+
+
+
+
+
+The Long Quest for Artificial Blood
+src: The New Yorker
+src: Published in the print edition of the February 10, 2025, issue, with the headline âTrue Blood.â
+By Nicola Twilley
+February 3, 2025
+
+Nicola Twilley, a frequent contributor to The New Yorker, is a host of the podcast âGastropod.â Her books include âFrostbite: How Refrigeration Changed Our Food, Our Planet, and Ourselvesâ.
+
+One of the most valuable substances in the world has never been replicated. Are we close?
+Blood is in high demand almost everywhere, but its seemingly endless complexity has confounded scientists for decades.
+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 âInstantly Soothe Anxious Rabbits (Tested).â 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 lunchâa cheese-and-pickle sandwich and a shiny red appleâand 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 shockâa 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, heâd pedalled that morning into a research facility on the outskirts of Cambridge, and planned to ride into work later that afternoon. âYes, I am a MAMIL,â 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 Greenâs bed, Cedric Ghevaert, a hematologist with National Health Service Blood and Transplant, was wading through the binderâs 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. âItâs a drug substance, therefore it has to be prescribed.â
+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 worldâs 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 couldnât know whether the stuff in the syringe was simply the donated blood orâmore intriguinglyâan 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.) âThere are companies and academic outfits that are looking to do this across the world,â Ghevaert, a boyish fiftysomething with an endearing French accent, said. But he and his co-lead, Rebecca Cardigan, are âthe first ones reaching the point where we are truly comparing the gold standard of donor cells with the manufactured red cells.â
+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 bleedsâor at least operates in the bodyâalmost 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 donât yet understand everything that blood does, or how it does it. Somehow, the various components of bloodâred and white cells, platelets, and plasmaâmanage 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.
+âYou know, itâs hard to compete with millennia of evolutionary pressure,â John Holcomb, a renowned trauma surgeon who honed his skills during two decades in the military, told me. âIâm not sure weâre that smart.â As Green and the rabbits awaited their syringes, I couldnât help but wonder: Can we really hope to imitate this magical fluidâand 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. âShare your lifeline, share your love,â a blood-donation coördinator wrote, encouraging me to book my next appointment. Blood is âthe priceless gift of hope,â 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 bodyâof the roughly thirty-six trillion cells that make up an average adult male, about thirty-two trillion are bloodâit is âamong the worldâs most precious liquids,â 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 bloodâs elevated status long predates our fossil-fuel era. It is the stuff of the most solemn oaths and the deepest bondsâthe essence of not only life but, as Virgil writes in his Aeneid, the âpurple soulâ 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 bloodâs value: it is, he tells Goetheâs Faust, âa very special juice.â
+Two people talking in a crowded deli.
+âThe only time I feel optimistic anymore is when I know a sandwich is on its way.â
+Cartoon by Sophie Lucido Johnson and Sammi Skolmoski
+Link copied
+For centuries, blood was described and imagined in these mythical terms. It wasnât 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. Harveyâs insights raised the thrilling possibility of introducing other substances directly into the blood, in order to infuse their qualities into the bodyâs essence. Christopher Wren, better known as the architect of St. Paulâs Cathedral, was a member of Harveyâs intellectual circle, and he conducted some of the very earliest transfusion experiments, injecting wine, ale, opium, antimony, and âother thingsâ into the bloodstream of dogs and observing the results. (They variously vomited, passed out, and became âextremely drunk.â)
+Hot on Wrenâs heels came a pair of scientistsâRichard Lower, a medical student from Cornwall, and Jean-Baptiste Denis, the physician to the King of Franceâwho wondered whether moving blood from one creatureâs veins into anotherâs might change an animalâs very nature. Perhaps a ferocious dog could be made gentle âby being . . . stocked with the blood of a cowardly Dog,â Robert Boyle, another scientist in Harveyâs circle, suggested. The diarist Samuel Pepys described an attempt to replicate one of Lowerâs 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. âThis did give occasion to many pretty wishes, as of the blood of a Quaker to be let into an Archbishop, and such like,â 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 âphrensiesâ 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 fluidâall, we now know, symptoms of a severe transfusion reaction in which the recipientâs 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 Mauroyâs 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 lifesavingâsometimes near-miraculousâtreatment in otherwise dire cases of traumatic injury and hemorrhage. It âraised hopes where formerly there had not been any,â 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 âsteal into the moribund ward,â conduct a transfusion on one of the patients, and pull âmany men back from the jaws of death.â
+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 procedureâs 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, bloodâs 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 âwas almost as if the sun had been made to stand still.â Then, there was the storage issue.
+âPeople forget that blood is alive,â Allan Doctor told me. âThey think itâs like urine or something. It is a bodily fluidâbut itâs living cells.â 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 didnât have a telephone, policemen and priests were often enlisted to track down donors at any hour of the day. It wasnât 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 Bristolâs northern edge, Britainâs 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. âTheyâll usually come in warm,â Naomi Jones, the centerâs 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 bloodâs volume, sits on top. Each bag looked different in ways that, Jones told me, can reflect its donorâs healthâsome had more or fewer red cells, while the plasma ranged in shade from lemonade to Coca-Cola. âIf youâre on the pill or anything like that, the hormones will make it green,â she said. âAnd people who have lots of fats in their blood, itâs like a banana milkshake.â
+During the bloodâs 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 isnât enough.
+Part of the problem is that a lot of people need it. An astonishing number of civilians die of injury each yearâupward of a hundred and fifty thousand in the U.S., and more than five million globally. âEvery! Year!â John Holcomb, the trauma surgeon, said. âItâs the leading cause of life years lost.â 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.
+âIf you go into hemorrhagic shock, you need blood products,â Holcomb said. âAnd the data are clear that, the earlier you get blood products, the better your survival.â 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 donât, for reasons that are demographic, biological, and economic. âNo. 1, thereâs not enough blood,â Holcomb said. âYou probably need another sixty to a hundred thousand units of blood available nationwide.â In the U.K., N.H.S.B.T. aims to have five to seven daysâ supply on hand; in the U.S., the goal is similar. The reality is that, at times, blood isnât available. Ghevaert told me that, on a recent trip to the U.S., heâd 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 clotâtheyâre 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.) âIn addition to that bad stuff, our population is aging,â Philip Spinella, an expert in transfusion medicine at the University of Pittsburgh and a co-founder of KaloCyte, the company developing ErythroMer, explained. âIn the next ten years, thereâll be twenty million more people above the age of sixty-five.â Across the developed world, societies are increasingly elderly, which squeezes the blood supply from two directions. âBaby boomers and the Greatest Generationâthey were the blood donors,â Mark Gladwin, the dean of the University of Maryland School of Medicine, told me. âOur young generation is not donating blood.â Meanwhile, the people over sixty-five âget cancer and have heart surgeryâthey need platelets and red cells,â Spinella went on. âWhereâs it going to come from? Right now, our donor base canât support todayâs needs. What about 2030?â
+
+Bloodâs 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 frozenâbut 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. Whatâs more, even meticulously stored blood is gradually dying. âWhen you put fish in the refrigerator and leave it for five days, itâs less good,â Holcomb said. âBlood is the same.â Doctor showed me research that measured how much oxygen cold-stored red blood cells were capable of moving. âItâs down to forty per cent of normal before itâs even outdated,â 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 areasâwhich 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.
+âThe problem here is that thereâs practically no reimbursement for prehospital blood by insurance and agencies,â Holcomb said. âThereâs nothing that has a bigger impact on survival than prehospital blood. Nothing. And yet the major impediment is not logisticsâweâve worked through that. Itâs not how to store the blood. Itâs reimbursement. And, in our system, if you donât get reimbursed you donât do it.â Spinella, who told me about a trial in Pittsburgh demonstrating that prehospital plasma greatly improves survival rates, is also outraged. âWe had to stop it after the trial was over because our E.M.S. system canât afford to put blood on the ambulances,â he said. âSo we proved it, and now we canât do it, because itâs unaffordable. Itâs criminal.â
+Similarly, although there is now evidence to show that giving whole, never-separated blood is more effective than red blood cells aloneâor even recombined red cells, plasma, and plateletsâblood 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.
+Emperor walks by naked and another unrelated man is also naked.
+âI get that the Emperor is âwearing new clothes,â but whatâs the deal with Dennis?â
+Cartoon by Maddie Dai
+Link copied
+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. âThe way blood banks have made products that are inventory-based and not patient-based is also criminal,â Spinella said. He recalled conversations with a former executive at the American Red Cross who told him, â âPhilip, whole blood is not in our business plan.â And I would say, âThatâs bullshit. Itâs my patientâs life plan.â â
+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 scientistsâ wish list for decades. And yet, when the first substitutes arrived, they, too, tended to be siloed, picking just one of bloodâs myriad functions to mimic. Volume seemed simplest: when thereâs not enough fluid in the circulatory system, thereâs not enough pressure to pump oxygen around the body. Water with some dissolved salts and sugarsâa solution medics call crystalloidâseemed 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. âThey were smart people back then, and they thought they were doing good, but crystalloid does not heal those porous holes,â Holcomb said. âSo now the fluid goes into the vessel and out into the tissue, and you get edema, and edema makes everything not workâthe brain, lungs, kidneys, muscle, everything.â 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 âBlood is for bleeding. Saltwater is for cooking pasta.â)
+Next, scientists focussed on the oxygen carriers themselves: red blood cells, arguably bloodâs 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 Japanâs biggest blood bank. (Naitoâs interest in blood dated back to the Second World War, when he served in Japanâs 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. âWhat the hell, weâll just get that out of the cell, purify it, and inject it into the bloodstream,â Doctor said, paraphrasing the thought process of an earlier generation of researchers. âWhat people didnât completely consider is, thereâs a reason itâs inside cells.â
+
+âAre you sure you donât want to try it, too?â 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. âI never have,â Doctor admitted. âI guess I canât not?â Together, we clinked plastic test tubes, sniffed, then slurped. The initial flavor note was salt, followed by a fatty finish. âIt has a little bit of a creamy feel,â Doctor said. âI donât think weâre going to be able to market it for taste.â 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. âThereâs no contact between the iron and your tongue,â he said. âBecause itâs hidden inside the membrane.â
+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 âRace for Artificial Blood Heats Upâ noted in passing that the companies had observed âan unexpected tendency of their products to cause blood vessels to constrict,â but that they were not concernedâindeed, the article continued, âBaxter says such vasoconstriction may be a benefit,â because it would âraise blood pressure in victims of acute blood loss.â
+This optimism turned out to be misplaced. âThe original HBOC trial by Baxter is one of the most lethal trials in critical-care history,â Gladwin, the dean of the University of Maryland School of Medicine, told me. âThatâs how toxic the stuff was.â Of the fifty-two patients infused with Baxterâs 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. âThey shut everything down, and the field kind of went dark,â Doctor said. âPeople thought it couldnât be doneâthe human body is too complicated, we donât really understand it, so screw it.â But ErythroMer, which Doctor and I had just chugged, is, technically, an HBOCâalthough, I was assured, a next-generation, probably nontoxic, version. âThis is not your grandfatherâs HBOC,â Spinella, who is also the chief medical officer at KaloCyte, said. âI mean, yes, it carries oxygen and it is hemoglobin-based, but itâs not that. All people do is hear that and go, âOh, failure.â â
+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. âThe problem that we were dealing with at the time, and still often deal with, is losing control of the circulatory system,â he said. âWe would fix infections and other things, and the kids would still die, and nobody really understood what was happening.â Part of the problem was well knownâin response to severe inflammation, blood vessels dilate, causing blood pressure to drop precipitouslyâbut 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 cellâs ability to manage blood flow.
+Doctor was, as he put it, âminding my own business doing thatâ 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. âI call it serendipity at its best,â Pan, ErythroMerâs 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 couldnât help but ponder whether hemoglobin could be placed inside one of the doughnuts. âBut Iâm a materials scientist, not an expert in red-blood physiology,â Pan said.
+âSo he called me up,â Doctor told me. âHe said, âI made this thing. I donât really know how to tell if it works or not. Are you interested?â â
+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 demandâa system optimized for both conserving energy and running away from predators. âYouâre just sitting there,â Doctor said, pointing at me. âSo only about ten to fifteen per cent of your capillaries are being used.â 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. âItâs like the WD-40 of blood vessels,â 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 isâmeaning 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 Panâs nanoparticle, these issues might be avoided. He and Pan also equipped the membrane with a substance they call KC1003. âThatâs the secret sauce,â Doctor told me. On its own, hemoglobin is very good at grabbing oxygen, but less good at letting it goâa 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. âIf youâre in Denver and you exercise,â 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. âItâs, like, Iâm in Denver, Iâm in St. Louis, Iâm in Denver, Iâm in St. Louis,â Doctor explained. âBut it thinks itâs in Denver only when itâs in your muscle, and it thinks itâs in St. Louis only when itâs in your lung.â (Would this neat little trick also make ErythroMer an ideal supplement for aspiring marathoners? âOh, yeah,â Doctor said. âTotally.â)
+Thus far, ErythroMer has shown promising results. âHe has some really nice data in animal models that suggest itâs improving oxygen delivery and itâs safe,â 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 ErythroMerâs, and it isnât capable of performing the same altitude trick.) One of the other big advances of Doctorâs 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 Doctorâs team forty-six million dollars to combine ErythroMer with synthetic platelets and freeze-dried human plasma, creating a âfield-deployable whole-blood equivalent.â
+âI hate to say it, but a lot of this is driven by what they think the next war is going to be,â Doctor said. âItâs expected to be a near-peer conflict with Russia or China.â 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. âThat means you have to be able to take care of people on the battlefield, and, if youâre dealing with battle wounds, you need blood,â Doctor said. âThatâs why DARPAâs decided to make this big investment.â
+Doctorâs team received the DARPA award in early 2023. As their second year of funding came to an end, he told me, theyâd 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 wasnât celebrating. He had yet to test the combination of his artificial red blood cell with a synthetic plateletâa tiny spherical liposome decorated with strings of amino acids, developed by researchers at Case Western Reserve Universityâand freeze-dried plasma. âThe thing Iâm most worried about are the interactions between the particles producing unanticipated safety problems,â he said. âIt would be naïve to think that everythingâs just going to work like we expect.â
+
+For all the ambition of DARPAâs whole-blood substitute program, the best-case scenario is just that: a substitute, without several of the downsidesâor all of the magicâof the real thing. But the alternativeâgrowing real red blood cells outside the bodyâhas 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 bodyâs 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 âcould only really make a little dusting of red cells,â Sabine Taylor, who joined the lab in 2009, said. âIt was just a little spot of red at the bottom of a tube.â
+Instead, they started taking their building blocks from donor bloodâspecifically, from the thin beige layer, known as a buffy coat, thatâs sandwiched between the red cells and the plasma. Pipette in hand, I followed Taylorâs 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. âIt does take a bit of practice,â 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.
+Two angels pitching ideas to God in Heaven.
+âThey tidy and they neaten and they straighten and they walk away all proud of themselves. And then, when they get backâBAM!âthis crap is all over the place.â
+Cartoon by David Ostow
+Link copied
+Taylorâs team looks for hematopoietic stem cells, which already know that their destiny is to become a blood cell, though they havenât determined which kind. âWeâre cheating a little bit by starting with something thatâs preprogrammed to go in the right direction,â 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 theyâre 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 sheâd 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, theyâre not even red cells. âWhat weâre actually making is the immediate precursor to a red cell,â she said. âThe last step of maturing happens in the body, but weâve not managed to replicate it.â
+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. âThereâs no backup,â he said. âMostly because we use all the stuff we culture, and this is the scale weâre culturing at.â
+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 alsoâaccording to Ashley Toye, who leads the red-blood-cell-products program at the U.K.âs National Institute for Health and Care Research, which is co-funding the RESTORE trialârequire enhancing artificial blood, in order to make it commercially viable. In 2022, Toyeâs startup, Scarlet Therapeutics, was founded to do exactly that.
+DARPA, which began funding a âblood pharmingâ initiative of its own, in 2008, quickly came to a similar realization. âWe immediately shifted to genetically modifying the blood,â Dan Wattendorf, the scientist who led the program between 2010 and 2016, said. âIf youâre competing with the commodity of everyoneâs arm to give a bag of blood, itâs 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.â 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. âEvolution has given us an incredible tool chest of hematopoietic stem cells,â Wattendorf said. âOnce we understand how to do this, itâs a massive, massive opportunity space.â
+Synthetic nanoparticles like ErythroMer have the same potential to host beneficial agents. âWhole blood is the marinara, itâs a one-size-fits-all,â Spinella said, deploying another pasta analogy. Right now, he told me, whole blood is still our best bet for all kinds of different situationsâobstetric bleeding, traumatic brain injury, heart surgeryâbut he foresees a future of custom blood blends. âMaybe the pathophysiology of postpartum hemorrhage requires more platelets or more plasma than an oncology patient or a liver-transplant patient,â he suggested. âOnce weâve got the basic recipe figured out, weâre going to get fancy and add eggplant or pork.â Doctor and Pan recently began collaborating on a new proposal for a DARPA initiative to develop nanoparticles that can latch on to soldiersâ red blood cells to enhance them in various ways. âThe 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 beingsâ,â 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. âWhat I cannot create, I do not understand,â 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 wouldnât 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. âThe more we figure out about how it works inside our body, the more practical it is to make it outside of the body,â Wattendorf said. âWe are truly in a golden era of understanding blood.â
+
+In the course of about ten minutes, an animal-research technician in Doctorâs 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 rabbitâs lactate levelsâa telltale marker of oxygen-deprived tissueâstarted falling almost instantly. Doctor scrutinized shifts in its pulse waveform, a clue to how hard its heart was working. âThe hump on the bottom is now flattening,â he pointed out. âYou can see itâs more comfortable.â Indeed, by the time the procedure was finished, the rabbit was sitting up in its cage, looking around, and panting considerably less. âHalf his blood is artificial now,â Doctor said.
+Meanwhile, in Cambridge, Ghevaert prepared to inject (potentially) manufactured red blood cells into a prominent vein on the back of Nick Greenâs 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. âItâs a slow push,â 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 Greenâs other arm every few minutes, on a strict schedule. âThat was very straightforward,â Green said. âI felt quite relaxed.â
+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. âIâve got the easy part, you knowâIâm just lying here, people are chatting to me,â he said. âIâm quite enjoying this.â
+In Baltimore, Rabbit No. 1 was also hopping around its cage like nothing had happened. âDonât pee on me, buddy,â Doctor said, as he picked it up to stroke its fluffy white fur. âHeâs looking pretty good, considering he was almost dead a few hours ago.â Sadly, things had not gone so well for Rabbit No. 2. âEven after resuscitation, twenty per cent of them will die,â Doctor explained. âThereâs a very big difference in the individual ability to tolerate shock.â
+An eighty-per-cent chance of survival from a potentially lethal injury is, to be honest, pretty good oddsâpossibly 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.
+
+
+
+
+
+
+
+
+
+
+
+
+
+