by Rose George
To conserve the loss of red cells, diluting agents such as hetastarch can be used before surgery. During procedures, clinicians can clamp off blood vessels to minimize bleeding. They can aim to do laparoscopic surgery, not open surgery. They can inject tiny beads into the bloodstream that block off the blood supply, a technique called radiological embolization. They can use drugs that aid clotting, such as tranexamic acid. There are tourniquets, vasoconstrictors, clamps. Apparently there are harmonic scalpels. I really should look up what they are but I don’t want to ruin my mental image of a choir of steel blades. Marginal gains may be got using common sense. Raising a patient, says Carter, will lower their arterial pressure. Some interventions are now done using a “beach chair” position.
Restricting blood use may have been sparked by Witnesses, and fueled by HIV and hepatitis, but it has spread beyond both. Restricting blood use in surgery is now common enough to have a vocabulary. Bloodlessness. Dry surgery. Restrictive transfusions. There is a Society for the Advancement of Blood Management, founded in 2001, whose aim is “that blood management ought to be the standard of care, and that blood transfusion should be viewed as the alternative.”38 Blood transfusion, writes the society, “is costly to us all. While blood transfusion is safer than it has ever been, serious health risks remain.” Acute and adverse reactions in a country with a good blood supply are highly unlikely, but they are not impossible. “Documented risks include potentially fatal transfusion reactions, acute lung injury, immune system changes that may lead to increased infection rate and circulatory overload.” Transfused patients stay longer in the hospital. Some suffer immune reactions after receiving blood. Studies have shown “an association between liberal transfusion policies and increased incidence of health-care associated infections including surgical site infections and sepsis.”39
Perhaps this occurs because of what red blood cells are mixed with. Perhaps it is the length of time they sit on the shelf. No cell is static; in thirty-seven days a lot can happen, and some of it might not be good. A new concept in blood is “appropriate.” A transfusion will often be transformative, but should it always be done? A recent study had fifteen experts survey a huge number of cases of transfusion in medical, surgical, and trauma cases, then vote on the outcome. Transfusion, they concluded, had been appropriate in only 11.8 percent of the cases. They judged 28.9 percent to be “uncertain,” and the highest fraction—nearly 60 percent—was inappropriate.40 Also, bloodlessness is better for budgets. In the United States, transfusion of 1 unit of red blood cells costs $1,200. If, as the society contests, up to half of blood transfusions are prescribed for no justifiable reason, then the United States is spending $8.4 billion a year on pointlessness. Patient blood management has meant that the use of red cells has been declining. Over the last fifteen years in the UK, red blood cell use has dropped by 25 percent.41 In the United States, the number of units collected and distributed by the American Red Cross dropped by 26.4 percent between 2009 and 2016. Transfusions have fallen by a quarter and may decrease by 40 percent by 2020 if the rate keeps up.42
Blood saves lives. It makes life better for millions of people. If you can, donate it. But perhaps we can use it better. Or what if we could replace it entirely?
* * *
Filling their empty veins with airy wine
That being concocted turns to crimson Blood
—Christopher Marlowe, Tamburlaine the Great
Dr. Kenji Igawa has invented synthetic blood. There is a powerful need for it in the world. Donors are increasingly hard to find and a safe blood supply must be expensively monitored and protected. How wonderful, then, to create something that can stand in for our blood; that can be carried to austere military environments more easily than the real fragile and perishable liquid; that can fill the gaps and fissures in the blood supply of developing nations. No more blood touts outside hospitals preying on desperate relatives. No more wastage. The WHO estimates that nearly two million blood donations globally are discarded because they could have transmitted infection.43 But many red cells also go to waste because they exceed their use-by date. In the United States, 9 percent of red cells are thrown out for this reason. That doesn’t sound like much, but 9 percent of 12.5 million, the number of red cells collected in 2015, is more than a million units.44
Attempting to mimic blood is an old human endeavor: as soon as William Harvey realized that blood was a circulating liquid, all manner of liquids that could circulate have been tried. Animal blood, but also wine and milk. In the late nineteenth century, two Canadian doctors, frustrated with the haphazard success rates of blood transfusion and desperate to deal with a cholera epidemic, decided to try cow and goat milk instead. The scientific basis for this was shaky: one doctor believed that the oil and fat particles of milk were transformed into white blood corpuscles, and that white blood became red blood. But a cow was brought to the hospital and milked, its milk filtered through gauze and injected. (Later, when the doctors applied to the city of Toronto for “a good cow” for their experiments and were refused, they resigned from their public posts.) Other doctors in the United States and the UK subsequently tried goat milk. Most patients reacted badly, by dying. One woman said her head was bursting. A Dr. Joseph Howe, not deterred by having failed to keep alive tuberculosis patients by giving them cow blood, decided human breast milk may be better.
He attempted the infusion of three ounces of milk obtained from a healthy postpartum woman. The patient, a woman with suppurative lung disease, complained of pain in her chest and back shortly after the injection began, and stopped breathing after two ounces had been given; however, she was resuscitated by artificial respiration and by “injections of morphine and whiskey.”45
There’s nothing old-fashioned about this concept or aspiration: we do something similar every time we give a bleeding patient a bag of a salty fluid called crystalloid. It’s not blood but an understudy.
So Igawa’s invention has been groundbreaking. Finally, a product that contains all the properties of blood, that can do the job of hemoglobin, and that has the benefits of blood’s many enzymes and proteins. People who receive his product have shown no side effects. It works. Except Igawa’s invention is called Tru Blood, and it is fake but not in the way we want. Igawa is a minor character in the vampire TV show True Blood, and Tru Blood is what vampires drink in place of humans. Synthetic blood is possible in film and fiction and, as yet, nowhere else.
The dizzying possibilities of a blood substitute are matched by the dizzying numbers of the sums so far spent on finding one. The possibility is so close and so far that “holy grail” is a phrase found even in sober scientific literature about artificial blood. Many blood substitutes have been tried. Some have got far enough along the research process to have been given brand names. PolyHeme. Hemopure. ErythroMer. Sanguinate. Most are hemoglobin carriers, or hemoglobin-based blood substitutes: they are designed to transport free hemoglobin from the lungs to tissues, as blood does, where it can deliver its oxygen, as blood does. Some use human hemoglobin and some use the bovine kind. But hemoglobin is contained within red cells for good reason. If freed from the confines of a cell, it scavenges nitric oxide from blood vessels, causing blood vessels to constrict, blood flow to drop, and strokes and heart attacks. Human or cow: same result. So far, the only thing that all these efforts have in common is that they are still limited. Hemopure, also known as HBOC-21, was licensed for clinical use in South Africa in 200146 but was never approved in the US or UK (though it can be used in trials).47 PolyHeme failed to get FDA approval after it was given to nearly eight hundred trauma patients across the Midwest without their consent—as they were severely injured ambulance patients, they could hardly give it—and there was an outcry.48
Dr. Dana Devine, who is also chief medical and scientific officer at Canadian Blood Services, doesn’t think a viable blood substitute will arrive in her lifetime or mine. “Mother Nature is a whole lot smarter than we are. We understand more than we used to,
but we haven’t overcome the problem of getting donor-derived blood.” She is more optimistic about blood brewing in a lab. “We can take the cells, put them in a culture, tickle them with hormones and grow blood.”
In a laboratory in Bristol, NHSBT scientists have done that. They took hematopoietic stem cells—the ones that grow blood—from an adult donor or from umbilical cords, which mothers can donate. Then they tried to mimic the bone marrow, brewing red cells in a laboratory. They weren’t the first to attempt this.49 A US team had done the same in 2008, and in 2011 in Paris volunteers received transfusions of ten billion artificially grown red blood cells. (That’s only two milliliters of blood.) Twenty-six days after transfusion, the cells were still circulating.50 And in the words of Dana Devine, “No one had keeled over.” But the NHSBT team, explains Dr. Nick Watkins, assistant director of research, have done something different. They have immortalized cells. The word is as arresting as the achievement. “When you take a stem cell from an adult or [umbilical] cord blood and you produce red blood cells from those,” says Watkins, “that’s a linear process, you can only do it once.” Instead, the NHSBT scientists have used proteins to create an erythroblast—an immature red cell—that will not become a red cell until it is given a signal. Millions of dormant cells, waiting to be activated, silent troops. The potential is alluring. “When you take a blood donation from a blood donor, the red blood cells you get vary in age from 0 days (i.e., just released from bone marrow) up to 120 days (the life span of a red blood cell). In a donation from a donor you have red blood cells that span that age gap. And the thinking behind the manufacturing process is that all the cells you produce are new and therefore you don’t have these 120-day cells in your donation and therefore they may survive longer.” When the cells are trialed on human volunteers, they will be tracked with a radioactive label, a small amount of radioactive material called chromium 51. I wonder at the chances of finding volunteers for that. “Will you accept fake blood with a dose of radiation, please? Sign here.” With a fair wind, Watkins says, trials should be under way by the end of 2017. (But they weren’t.)
Dr. Harvey Klein has sat on the NHSBT review board for many years. He is impressed, though cautiously. “These are major strides forward,” he says. “And yet no one there has any illusions that this technology is going to provide millions of units of blood in the foreseeable future.” It is far too expensive. “It isn’t even close to providing as much blood as we can provide Guinness,” says Klein, with one of the more unexpected analogies I’ve encountered while interviewing blood experts. “The research in the stem cell and hematopoiesis space is scientifically very satisfying,” says Devine. “But the economic picture is just awful.” It could be useful for giving blood to people with rare diseases or rare blood types. Watkins points to the famous case of a French teenager with sickle cell disease. Sickle cell is caused by a defect in the gene that governs hemoglobin, which causes hemoglobin to clump, and blockages and awful pain. It can be successfully treated with a stem cell transplant, but finding a donor is as easy as with any other transplant: it’s not. When the boy was thirteen, stem cells were withdrawn and genetically manipulated to produce a functioning version of the hemoglobin gene. Two years later, they were transplanted back into him, and within three months his body was producing red cells with normal hemoglobin. He came off powerful opioids, he stopped getting painful episodes, and he is considered cured.51 “I can imagine a scenario in the future in the Western world,” says Watkins, “where patients with sickle cell disease might be faced with a choice of how they are treated. Do they receive donated blood, manufactured product, or do they have an autologous genetically engineered stem cell transplant? I think that’s where the field will go in ten or twenty years. There will be more choice for the patient.”
Watkins sounds like a scientist. Measured, cautious, but actually excited. There is possibility and promise. I glimpse this excitement in the names of companies founded to sound the depths of what blood can do for us. I read about Illumina, a massive DNA-sequencing company that has launched a start-up to work on a blood test that can detect cancer. It has raised $1 billion in funding from investors including Jeff Bezos and Bill Gates. Of course it is called Grail.52 My database has hundreds of documents and articles about the widening and deepening abilities of blood to diagnose, defy death, defeat disease, with what has come to be called a liquid biopsy. I learn that blood will soon be able to diagnose manifold cancers, dementia, depression, with what is always called “a simple blood test.” When I ask Dana Devine about the potential of liquid biopsies, she is as circumspect as other hematologists and transfusion specialists I speak to. “Liquid biopsy is not a magic bullet. If you read some of the accessible literature, you think it’s going to be like a Star Trek tricorder.” Take prostate-specific antigen, which can be detected in blood. “The great white hope years ago was PSA. But as we acquired more and more data, some people with elevated PSA did have prostate cancer, but some didn’t and some with cancer didn’t have elevated PSA. You have to be careful.”
Harvey Klein is more optimistic. “We hear a lot of press today about precision medicine to the point where some people just think it’s being overhyped, but the technology is advancing so rapidly. Will liquid biopsies replace the pathology laboratory? No. But they are going to make it a lot easier, faster, better than it is today where we have to go in and use an imaging procedure to find something and biopsy it.”
There will be no tricorders for a while, but what we can do already is futuristic enough. To trap a stem cell and use it as the NHSBT team has done is called making it immortal. Immortality, elixirs, blood chimerism, for those equally trapped and tricked stitched-together rodents, that are “sacrificed” after use. The holy grail of that immensely powerful simple blood test sought by Grail. I wonder at this language of myth and fairy tale in sober science. I wonder if science reaches for words that belong to fairies and stories because they seem richer than ordinary language and life. So they suit blood better, because they convey better that despite all the simple blood tests there is nothing simple about blood.
Such possibility. It glitters like the gold and stardust inside us. But still we are the cowherds. The future holds people who will look back at us and think our achievements as limited as the belief that cows can breathe good health despite our editing DNA and growing stem cells and transforming lives by giving people blood. It’s an extraordinary thing already, to achieve “the amending of bad blood by borrowing from a better body,” as Samuel Pepys wrote five hundred years ago. But we will do better yet. Blood is not done teaching us what it can do. More wonder will come.
NOTES
*Please note some of the links referenced in this work may no longer be active.
ONE: MY PINT
1. A donation of blood in the UK is 470 ml (www.blood.co.uk/the-donation-process/what-happens-on-the-day/). There are precise ways to calculate a person’s blood volume, but the general rule is that blood volume makes up 8 percent of a person’s body weight. Roughly (www.blood.co.uk/the-donation-process/after-your-donation/how-your-body-replaces-blood/). Also www.hematology.org/Patients/Basics/.
2. I weigh 65 kilograms (143 pounds). Eight percent of 65 kilograms is 5.2 kilograms. Converting kilograms to pints (though it’s mass to liquid) gets 9.15 pints. Dr. Harvey Klein, chief of transfusion medicine at the US National Institutes of Health, backed me up on this. “I’ve seen your TED talk. Yes, I’d say about nine pints.”
3. When mixed with additives, red blood cells are allowed to be kept and used for twenty-one days in Japan, thirty-five days in the UK, forty-two days in the United States, Canada, China, and many other countries, and between forty-two and forty-nine days in Germany, depending on the additive used. Willy A. Flegel, Charles Natanson, and Harvey G. Klein, “Does Prolonged Storage of Red Blood Cells Cause Harm?,” British Journal of Haematology 165, no. 1 (2014): 3–16.
4. “I remained ther
e steadfastly until my mother came up and drank the dark blood. At once then she knew me, and with wailing she spoke to me winged words.” Odyssey 11:155 from Homer, The Odyssey, trans. A. T. Murray, 2 vols. (Cambridge, MA: Harvard University Press, 1919), http://data.perseus.org/citations/urn:cts:greekLit:tlg0012.tlg002.perseus-eng1:11.138-11.179 (accessed January 2018).
5. The death of supernovas. https://spaceplace.nasa.gov/review/dr-marc-space/supernovas.html.
6. “That Lance Armstrong used banned blood transfusions to cheat. That Lance Armstrong would have his blood withdrawn and stored throughout the year and then receive banned blood transfusions in the team doctor’s hotel room on nights during the Tour de France.” Report on Proceedings Under the World Anti-Doping Code and the USADA Protocol, United States Anti-Doping Agency, Claimant, v. Lance Armstrong, Respondent. Reasoned Decision of the United States Anti-Doping Agency on Disqualification and Ineligibility, pp. 14, 61, 62.
7. The following are prohibited: “the administration or reintroduction of any quantity of autologous, allogenic (homologous) or heterologous blood, or red blood cell products of any origin into the circulatory system” (World Anti-Doping Agency, “Prohibited List,” January 2017, p. 5).
