe acquired three ounces of breast milk from a new mother. In that final demonstration, the patient’s breathing stopped by the second ounce administered and she was supposedly revived by artificial respiration and “injections of morphine and whiskey” (a story for another time). Only then did Howe relent; human milk, he conceded, was not the substitute for blood he and other doctors had hoped—and somewhat mercilessly attempted to prove—it was.
Human blood is a cocktail of proteins, salt, platelets, and red and white blood cells perfectly engineered to deliver oxygen and nutrients throughout the body with precision and efficiency. Blood vessels ribbon the inside of our bodies providing a highway—literally about 100,000 miles for the average adult—along which blood trucks cellular waste to the kidneys, transports antibodies, and circulates hormones. When we’re injured, blood forms a clot to plug the wound. One of its critical ingredients, the oxygen-conveying protein hemoglobin, is so vital to life that it can be found in creatures ranging from the skink lizard to intestinal roundworms.
Since the early 1600s, physicians have unsuccessfully pursued a suitable substitute for the life-giving elixir of blood, injecting everything from milk to urine, beer, sheep’s blood, saline solutions, and perfluorochemicals (a group of polymers similar to Teflon) into animal and human subjects. We’ve come a long way since Howe’s ill-fated attempts, but the modern demand for blood transfusion still poses enormous problems of supply and delivery. “It’s not appreciated how commonly we prescribe blood,” said Allan Doctor, a pediatrics and biochemistry professor at Washington University School of Medicine. “Or that these are living cells; they’re not inert. It’s like doing a little transplant.”
Anything from surgery to cancer treatments, injury care, organ transplants, and childbirth might require a supply of blood. In catastrophic scenarios—car accidents in remote places, natural disasters, overseas combat—lack of access to blood becomes its own medical crisis. Each year, about 60,000 people in the U.S. die from hemorrhaging before they can reach an emergency room. Among the main issues with storing and transporting blood are the fragile nature and unique signature of the vital fluid itself: Once donated, the fluid must be screened for hepatitis, HIV, and other pathogens. It must match the blood type of a recipient. It also needs to be refrigerated and even then, the stuff expires after 42 days. Despite rigorous and noble administration and donation efforts, shortages continue. “The amount of blood we need never matches the amount of blood donated,” said Anirban Sen Gupta, a professor of biomedical engineering at Case Western Reserve University in Cleveland, Ohio. “We simply don’t have enough.”
This all means that a blood substitute, if a scientific group were to create an effective one that is, would be an extremely lucrative endeavor. Over the last hundred years, in particular, world wars and the HIV crisis have only increased interest in a non-human-derived blood supply. By one estimate, the artificial blood market could be worth $15.6 billion by 2027 if companies can develop products that do everything from carry oxygen, deliver drugs, and enhance healing. Today, a small number of U.S. research groups is committed to finding a synthetic solution to this seemingly unsolvable biological puzzle. For now, this much is true: a century and a half have passed since Dr. Howe’s futile milk experiments and there is still no safe, effective artificial blood product approved in the United States or Europe to give to people in desperate medical need of the vital—and so far, inimitable—substance.
‘An unsolvable problem’?
Efforts to imitate one of nature’s most mysterious concoctions began in earnest in the 1660s, around the time English doctor Richard Lower used quills as a sort of aqueduct in dog-to-dog blood transfusions.
“This done, (sew) up the skin and dismiss him, and the Dog will leap from the Table and shake himself and run away, as if nothing ailed him,” Lower wrote in a letter to the chemist Robert Boyle. Soon after, Lower transfused lamb blood into a clergyman (animal blood transfusions would eventually be outlawed, but not until the end of the 17th century).
One hundred years after that, Philadelphia physician Dr. Philip Syng Physick—known as the Father of American Surgery and who counted President Andrew Jackson, Chief Justice John Marshall and the wives and children of several other U.S. presidents among his patients—reportedly performed the first human blood transfusion in 1795 (all that is known of this transfusion is that it occurred, based on a two-line footnote published in a later medical article). Further experiments quickly followed, and within decades of that initial blood exchange, a British obstetrician saved a life with the procedure. To rescue a new mother from postpartum hemorrhaging, he injected four ounces of her husband’s blood, via syringe, into her veins. While the quest for blood substitutes goes back centuries, true progress, however, has only been made in recent decades. Still, the hunt for an easy substitute for blood was (and remains) far more appealing than performing the messy transfer of one person’s bodily fluids to another.
In 1966, biochemist Leland Clark first demonstrated the oxygen-carrying abilities of perfluorochemicals (PFC). These liquid compounds are often used for coatings in products like furniture, food packaging, and electrical wire insulation. Clark and others found droplets of perfluorochemicals could capture and transport dissolved oxygen in its liquid core, albeit not as efficiently as hemoglobin.
In the 1970s and 1980s, a number of physicians attempted to use PFC emulsions as blood substitutes, but subsequent clinical trials demonstrated patients developed severe side effects including increased risk of stroke, low platelet count, and flu-like symptoms.
The most successful strategy has been a pursuit of hemoglobin-based blood substitutes, or HBOCs as they are called, that mimic the oxygen transport functioning of red blood cells by synthetically creating and packaging human or cow hemoglobin.
HBOCs though, have a perilous past. In the 1930s, researchers first experimented with them in cats by completely replacing the animals’ blood with a cell-free hemoglobin solution. The treatment wreaked renal havoc on their feline subjects, but efforts continued, and in 1949 a group even performed human clinical trials of this artificial hemoglobin solution; the trial led to serious kidney dysfunction in 5 of the 14 patient subjects. By the 1980s, a handful of researchers from Illinois to Cambridge began testing new, chemically-modified HBOCs in humans with military funding. None would even come close to FDA approval.
In 2001, the HBOC Hemopure, developed by biopharmaceutical company Biopure Corporation, became the only blood substitute ever to be approved for sale in South Africa (Hemopure is not FDA-approved and can only be administered in the U.S. under specific circumstances, such as when Jehovah’s Witnesses refuse human blood transfusions).
At first, the future seemed bright for Hemopure, but safety and health concerns cut short any optimism. The mechanisms aren’t fully understood, but studies suggest free hemoglobin molecules are toxic to many human organs. One study in particular analyzed 16 HBOC clinical trials and described a three-fold increase in the risk of heart attacks in people who received the substitutes compared to those who were given donor blood.
It was a major blow for research studies on artificial blood and by 2010, investors had fled. Blood remained as mysterious an elixir as ever.
“The field went dark until recently,” said Dr. Dipanjan Pan, a bioengineering professor at the University of Illinois. Now, he adds, “there’s a thaw in the field.”
Today, researchers armed with major advancements in nanotechnology, materials engineering, and blood cell biology have a new strategy: Instead of replicating blood’s symphony, labs are imitating its individual instruments.
“Mimicking nature is always a challenge,” Case Western’s Sen Gupta said. “It doesn’t have to be as good as real blood to have value. It may not have to be as complex as a real red blood cell to do the job.”
Scientists have also begun focusing on designing products to be used in places where a standard blood transfusion isn’t an option: In the back-country, on a cruise ship, aboard the international space station, or, someday, on the surface of Mars.
Pan, Doctor, and Philip Spinella, a pediatrician at Washington University Medical School, for example, have created Erythromer, a bagel-shaped artificial red blood cell with a nanometer-sized synthetic packet of purified hemoglobin (taken from expired donated blood) sheathed in a synthetic shell. Unlike regular blood donations, it can be freeze-dried, stored at room temperature for extended periods of time, and injected into any human regardless of blood type. Hypothetically, EMS could keep a bag of Erythromer in ambulances, and reconstitute the powder with water—”like tang,” Doctor said—to keep patients alive until they reach a hospital. “It still doesn’t come close to all the things blood does,” Pan said, comparing Erythromer instead to a sort of internal bandage that stabilizes until proper treatment. “It’s a bridge.” Erythromer’s research lab just moved from mice to rabbit testing, but still has to get through testing on larger animal and non-human primates before human trials for FDA approval. In other words, they still have a long way to go.
Other labs have focused on mimicking the clotting function of platelets, crucial for ensuring someone doesn’t bleed out. Materials engineer Erin Lavik’s lab at the University of Maryland, Baltimore County, is developing a synthetic polymer nanostructure that binds with platelets to help them to pile up more quickly. At North Carolina State, bioengineer Ashley Brown leads a group in developing synthetic nano- and microparticles that are decorated with specific proteins that help augment the natural clotting process. In 2016, Sen Gupta co-founded the biotech startup Haima Therapeutics, whose platelet substitute Synthoplate, is currently in pre-clinical animal testing. Sen Gupta said he expects to begin safety and toxicology evaluations under FDA requirements in two or three years.
Both Erythromer and Haima Therapeutics are about five years out from commercialization, founders say.
“When you’re trying something that hasn’t been done before, in a field where a lot of people have failed, it’s quite humbling, even unsettling, to think we might be able to get a little further,” Doctor said.
At least for now, artificial blood remains a holy grail of trauma medicine.