In a pair of fluorescent-lit rooms on both sides of the Atlantic, the guinea pigs awaited their fate. They were not literally guinea pigs. Two were lightly sedated, extremely fluffy white rabbits resting on pee pads; the other was Nick Green, a sixty-four-year-old part-time administrator at the University of Cambridge who reclined, hands clasped atop his patterned sweater, on the starched sheets of a hospital bed. All three were hooked up to machines that provided a readout of their vital signs, and all three were prepared to have a syringe of manufactured blood injected into their veins.
There were, of course, some differences. In their metal cages in Baltimore, the rabbits were pampered with fleece blankets and fresh hay, water, and pellets, which were served in front of a screen that streamed a ten-hour YouTube video titled “Instantly Soothe Anxious Rabbits (Tested).” The video showed an endless sequence of bunnies hopping through meadows and being gently tickled behind the ears. Meanwhile, Green made do with a slightly depressing cafeteria lunch—a cheese-and-pickle sandwich and a shiny red apple—and some chitchat about the weather.
Perhaps more significantly, the rabbits were not in the best of shape. Their pink eyes blinked laboriously; they panted and shivered. Half their blood had been drained from their bodies, sending them into hemorrhagic shock—a disastrous multi-organ shortage of oxygen that, even with prompt resuscitation, frequently proves fatal. Green, on the other hand, was fit and well. A keen cyclist, he’d pedalled that morning into a research facility on the outskirts of Cambridge, and planned to ride into work later that afternoon. “Yes, I am a MAMIL,” he confessed, using the popular British acronym for middle-aged men in Lycra, perched on their expensive bikes.
A few steps down the hallway from Green’s bed, Cedric Ghevaert, a hematologist with National Health Service Blood and Transplant, was wading through the binder’s worth of paperwork that was required to authorize the syringe, which contained a couple of teaspoons of a mysterious dark-red fluid. Manufactured blood is not classified as blood by U.K. regulators, Ghevaert told me. “It’s a drug substance, therefore it has to be prescribed.”
The liquid had its origins in a pint of blood that had been donated at the Cambridge clinic a few weeks earlier; it had since taken a tour of the country, spending time in Bristol, where N.H.S.B.T. maintains one of the world’s largest blood-processing facilities, and then in London, where it had been laced with radioactive chromium-51. There was a deliberate uncertainty about what had happened to it in Bristol. Green couldn’t know whether the stuff in the syringe was simply the donated blood or—more intriguingly—an entirely fabricated substitute, produced using stem cells found in that original pint.
The reason for this secrecy was that Green was one of thirteen participants in the first clinical trial to transfuse lab-grown red blood cells into humans. RESTORE, as the N.H.S.B.T.-funded trial is known, is designed to measure the survival and circulation of these cells, compared with normal donated ones. (The radioactive labelling would allow the team to count the infused cells for several months post-injection.) “There are companies and academic outfits that are looking to do this across the world,” Ghevaert, a boyish fiftysomething with an endearing French accent, said. But he and his co-lead, Rebecca Cardigan, are “the first ones reaching the point where we are truly comparing the gold standard of donor cells with the manufactured red cells.”
In Baltimore, the rabbits were receiving a somewhat different concoction. They belonged to the lab of Allan Doctor, the director of the Center for Blood Oxygen Transport and Hemostasis, at the University of Maryland School of Medicine, and the co-inventor of ErythroMer, a synthetic nanoparticle that mimics the oxygen-carrying role of red blood cells. If the RESTORE trial aims to create the lab-grown burger of blood, Doctor is leading an initiative to create its Impossible equivalent: an artificial substitute that bleeds—or at least operates in the body—almost exactly like the real thing.
But, as even the most ardent alt-meat advocate will admit, plants or lab-grown cells dressed up as steak are hardly one-for-one substitutes in terms of flavor, nutrition, or cost. Meanwhile, scientists don’t yet understand everything that blood does, or how it does it. Somehow, the various components of blood—red and white cells, platelets, and plasma—manage to perform an entire spectrum of life-promoting functions. In addition to picking up oxygen in the lungs and releasing it throughout the body, blood delivers nutrients; transports hormones; carts away toxic waste products such as carbon dioxide, urea, and lactic acid; regulates body temperature, pH, and over-all chemical and fluid balance; monitors for and raises the alarm about organ damage; recalls, detects, and defends against immune-system threats; and is even responsible for the hydraulics behind tissue engorgement, as the more prudish textbooks might put it.
“You know, it’s hard to compete with millennia of evolutionary pressure,” John Holcomb, a renowned trauma surgeon who honed his skills during two decades in the military, told me. “I’m not sure we’re that smart.” As Green and the rabbits awaited their syringes, I couldn’t help but wonder: Can we really hope to imitate this magical fluid—and what might it mean if we do?
On a sunny afternoon in Pasadena, California, I went for a swim at my local pool, showered, then strolled over to a bloodmobile stationed in the parking lot. After filling out several forms, I was invited to put my feet up on a plastic-covered recliner and given a rubber ball to squeeze. As I pondered what to make for dinner, a nurse slid a needle into my arm and siphoned off one of the nine pints of O-positive blood coursing through my body. Fifteen minutes and a complimentary granola bar later, I was on my way.
A follow-up e-mail arrived almost immediately. “Share your lifeline, share your love,” a blood-donation coördinator wrote, encouraging me to book my next appointment. Blood is “the priceless gift of hope,” according to the American Red Cross, which collects, processes, and sells forty per cent of the U.S. donor-blood supply. Indeed, for something that is by far the most common component of the human body—of the roughly thirty-six trillion cells that make up an average adult male, about thirty-two trillion are blood—it is “among the world’s most precious liquids,” the journalist Douglas Starr writes in his book on the subject, noting that a barrel of blood would retail for more than a thousand times its equivalent in crude oil.
But blood’s elevated status long predates our fossil-fuel era. It is the stuff of the most solemn oaths and the deepest bonds—the essence of not only life but, as Virgil writes in his Aeneid, the “purple soul” itself. My donation might have been appreciated, but it pales in comparison with the blood sacrificed to appease ancient gods or shed by Jesus to cleanse humanity of its sins. Even the Devil, via his agent Mephistopheles, recognized blood’s value: it is, he tells Goethe’s Faust, “a very special juice.”
For centuries, blood was described and imagined in these mythical terms. It wasn’t until the sixteen-hundreds, after the Catholic Church relaxed its prohibition on dissecting the human body, that the English physician William Harvey discovered the truth: the purple soul was nothing more than a liquid that was pumped through the body, like water through plumbing. Harvey’s insights raised the thrilling possibility of introducing other substances directly into the blood, in order to infuse their qualities into the body’s essence. Christopher Wren, better known as the architect of St. Paul’s Cathedral, was a member of Harvey’s intellectual circle, and he conducted some of the very earliest transfusion experiments, injecting wine, ale, opium, antimony, and “other things” into the bloodstream of dogs and observing the results. (They variously vomited, passed out, and became “extremely drunk.”)
Hot on Wren’s heels came a pair of scientists—Richard Lower, a medical student from Cornwall, and Jean-Baptiste Denis, the physician to the King of France—who wondered whether moving blood from one creature’s veins into another’s might change an animal’s very nature. Perhaps a ferocious dog could be made gentle “by being . . . stocked with the blood of a cowardly Dog,” Robert Boyle, another scientist in Harvey’s circle, suggested. The diarist Samuel Pepys described an attempt to replicate one of Lower’s early canine trials, in which he stitched the artery of a donor dog and the jugular vein of the recipient to opposite ends of a hollow reed, so that the blood flowed from one to the other. “This did give occasion to many pretty wishes, as of the blood of a Quaker to be let into an Archbishop, and such like,” Pepys wrote. Doctors speculated that the elderly might be rejuvenated with the blood of children; that melancholics could be cheered up using the blood of happy souls; and that clashing couples might resolve their differences by exchanging blood.
All this excitement came to an abrupt end when, during the winter of 1667, Denis began transfusing the blood of a calf into a thirty-four-year-old manservant named Antoine Mauroy, who was subject to “phrensies” during which he would beat his wife, take off all his clothes, and run around Paris setting homes on fire. Denis hoped that blood from the gentle calf might serve as a kind of tranquillizer, calming the troubled Mauroy. After the first couple of infusions, Mauroy sweated, vomited, complained of lower-back pain, and pissed charcoal-black fluid—all, we now know, symptoms of a severe transfusion reaction in which the recipient’s antibodies attempt to destroy the newly introduced foreign substance. Nonetheless, he soon not only recovered but seemed to be a changed man, speaking lucidly, whistling merrily, and treating his wife with unprecedented tenderness. Unfortunately, a couple of months later, just as the third transfusion was about to get under way, he died. Suspicion fell on his wife, who had, it was alleged, put arsenic in Mauroy’s soup, but the damage had been done: before long, the French authorities had officially banned blood transfusion in humans, with the British government and the Pope following suit shortly thereafter.
It took more than a century for medicine to return to the technique, this time as a means to replace blood lost during childbirth. Gradually, blood transfusions came to be seen as a potentially lifesaving—sometimes near-miraculous—treatment in otherwise dire cases of traumatic injury and hemorrhage. It “raised hopes where formerly there had not been any,” as Geoffrey Keynes, the surgeon brother of the economist John Maynard, put it in his memoir, recalling how, during the First World War, he would “steal into the moribund ward,” conduct a transfusion on one of the patients, and pull “many men back from the jaws of death.”
Yet death was still a frequent result of transfusion, and it was only in the early decades of the twentieth century that some of the procedure’s most significant problems were ironed out. The Nobel Prize-winning discovery of blood types, in 1900, ultimately improved the odds of survival; no longer was the avoidance of dangerous transfusion reactions a matter of luck. Still, blood’s habit of coagulating, so useful in the body, proved a challenge outside of it: within a few minutes of beginning a transfusion, clots would gum up the needles and tubes, seriously limiting the quantity of blood that could be moved from person to person. In the nineteen-tens, a doctor at Mount Sinai Hospital, in New York, discovered that adding a tiny amount of sodium citrate to donor blood would keep it flowing without poisoning the recipient, an advance so transformative that, according to one of his colleagues, it “was almost as if the sun had been made to stand still.” Then, there was the storage issue.
“People forget that blood is alive,” Allan Doctor told me. “They think it’s like urine or something. It is a bodily fluid—but it’s living cells.” Keeping those cells alive outside the body requires very particular conditions, and, through the nineteen-twenties, blood transfusion required the presence of a live donor. In London, Geoffrey Keynes relied on a directory of on-call volunteers; in a time when many people didn’t have a telephone, policemen and priests were often enlisted to track down donors at any hour of the day. It wasn’t until the Spanish Civil War in 1936 that a Canadian surgeon figured out how to keep blood intact for up to a week, refrigerated in glass milk bottles, and the modern era of blood transfusion finally began.
In Filton, a suburb on Bristol’s northern edge, Britain’s National Health Service operates a blood factory that can receive and process up to three thousand units a day. Inside the vast, white manufacturing hall, bags and bags of blood dangle overhead, suspended from a steel rail like macabre baubles. “They’ll usually come in warm,” Naomi Jones, the center’s then deputy head, who was clad in a hairnet and blue coveralls, told me. The fresh blood separates slightly as it hangs: the dark-red cells, heavy owing to their iron content, sink to the bottom, and the plasma, which makes up more than half of blood’s volume, sits on top. Each bag looked different in ways that, Jones told me, can reflect its donor’s health—some had more or fewer red cells, while the plasma ranged in shade from lemonade to Coca-Cola. “If you’re on the pill or anything like that, the hormones will make it green,” she said. “And people who have lots of fats in their blood, it’s like a banana milkshake.”
During the blood’s sojourn on the rack, white blood cells are filtered out. Then, in dedicated pods staffed by one or two people, the bags are broken down into the rest of their component parts, which are weighed, labelled, and put on conveyor belts that transport them into storage. Red blood cells are stacked in plastic crates in a refrigerator, separated by blood type; plasma is blast-frozen; and platelets, which must be kept in gentle motion, are extracted from the thin beige layers in between, pooled together, and placed on metal shelves inside an incubator that jiggles from side to side.
Modern on-demand blood, it turns out, is a logistical miracle: rubber tubing and milk bottles have been replaced by an engineered process that gathers the liquid, tests it, and then stores each of its elements for maximum shelf life, before getting it to the patients who need it. But not to all of them. Despite the high throughput of the N.H.S.B.T. blood factory, and despite the fact that a unit of blood is transfused every two seconds in the United States, there just isn’t enough.
Part of the problem is that a lot of people need it. An astonishing number of civilians die of injury each year—upward of a hundred and fifty thousand in the U.S., and more than five million globally. “Every! Year!” John Holcomb, the trauma surgeon, said. “It’s the leading cause of life years lost.” Accidental injury is the primary cause of death for anyone forty-four or younger, and blood loss is the most common cause of potentially preventable trauma deaths. Holcomb and his colleagues estimate that in the U.S. alone there are likely thirty thousand preventable deaths each year, owing to hemorrhage. In one paper, they combed through the 2014 mortality data for the county encompassing Houston, Texas: even in a major metropolitan area with a well-resourced trauma-care network, more than one in three people who died from bleeding could have possibly been saved.
“If you go into hemorrhagic shock, you need blood products,” Holcomb said. “And the data are clear that, the earlier you get blood products, the better your survival.” Every minute matters; ideally, injured individuals would receive blood on the street or in an ambulance, before they even reach a hospital. Many of them don’t, for reasons that are demographic, biological, and economic. “No. 1, there’s not enough blood,” Holcomb said. “You probably need another sixty to a hundred thousand units of blood available nationwide.” In the U.K., N.H.S.B.T. aims to have five to seven days’ supply on hand; in the U.S., the goal is similar. The reality is that, at times, blood isn’t available. Ghevaert told me that, on a recent trip to the U.S., he’d been informed that, on that particular day, there were no platelets left at 11 A.M. in the New Orleans area. Platelets are what allow blood to clot—they’re lifesaving for patients who are hemorrhaging after surgery, traumatic injury, or childbirth.
This shortage is caused by the fact that too few people give blood. Of the thirty-eight per cent of Americans who are eligible to donate, less than three per cent regularly do. (Some trauma experts suggest that reintroducing payment for blood donations, which are currently voluntary, would boost supply, though the U.S. has a sordid history of such arrangements leading to the exploitation of the poor.) “In addition to that bad stuff, our population is aging,” Philip Spinella, an expert in transfusion medicine at the University of Pittsburgh and a co-founder of KaloCyte, the company developing ErythroMer, explained. “In the next ten years, there’ll be twenty million more people above the age of sixty-five.” Across the developed world, societies are increasingly elderly, which squeezes the blood supply from two directions. “Baby boomers and the Greatest Generation—they were the blood donors,” Mark Gladwin, the dean of the University of Maryland School of Medicine, told me. “Our young generation is not donating blood.” Meanwhile, the people over sixty-five “get cancer and have heart surgery—they need platelets and red cells,” Spinella went on. “Where’s it going to come from? Right now, our donor base can’t support today’s needs. What about 2030?”
Blood’s innate fragility exacerbates this crisis. It has a remarkably short shelf life: five days for platelets, and forty-two for red blood cells. If you add a cryoprotectant, red blood cells can be successfully frozen—but then they have to be defrosted, and the antifreeze has to be washed out with extreme care, so as not to damage the cells. This can delay the process by hours, during which time most hemorrhaging patients will be long gone. What’s more, even meticulously stored blood is gradually dying. “When you put fish in the refrigerator and leave it for five days, it’s less good,” Holcomb said. “Blood is the same.” Doctor showed me research that measured how much oxygen cold-stored red blood cells were capable of moving. “It’s down to forty per cent of normal before it’s even outdated,” he said.
The rapid turnover rate of fresh blood, combined with the equipment required to slow its decline, means that its use tends to be restricted to large trauma centers in major urban areas—which means that people who get injured far from such resources, whether they are an hour outside Houston or almost anywhere in the developing world, have a much higher chance of dying from trauma. There are ways around this: in Rwanda, blood is often delivered by drone; in the United States, it could be carried in an ice chest on every ambulance or medevac helicopter. The fact that it is not is almost purely economic.
“The problem here is that there’s practically no reimbursement for prehospital blood by insurance and agencies,” Holcomb said. “There’s nothing that has a bigger impact on survival than prehospital blood. Nothing. And yet the major impediment is not logistics—we’ve worked through that. It’s not how to store the blood. It’s reimbursement. And, in our system, if you don’t get reimbursed you don’t do it.” Spinella, who told me about a trial in Pittsburgh demonstrating that prehospital plasma greatly improves survival rates, is also outraged. “We had to stop it after the trial was over because our E.M.S. system can’t afford to put blood on the ambulances,” he said. “So we proved it, and now we can’t do it, because it’s unaffordable. It’s criminal.”
Similarly, although there is now evidence to show that giving whole, never-separated blood is more effective than red blood cells alone—or even recombined red cells, plasma, and platelets—blood banks on both sides of the Atlantic continue to break blood down into its components. The practice was pioneered during the Second World War, partly to stretch limited resources, and became common in the sixties, when the rise of chemotherapy led to an increased demand for platelet and plasma transfusions for immunosuppressed patients.
The theory makes sense: by splitting blood, a single unit can treat multiple people, as doctors deliver just the part of it that their patients need. In practice, though, bleeding patients certainly need red blood cells to get oxygen to their brains, but they also need platelets to help stop the bleeding, and plasma to help restore lost blood pressure and thus circulation. “The way blood banks have made products that are inventory-based and not patient-based is also criminal,” Spinella said. He recalled conversations with a former executive at the American Red Cross who told him, “ ‘Philip, whole blood is not in our business plan.’ And I would say, ‘That’s bullshit. It’s my patient’s life plan.’ ”
For all these reasons, developing a substitute for blood that could be produced at will, stored for eternity, and given to anyone, avoiding the drag of blood-type matching, has been high on scientists’ wish list for decades. And yet, when the first substitutes arrived, they, too, tended to be siloed, picking just one of blood’s myriad functions to mimic. Volume seemed simplest: when there’s not enough fluid in the circulatory system, there’s not enough pressure to pump oxygen around the body. Water with some dissolved salts and sugars—a solution medics call crystalloid—seemed as though it would do the trick.
Unfortunately, in response to the disastrous lack of fluid after blood loss, the lining of the vessel walls becomes porous. “They were smart people back then, and they thought they were doing good, but crystalloid does not heal those porous holes,” Holcomb said. “So now the fluid goes into the vessel and out into the tissue, and you get edema, and edema makes everything not work—the brain, lungs, kidneys, muscle, everything.” Nonetheless, to this day, saline infusions are the standard of care in situations where blood is not yet available. (This upsets Spinella so much that he made T-shirts that read “Blood is for bleeding. Saltwater is for cooking pasta.”)
Next, scientists focussed on the oxygen carriers themselves: red blood cells, arguably blood’s most important component. Early bets were placed on a class of synthetic organic chemicals called perfluorocarbons (PFCs), initially employed in the separation of uranium as part of the Manhattan Project. The leading contender, Fluosol-DA, was developed by Ryoichi Naito, the head of Japan’s biggest blood bank. (Naito’s interest in blood dated back to the Second World War, when he served in Japan’s Unit 731, notorious for conducting almost unimaginably inhumane experiments on prisoners.) PFCs were chemically inert and could carry large amounts of dissolved oxygen; however, they typically required frozen storage, were frequently accompanied by toxic side effects, and worked only if the patient was also breathing enriched oxygen, all of which limited their utility. Fluosol-DA was approved for use by the F.D.A. in 1989, before being withdrawn five years later, as evidence emerged that its risks outweighed any benefits.
Other scientists decided to copy nature more faithfully. The molecule responsible for carrying oxygen in red cells is hemoglobin, an iron-rich protein with a sophisticated structure that allows it to pick up the gas, ferry it safely around the body, and release it according to availability and need. “What the hell, we’ll just get that out of the cell, purify it, and inject it into the bloodstream,” Doctor said, paraphrasing the thought process of an earlier generation of researchers. “What people didn’t completely consider is, there’s a reason it’s inside cells.”
“Are you sure you don’t want to try it, too?” I asked Doctor, as he used a pipette to add some water to a Barbie-pink powder. This was ErythroMer, his freeze-dried artificial red blood cells, which, when hydrated, turned into what looked like a shot of raspberry milk. “I never have,” Doctor admitted. “I guess I can’t not?” Together, we clinked plastic test tubes, sniffed, then slurped. The initial flavor note was salt, followed by a fatty finish. “It has a little bit of a creamy feel,” Doctor said. “I don’t think we’re going to be able to market it for taste.” When I complained that I could detect none of the metallic sucking-on-a-penny note of real blood, he told me that was precisely the point. “There’s no contact between the iron and your tongue,” he said. “Because it’s hidden inside the membrane.”
In the nineties, several major pharmaceutical companies, including Baxter International, were confident enough in their hemoglobin-based oxygen carriers (HBOCs) that they had progressed all the way to Phase III clinical trials, the final hurdle before F.D.A. approval. A 1994 report in the New York Times titled “Race for Artificial Blood Heats Up” noted in passing that the companies had observed “an unexpected tendency of their products to cause blood vessels to constrict,” but that they were not concerned—indeed, the article continued, “Baxter says such vasoconstriction may be a benefit,” because it would “raise blood pressure in victims of acute blood loss.”
This optimism turned out to be misplaced. “The original HBOC trial by Baxter is one of the most lethal trials in critical-care history,” Gladwin, the dean of the University of Maryland School of Medicine, told me. “That’s how toxic the stuff was.” Of the fifty-two patients infused with Baxter’s product, twenty-four died, compared with only eight of the forty-six control patients, who were given a standard saline solution. The trials cast a pall over the entire project of engineering blood. “They shut everything down, and the field kind of went dark,” Doctor said. “People thought it couldn’t be done—the human body is too complicated, we don’t really understand it, so screw it.” But ErythroMer, which Doctor and I had just chugged, is, technically, an HBOC—although, I was assured, a next-generation, probably nontoxic, version. “This is not your grandfather’s HBOC,” Spinella, who is also the chief medical officer at KaloCyte, said. “I mean, yes, it carries oxygen and it is hemoglobin-based, but it’s not that. All people do is hear that and go, ‘Oh, failure.’ ”
Doctor never had any intention of devoting his energies to this ill-starred field. Back in 2012, he was a professor working in pediatric intensive care at Washington University in St. Louis. “The problem that we were dealing with at the time, and still often deal with, is losing control of the circulatory system,” he said. “We would fix infections and other things, and the kids would still die, and nobody really understood what was happening.” Part of the problem was well known—in response to severe inflammation, blood vessels dilate, causing blood pressure to drop precipitously—but Doctor wondered whether the root cause was red-cell injury. His lab began trying to tease out the subtle cues that governed a red blood cell’s ability to manage blood flow.
Doctor was, as he put it, “minding my own business doing that” when he received a call from Dipanjan Pan, a chemist and bioengineer who was also based at Washington University, and who specialized in creating nanoparticles for medical use. “I call it serendipity at its best,” Pan, ErythroMer’s co-inventor, told me. One day, he was looking at a nanoparticle under a microscope and noticed that its doughnut shape resembled a red blood cell. Though he knew of the long, inglorious history of blood substitutes, he couldn’t help but ponder whether hemoglobin could be placed inside one of the doughnuts. “But I’m a materials scientist, not an expert in red-blood physiology,” Pan said.
“So he called me up,” Doctor told me. “He said, ‘I made this thing. I don’t really know how to tell if it works or not. Are you interested?’ ”
By this point, scientists had concluded that the major issue with HBOCs was tied to the vasoconstriction that Baxter had reportedly hoped might be a feature, not a bug. It turns out that our capillaries have evolved to inflate and deflate on demand—a system optimized for both conserving energy and running away from predators. “You’re just sitting there,” Doctor said, pointing at me. “So only about ten to fifteen per cent of your capillaries are being used.” If I were to suddenly sprint, he told me, my body would pop open thousands more, to insure adequate oxygen distribution. One of the molecules that causes those capillaries to open up is called nitric oxide; the discovery of its role in circulation was rewarded with a Nobel Prize, in 1998, and led to, among other things, the development of Viagra. “It’s like the WD-40 of blood vessels,” Gladwin told me. His own research has helped show that even tiny amounts of hemoglobin outside a red cell can cause immense damage by scavenging nitric oxide. The less nitric oxide in a blood vessel, the tighter it is—meaning that the hemoglobin Baxter put in severely injured patients went around shutting down circulation at the very moment it was most needed.
Doctor immediately realized that, if the hemoglobin could be safely sheathed inside the membrane of Pan’s nanoparticle, these issues might be avoided. He and Pan also equipped the membrane with a substance they call KC1003. “That’s the secret sauce,” Doctor told me. On its own, hemoglobin is very good at grabbing oxygen, but less good at letting it go—a process that, in real red blood cells, is triggered by ambient pH and CO2 levels, so that the cells can pick up oxygen in the lungs and then release it into the tissues that need it. KC1003 performs the same trick, which allows ErythroMer to get the most oxygen-delivery bang for its nanoparticular buck. “If you’re in Denver and you exercise,” Doctor told me, your red blood cells produce a molecule that insures more oxygen is released into tissue. ErythroMer is stuffed full of that molecule, which is switched on by KC1003 in tissues but shut off in the lungs, where oxygen uptake is the priority. “It’s, like, I’m in Denver, I’m in St. Louis, I’m in Denver, I’m in St. Louis,” Doctor explained. “But it thinks it’s in Denver only when it’s in your muscle, and it thinks it’s in St. Louis only when it’s in your lung.” (Would this neat little trick also make ErythroMer an ideal supplement for aspiring marathoners? “Oh, yeah,” Doctor said. “Totally.”)
Thus far, ErythroMer has shown promising results. “He has some really nice data in animal models that suggest it’s improving oxygen delivery and it’s safe,” Gladwin said. (Another hemoglobin nanoparticle, hbV, has been developed by researchers in Japan, and small amounts have been safely injected into healthy humans, though its circulatory half-life seems to be shorter than ErythroMer’s, and it isn’t capable of performing the same altitude trick.) One of the other big advances of Doctor’s substitute is its ease of storage. Unlike first-generation HBOCs, ErythroMer is a lightweight, shelf-stable powder that can be rehydrated in minutes. The possibility of a cold-chain-free blood substitute has drawn the attention of the U.S. military, specifically the Defense Advanced Research Projects Agency, or DARPA, which recently awarded Doctor’s team forty-six million dollars to combine ErythroMer with synthetic platelets and freeze-dried human plasma, creating a “field-deployable whole-blood equivalent.”
“I hate to say it, but a lot of this is driven by what they think the next war is going to be,” Doctor said. “It’s expected to be a near-peer conflict with Russia or China.” Jean-Paul Chretien, a former DARPA program manager, was more circumspect, but confirmed that, without air superiority, the U.S. might not be able to evacuate injured soldiers to a medical facility capable of storing and being regularly resupplied with cold blood. “That means you have to be able to take care of people on the battlefield, and, if you’re dealing with battle wounds, you need blood,” Doctor said. “That’s why DARPA’s decided to make this big investment.”
Doctor’s team received the DARPA award in early 2023. As their second year of funding came to an end, he told me, they’d successfully created a nifty packaging prototype, which will allow medics to rehydrate and heat the blood powder by opening a folded plastic pack and massaging it gently. Doctor had met or exceeded enough of the second-year DARPA benchmarks to graduate into the next phase of the project, but he wasn’t celebrating. He had yet to test the combination of his artificial red blood cell with a synthetic platelet—a tiny spherical liposome decorated with strings of amino acids, developed by researchers at Case Western Reserve University—and freeze-dried plasma. “The thing I’m most worried about are the interactions between the particles producing unanticipated safety problems,” he said. “It would be naïve to think that everything’s just going to work like we expect.”
For all the ambition of DARPA’s whole-blood substitute program, the best-case scenario is just that: a substitute, without several of the downsides—or all of the magic—of the real thing. But the alternative—growing real red blood cells outside the body—has proved even more challenging. In a small laboratory at the N.H.S.B.T. campus in Filton, steps away from the gallons of fresh donor-derived blood being processed in the manufacturing hall, I was initiated into the much more artisanal craft of culturing red blood cells.
For something that the body makes roughly two million of every single second, red cells are astonishingly difficult to grow outside of it. Attempts began in the late nineties, following the isolation of human embryonic stem cells. These are pluripotent, meaning that they can be nudged to become any one of the body’s estimated two hundred different cell types, given the appropriate conditions. Determining those conditions for red blood cells took a lot of trial and error. After a decade, the team at Filton “could only really make a little dusting of red cells,” Sabine Taylor, who joined the lab in 2009, said. “It was just a little spot of red at the bottom of a tube.”
Instead, they started taking their building blocks from donor blood—specifically, from the thin beige layer, known as a buffy coat, that’s sandwiched between the red cells and the plasma. Pipette in hand, I followed Taylor’s instructions, carefully vacuuming up and dumping out as much plasma as I could without disturbing the buffy coat, before trying, and failing, to suck it up with one graceful plunger release. “It does take a bit of practice,” she said, sympathetically. She gently washed off the red residue stuck to my buffy coat before we tackled the next challenge: finding our starter cells.
Taylor’s team looks for hematopoietic stem cells, which already know that their destiny is to become a blood cell, though they haven’t determined which kind. “We’re cheating a little bit by starting with something that’s preprogrammed to go in the right direction,” Taylor said. Only one in a thousand of the cells in my buffy coat would be a hematopoietic stem cell; fortunately, its surface chemistry is quite distinctive. By equipping a protein that binds exclusively to that surface with tiny magnetic beads, Taylor and her colleagues can pull the needle they’re looking for out of the bloody haystack.
At this point, hours had passed. Several more rounds of washing and filtration had yet to take place before lunch, which was a priority for the hematopoietic cells: they have to be fed exactly the right nutrients, at the right times, to commit to becoming red blood. (Taylor told me that she and her colleagues come in on weekends for feeds.) As I admitted defeat, she showed me some she’d made earlier: a flask full of cranberry-juice-colored liquid sitting in an incubator. Under a microscope, we compared them with real red blood cells; ironically, the natural ones were so identically perfect that they appeared to have been manufactured, whereas the lab-grown cells looked, to put it diplomatically, handmade. In fact, Taylor confessed, they’re not even red cells. “What we’re actually making is the immediate precursor to a red cell,” she said. “The last step of maturing happens in the body, but we’ve not managed to replicate it.”
These are the cells that are being injected into Nick Green, and other volunteers, as part of the RESTORE trial. In Cambridge, as Ghevaert weighed a syringe, which held a grand total of eight millilitres of red cells, I asked him whether the Filton team had prepared a backup, just in case. “There’s no backup,” he said. “Mostly because we use all the stuff we culture, and this is the scale we’re culturing at.”
By painstakingly tweaking their processes, Taylor and her colleagues have scaled production from a pinprick to two teaspoonfuls at a time, at a cost that Ghevaert estimated at roughly seventy-five thousand dollars per syringe. (In contrast, the American Red Cross charges hospitals around two hundred dollars for a pint of donated red blood cells.) The vision of multistory steel bioreactors brewing pure, safe, universally tolerated O-negative blood by the gallon is still a long way off. It will also—according to Ashley Toye, who leads the red-blood-cell-products program at the U.K.’s National Institute for Health and Care Research, which is co-funding the RESTORE trial—require enhancing artificial blood, in order to make it commercially viable. In 2022, Toye’s startup, Scarlet Therapeutics, was founded to do exactly that.
DARPA, which began funding a “blood pharming” initiative of its own, in 2008, quickly came to a similar realization. “We immediately shifted to genetically modifying the blood,” Dan Wattendorf, the scientist who led the program between 2010 and 2016, said. “If you’re competing with the commodity of everyone’s arm to give a bag of blood, it’s going to be very hard to overcome that cost hurdle. If you add value to the blood by genetically modifying it, then you can get a much higher margin.” To secure the investment required to reach the bioreactor scale, lab-grown red blood cells need to tap into pharmaceutical-industry money, by making a red blood cell that is also a medicine.
There is a precedent for this: researchers have already genetically engineered T cells, part of the white-blood-cell family, to recognize and attack cancer cells. The first such drug, known as CAR-T-cell therapy, received F.D.A. approval in 2017, as a treatment for leukemia. Red blood cells are not killers, like their white counterparts, but they do have certain advantages. For one, the same membrane that so effectively sheathes hemoglobin can also hide novel enzymes from the immune system. A lab-grown red blood cell that contains an enzyme engineered to pump out therapeutic proteins is, essentially, a tiny, stealth drug factory that distributes a steady supply of medicine around the body for up to a hundred and twenty days. “Evolution has given us an incredible tool chest of hematopoietic stem cells,” Wattendorf said. “Once we understand how to do this, it’s a massive, massive opportunity space.”
Synthetic nanoparticles like ErythroMer have the same potential to host beneficial agents. “Whole blood is the marinara, it’s a one-size-fits-all,” Spinella said, deploying another pasta analogy. Right now, he told me, whole blood is still our best bet for all kinds of different situations—obstetric bleeding, traumatic brain injury, heart surgery—but he foresees a future of custom blood blends. “Maybe the pathophysiology of postpartum hemorrhage requires more platelets or more plasma than an oncology patient or a liver-transplant patient,” he suggested. “Once we’ve got the basic recipe figured out, we’re going to get fancy and add eggplant or pork.” Doctor and Pan recently began collaborating on a new proposal for a DARPA initiative to develop nanoparticles that can latch on to soldiers’ red blood cells to enhance them in various ways. “The red blood cells can be loaded with agents that will make the oxygen binding and release capacity of these soldiers much higher than normal human beings’,” Pan said.
Regardless of whether any of these efforts will actually translate into clinical reality, the quest to synthesize and even improve on blood has taught us volumes about it. “What I cannot create, I do not understand,” the theoretical physicist Richard Feynman famously scribbled on his Caltech blackboard. In the process of trying and failing to mimic the magic that takes place in the human body, researchers have answered questions they wouldn’t otherwise have thought to ask, learning about everything from the role of nitric oxide in the body to the particular choreography of chemical signals that trigger the release of platelets from their mother cells. “The more we figure out about how it works inside our body, the more practical it is to make it outside of the body,” Wattendorf said. “We are truly in a golden era of understanding blood.”
In the course of about ten minutes, an animal-research technician in Doctor’s lab gently injected the first rabbit with sixty millilitres of synthetic red blood cells. Its vital signs were displayed on a nearby screen, and Doctor narrated the action in real time, reeling off statistics like a baseball commentator. The rabbit’s lactate levels—a telltale marker of oxygen-deprived tissue—started falling almost instantly. Doctor scrutinized shifts in its pulse waveform, a clue to how hard its heart was working. “The hump on the bottom is now flattening,” he pointed out. “You can see it’s more comfortable.” Indeed, by the time the procedure was finished, the rabbit was sitting up in its cage, looking around, and panting considerably less. “Half his blood is artificial now,” Doctor said.
Meanwhile, in Cambridge, Ghevaert prepared to inject (potentially) manufactured red blood cells into a prominent vein on the back of Nick Green’s hand. As Green confirmed his name and date of birth, Ghevaert ran some saline through the line, checking that it was clear, and then began the transfusion. “It’s a slow push,” he said. Green reported no sensation. The whole thing took about sixty seconds, followed by a flurry of activity as the nurses extracted samples from Green’s other arm every few minutes, on a strict schedule. “That was very straightforward,” Green said. “I felt quite relaxed.”
Half an hour later, we were talking about cricket as Ghevaert finished his paperwork. The entire thing had concluded with a distinct lack of fanfare, considering the fact that Green was perhaps one of very few humans to have lab-grown red blood cells in his veins. “I’ve got the easy part, you know—I’m just lying here, people are chatting to me,” he said. “I’m quite enjoying this.”
In Baltimore, Rabbit No. 1 was also hopping around its cage like nothing had happened. “Don’t pee on me, buddy,” Doctor said, as he picked it up to stroke its fluffy white fur. “He’s looking pretty good, considering he was almost dead a few hours ago.” Sadly, things had not gone so well for Rabbit No. 2. “Even after resuscitation, twenty per cent of them will die,” Doctor explained. “There’s a very big difference in the individual ability to tolerate shock.”
An eighty-per-cent chance of survival from a potentially lethal injury is, to be honest, pretty good odds—possibly better than the chances that either of these blood substitutes will make it into therapeutic use. Regardless, the quest for artificial blood will continue: for all its wonders, the real stuff is no longer enough. ♦
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