7. THE HEART AND BLOOD Stopped. -- LAST WORD OF THE BR ITISH SURGEON AND ANATOMIST JOSEPH HENRY GREEN (1791- 1863) WHILE FEELING HIS OWN PULSE I THE HEART IS the most misperceived of our organs. For a start, it looks nothing like the traditional symbol associated with Valentine's Day and lovers' initials carved into tree trunks and the like. (That symbol first appeared, as if from out of nowhere, in paintings from northern Italy in the early fourteenth century, but no one knows what inspired it.) Nor is the heart where we place our right hand during patriotic moments; it is more centrally located in the chest than that. Most curious of all, perhaps, is that we make it the emotional seat of our being, as when we declare that we love someone with all our heart or profess a broken heart when they abandon us. Don't misunderstand me. The heart is a wondrous organ and fully deserving of our praise and gratitude, but it is not invested even slightly in our emotional well-being. That's a good thing. The heart has no time for distractions. It is the most single-minded thing within you. It has just one job to do, and it does it supremely well: it beats. Slightly more than once every second, about 100,000 times a day, as many as 3.5 billion times in a lifetime, it rhythmically pulses to push blood through your body--and these aren't gentle thrusts. They are jolts powerful enough to send blood spurting up to three meters if the aorta is severed. With such an unrelenting work rate, it is a miracle that most hearts last as long as they do. Every hour your heart dispenses around 70 gallons of blood. That's 1,680 gallons in a day--more gallons pushed through you in a day than you are likely to put in your car in a year. The heart must pump with enough force not merely to send blood to your outermost extremities but to help bring it all the way back again. If you are standing, your heart is roughly four feet above your feet, so there's a lot of gravity to overcome on the return trip. Imagine squeezing a pump the size of a grapefruit with enough force to move a fluid four feet up a tube. Now do that again once every second or so, around the clock, unceasingly, for decades, and see if you don't feel a bit tired. It has been calculated (and goodness knows how, it must be said) that during the course of a lifetime the heart does an amount of work sufficient to lift a one-ton object 150 miles into the air. It is a truly remarkable implement. It just doesn't care about your love life. For all it does, the heart is a surprisingly modest thing. It weighs less than a pound and is divided into four simple chambers: two atria and two ventricles. Blood enters through the atria (Latin for "entry rooms") and exits via the ventricles (from another Latin word for "chambers"). The heart is not really one pump but two: one that sends blood to the lungs and one that sends it around the body. The output of the two must be in balance, every single time, for it all to work correctly. Of all the blood pumped out of your heart, the brain takes 15 percent, but actually the greatest amount, 20 percent, goes to the kidneys. The journey of blood around your body takes about fifty seconds to complete. Curiously, the blood passing through the chambers of the heart does nothing for the heart itself. The oxygen that nourishes it arrives via the coronary arteries, in exactly the way oxygen reaches other organs. The two phases of a heartbeat are known as the systole (when the heart contracts and pushes blood out into the body) and diastole (when it relaxes and refills). The difference between these two is your blood pressure. The two numbers in a blood pressure reading--let's say 120/80, or "120 over 80" when spoken--simply measure the highest and lowest pressures your blood vessels experience with each heart-beat. The first, higher number is the systolic pressure; the second, the diastolic. The numbers specifically measure how many millimeters of mercury is pushed up a calibrated tube. Keeping every part of the body supplied with sufficient quantities of blood at all times is a tricky business. Every time you stand up, roughly a pint and a half of your blood tries to drain downward, and your body has to somehow overcome the dead pull of gravity. To manage this, your veins contain valves that stop blood from flow-ing backward, and the muscles in your legs act as pumps when they contract, helping blood in the lower body get back to the heart. To contract, however, they need to be in motion. That's why it's important to get up and move around regularly. On the whole, the body manages these challenges pretty well. "For healthy people there is a less than 20 percent difference between blood pressure at the shoulder and at the ankle," Siobhan Loughna, a lecturer in anatomy at the University of Nottingham Medical School, told me one day. "It's really quite remarkable how the body sorts that out." As you may gather from this, blood pressure isn't a fixed figure, but changes from one part of the body to another, and across the body as a whole throughout the day. It tends to be highest during the day when we are active (or ought to be active) and to fall at night, reaching its lowest point in the small hours. It has long been known that heart attacks are more common in the dead of night, and some authorities think the nightly change in blood pressure may somehow act as a trigger. Much of the early research on blood pressure was done in a series of decidedly gruesome experiments on animals conducted by the Reverend Stephen Hales, an Anglican curate of Teddington, Middlesex, near London, in the early eighteenth century. In one experiment, Hales tied down an aged horse and attached a nine-foot-long glass tube to its carotid artery by means of a brass cannula. Then he opened the artery and measured how high blood shot up the tube with each dying pulse. He killed quite a number of helpless creatures in his pursuit of physiological knowledge and was roundly condemned for it--the poet Alexander Pope, who lived locally, was especially vocal on the matter--but among the scientific community his achievements were celebrated. Hales thus had the double distinction of advancing science while at the same time giving it a bad name. Though Hales was denounced by animal lovers, the Royal Society awarded him its very highest honor, the Copley Medal, and for a century or so Hales's book Haemastaticks was the last word on blood pressure in animals and man. Well into the twentieth century, many medical authorities believed that high blood pressure was a good thing because it indicated vigor-ous flow. We now know, of course, that chronically elevated blood pressure very seriously raises the risk of a heart attack or stroke. A more difficult question is, What exactly constitutes high blood pres-sure? For a long time, a reading of 140/90 was generally considered the baseline for hypertension, but in 2017 the American Heart Association surprised nearly everyone by abruptly pushing the number downward to 130/80. That small reduction tripled the number of men and doubled the number of women aged forty-five or under who were deemed to have high blood pressure and lifted practically all people over sixty- five into the danger zone. Almost half of all American adults-- 103 million people--are on the wrong side of the new blood pressure threshold, up from 72 million previously. At least 50 million Americans, it is thought, are not receiving appropriate medical atten-tion for the condition. Heart health has been one of the success stories of modern medi-cine. The death rate from heart diseases has fallen from almost 600 per 100,000 in 1950 to just 168 per 100,000 today. As recently as 2000, it was 257.6 per 100,000. But it is still the leading cause of death. In the United States alone, more than eighty million people suffer from cardiovascular disease, and the cost to the nation of treating heart disease has been put as high as $300 billion a year. There are lots of ways the heart can falter. It can skip a beat, or more usually have an extra beat, because an electrical impulse misfires. Some people can have as many as ten thousand of these palpitations a day without being aware of it. For others, an arrhythmic heart is an endless discomforting ordeal. When the heart's rhythm is too slow, the condition is called bradycardia; when too fast, it is tachycardia. A heart attack and a cardiac arrest, though usually confused by most of us, are in fact two different things. A heart attack occurs when oxygenated blood can't get to heart muscle because of a blockage in a coronary artery. Heart attacks are often sudden--that's why they are called attacks--whereas other forms of heart failure are often (though not always) more gradual. When heart muscle downstream of a block-age is deprived of oxygen, it begins to die, usually within about sixty minutes. Any heart muscle we lose in this way is gone forever, which is a bit galling when you consider that other creatures much simpler than we are--zebra fish, for instance--can regrow damaged heart tissue. Why evolution deprived us of this useful facility is yet another of the body's many imponderables. Cardiac arrest is when the heart stops pumping altogether, usu-ally because of a failure in electrical signaling. When the heart stops pumping, the brain is deprived of oxygen and unconsciousness swiftly follows, with death not far behind unless treatment is quickly applied. A heart attack will often lead to cardiac arrest, but you can suffer cardiac arrest without having a heart attack. The distinction between the two is medically important because they require different treat-ments, though the distinction may be a touch academic to the sufferer. All forms of heart failure can be cruelly sneaky. For about a quarter of victims, the first (and, more unfortunately, last) time they know they have a heart problem is when they suffer a fatal heart attack. No less appallingly, more than half of all first heart attacks (fatal or otherwise) occur in people who are fit and healthy and have no known obvious risks. They don't smoke or drink to excess, are not seriously overweight, and do not have chronically high blood pressure or even bad cholesterol readings, but they get a heart attack anyway. Living a virtuous life doesn't guarantee that you will escape heart problems; it just improves your chances. No two heart attacks are quite the same, it seems. Women and men have heart attacks in different ways. A woman is more likely to experience abdominal pain and nausea than a man, which makes it more likely that the problem will be misdiagnosed. Partly for this reason, women who have heart attacks before their mid-fifties are twice as likely to die as a man. Women have more heart attacks than is generally supposed. Twenty-eight thousand women suffer fatal heart attacks in the U.K. each year; about twice as many die of heart disease as die of breast cancer. Some people who are about to experience catastrophic heart failure suffer a sudden, terrifying premonition of impending death. The condition is commonly enough observed that it has a medical name: angor animi, or "anguish of the soul." For a lucky few victims (insofar as good fortune can be attached to a fatal event), death comes so swiftly that they appear to feel no pain. My own father went to bed one night in 1986 and never woke up. As far as could be told, he died without pain or distress or indeed aware-ness. For reasons unknown, the Hmong people of Southeast Asia are particularly susceptible to a condition known as sudden unexplained nocturnal death syndrome. In it, victims' hearts simply stop beating while they are asleep. Autopsies nearly always show the hearts to look normal and healthy. Hypertrophic cardiomyopathy is the condition that makes ath-letes die suddenly on playing fields. It arises from an unnatural (and nearly always undiagnosed) thickening of one of the ventricles and causes eleven thousand sudden unexpected deaths a year among people under forty-five in the United States. The heart has more named conditions than just about any other organ, and they are all bad news. If you can go through life without experiencing Prinzmetal angina, Kawasaki disease, Ebstein's anomaly, Eisenmenger syndrome, Takotsubo cardiomyopathy, or many, many others, you may consider yourself fortunate indeed. Heart disease is now such a common complaint that it is a little surprising to learn that it is largely a modern preoccupation. Until the 1940s, the principal focus of health care was with conquering infec-tious diseases like diphtheria, typhoid fever, and tuberculosis. Only after many of those were cleared out of the way did it become evident that we had another, growing epidemic on our hands in the form of cardiovascular disease. The triggering event for public awareness seems to have been the death of Franklin Delano Roosevelt. In early 1945, his blood pressure soared to 300/190, and it was clear that this was not a sign of vigor but quite the opposite. When he died soon afterward, aged just sixty- three, the world seemed suddenly to realize that heart disease had become a serious and widespread problem and that it was time to try to do something about it. The result was the celebrated Framingham Heart Study, conducted in the town of Framingham, Massachusetts, just west of Boston. Starting in the autumn of 1948, the Framingham study recruited five thousand local adults and followed them carefully for the rest of their lives. Though the study has been criticized for being almost entirely composed of white people (a deficiency since corrected), it did at least include women, which was unusually farsighted for the time, particularly because women were not thought to suffer unduly from heart problems then. The study is now in its third generation of volunteers. The idea from the outset was to determine the factors that led some people to have heart problems and others to escape them. It was thanks to the Framingham study that most of the major risks for heart disease were identified or confirmed--diabetes, smoking, obesity, poor diet, chronic indolence, and so on. In fact, the term "risk factor" is said to have been coined in Framingham. The twentieth century could with some justification be called the Century of the Heart, for no other area of medicine experienced more rapid and revolutionary technical progress. In a single lifetime, we have gone from barely being able to touch a beating heart to operating on them routinely. As with any complicated and risky medical pro-cedure, it took years of patient work by lots of people to perfect the techniques and devise the apparatus to make it all possible. The dar-ing and personal risk that some researchers took on is sometimes quite extraordinary. Consider the case of Werner Forssmann. In 1929, Forssmann was a young, newly qualified doctor working in a hospital near Berlin when he became curious to know if it would be possible to gain direct access to the heart by means of a catheter. Without any idea what the consequences would be, he fed a catheter into an artery in his arm and cautiously pushed it up toward his shoulder and on into his chest until it reached his heart, which, he was gratified to discover, didn't go into arrest when a foreign object invaded it. Then, realizing he needed proof of what he had done, Forssmann walked to the hospital's radiology department, on another floor of the building, and had himself X- rayed to show the shadowy and startling image of the catheter in situ in his heart. Forssmann's procedure would eventu-ally revolutionize heart surgery, but it attracted almost no attention at the time, largely because he reported it in a minor journal. Forssmann would be a rather more sympathetic figure except that he was an early and ardent supporter of the Nazi Party and the National Socialist German Physicians' League, which was behind the purging of Jews in the quest for German racial purity. It's not entirely clear how much personal evil he engaged in during the Holocaust, but at the very least he was philosophically despicable. After the war, partly to escape retri-bution, Forssmann worked in obscurity as a family physician in a small town in the Black Forest. He would have been forgotten altogether in the wider world except that two academics from Columbia University in New York, Dickinson Richards and André Cournand, whose work was directly reliant on Forssmann's original breakthrough, tracked him down and publicized his contribution to cardiology. In 1956, all three men were awarded the Nobel Prize in Physiology or Medicine. Far more personally noble than Forssmann, and no less stoic in his capacity for experimental discomfort, was Dr. John H. Gibbon of the University of Pennsylvania. In the early 1930s, Gibbon began a long and patient quest to build a machine that could oxygenate blood artificially, to make open-heart surgery possible. To test the capacity of blood vessels deep within the body to dilate or constrict, Gibbon stuck a thermometer up his rectum, swallowed a stomach tube, and then had icy water poured down it to determine its effect on his internal body temperature. After twenty years of refinements, and much heroic swallowing of iced water, Gibbon unveiled the world's first heart- lung machine at the Jefferson College Hospital in Philadelphia in 1953 and successfully patched a hole in the heart of an eighteen-year-old woman who would otherwise have died. Thanks to his efforts, the woman lived another thirty years. Unfortunately, the next four patients died, and Gibbon gave up on the machine. It then fell to a surgeon in Minneapolis, Walton Lillehei, to improve both the technology and the surgical techniques. Lillehei introduced a refinement known as controlled cross-circulation in which the patient was hooked up to a temporary donor (usually a close family member) whose blood was circulated through the patient during the period of surgery. The technique worked so well that Lille-hei became widely known as the father of open-heart surgery and enjoyed a great deal of acclaim and financial success. Unfortunately, he wasn't quite as impeccable in his private affairs as he might have been. In 1973, he was convicted of five counts of tax evasion and a great deal of very imaginative bookkeeping. Among much else, he had claimed a $100 payment to a prostitute as a charitable tax deduction. Although open-heart surgery allowed surgeons to correct many faults they previously couldn't get at, it couldn't solve the problem of a heart that wouldn't beat right. That required the device now universally known as a pacemaker. In 1958, a Swedish engineer named Rune Elmqvist, working in collaboration with the surgeon Åke Senning of the Karolinska Institute in Stockholm, built a pair of experimental cardiac pacemakers at his kitchen table. The first was inserted into the chest of Arne Larsson, a forty-three-year-old patient (and himself an engineer) who was very near death from a heart arrhythmia as a result of a viral infection. The device failed after just a few hours. The backup was inserted and it lasted for three years, though it kept breaking down and the batteries had to be recharged every few hours. As technology improved, Larsson was routinely fitted with new pacemakers and lived another forty-three years. When he died in 2002 at the age of eighty-six, he was on his twenty-sixth pacemaker and had outlived both his surgeon Senning and his fellow engineer Elmqvist. The first pacemaker was about the size of a pack of cigarettes. Today's are no bigger than one American quarter and can last up to ten years. The coronary bypass, which involved taking a length of healthy vein from a person's leg and transplanting it to direct blood flow around a diseased coronary artery, was devised in 1967 by René Favaloro at the Cleveland Clinic in Ohio. Favaloro's was a story at once inspiring and tragic. He grew up poor in Argentina and became the first member of his family to attain a higher education. Upon qualifying as a doctor, he spent twelve years working among the poor but came to the United States in the 1960s to improve his skills. At the Cleveland Clinic, he was little more than a trainee at first but quickly proved himself adept at heart surgery and in 1967 invented the bypass. It was a comparatively simple but ingenious procedure, and it worked brilliantly. Favaloro's first patient, a man too ill to walk up a flight of stairs, recovered completely and lived another thirty years. Favaloro grew wealthy and celebrated and in the twilight of his career decided to return home to Argentina to build a heart clinic and teaching hospital, where doctors could be trained and needy people treated whether they could afford payment or not. All of this he achieved, but because of challenging economic conditions in Argentina, the hospital got into financial difficulties. Unable to see a way out, in 2000 he killed himself. The great dream was to transplant a heart, but in many places it faced a seemingly insuperable obstacle: a person could not be declared dead until his heart had been stopped for a specified period, but that was all but certain to render the heart unusable for transplant. To remove a beating heart, no matter how far gone the owner was in all other respects, was to risk prosecution for murder. One place where that law did not apply was South Africa. In 1967, at exactly the time that René Favaloro was perfecting bypass surgery in Cleveland, Christiaan Barnard, a surgeon in Cape Town, attracted far more of the world's attention by transplanting the heart of a young woman fatally injured in a car accident into the chest of a fifty-four-year-old man named Louis Washkansky. It was hailed as a great medical breakthrough, though in fact Washkansky died after just eighteen days. Barnard had much better luck with his second transplant patient, a retired dentist named Philip Blaiberg, who survived for nineteen months.* Following Barnard, other nations moved to let brain death be used as an alternative measure of irreversible lifelessness, and soon heart transplants were being attempted all over, though nearly always with discouraging results. The main issue was an absence of a wholly reliable immunosuppressive drug to deal with rejection. A drug called azathioprine worked sometimes but couldn't be relied on. Then, in 1969, an employee of the Swiss pharmaceutical company Sandoz named H. P. Frey, while on holiday in Norway, collected soil samples to take back to the Sandoz labs. The company had asked employees to do so when traveling in the hope that they would find potential new antibiotics. Frey's sample contained a fungus, Tolypocladium inflatum, which had no useful antibiotic properties but proved excellent at sup-pressing immune responses--just the thing needed to make organ transplants possible. Sandoz converted Herr Frey's little bag of dirt, and a similar sample subsequently found in Wisconsin, into a best-selling medicine called cyclosporine. Thanks to it and some associated technical improvements, by the early 1980s heart transplant surgeons were managing success rates of 80 percent, an extraordinary achieve-ment in a decade and a half. Today some four to five thousand heart transplants are performed globally each year, with an average survival time of fifteen years. The longest-surviving transplant patient so far was the Briton John McCafferty, who lived thirty-three years with a transplanted heart before dying in 2016 aged seventy-three. Incidentally, brain death turned out to be not as straightforward as originally thought. Some peripheral parts of the brain, we now know, may live on after all the rest has grown still. At the time of this writing, that is the issue at the center of a long-running case involving a young woman in the United States who was declared brain- dead in 2013 but who has continued to menstruate, a process that requires a functioning hypothalamus--very much a key part of the brain. The young woman's parents argue that anyone with even part of the brain functioning cannot reasonably be declared brain-dead. As for Christiaan Barnard, the man who began it all, success rather went to his head. He traveled the world, dated movie stars (Sophia Loren and Gina Lollobrigida notably), and became, in the words of someone who knew him well, "one of the world's great womanizers." Even worse for his reputation, he made a fortune claiming rejuvenative benefits for a range of cosmetics that he most assuredly knew were bogus. He died in 2001, aged seventy-eight, of a heart attack while enjoying himself in Cyprus. His reputation was never again quite what it had been. Remarkably, even with all the improvements in care, you are 70 percent more likely to die from heart disease today than you were in 1900. That's partly because other things used to kill people first, and partly because a hundred years ago people didn't spend five or six hours an evening in front of a television with a big spoon and a tub of ice cream. Heart disease is far and away the Western world's number one killer. As Michael Kinch has written, "Heart disease kills about the same number of Americans each year as cancer, influenza, pneumonia, and accidents combined. One in three Americans dies of heart disease and more than 1.5 million suffer a heart attack or stroke each year." Today the problem is as likely to be overtreatment as under, according to some authorities. Balloon angioplasties as a treatment for angina (or chest pains) are a case in point, it seems. With an angio-plasty, a balloon is inflated inside a constricted coronary blood vessel to widen it, and a stent, or piece of tubular scaffolding, is left behind to keep the vessel permanently open.* The operation is unquestionably a lifesaver in emergencies, but it has also proven highly popular as an elective procedure. By 2000, a million precautionary angioplasties were being undertaken in the United States every year, but without any proof that they saved lives. When clinical trials were finally undertaken, the results were sobering. According to The New England Journal of Medicine , for every one thousand nonemergency angioplas-ties in America, two patients died on the operating table, twenty-eight suffered heart attacks brought on by the procedure, between sixty and ninety experienced a "transient" improvement in their health, and the rest--about eight hundred people--experienced neither benefit nor harm (unless of course you count the cost, the loss of time, and the anxiety of surgery as harm, in which case there was plenty). Despite this, angioplasties remain extremely popular. In 2013, the former president George W. Bush had an angioplasty at the age of sixty-seven, even though he was in good shape and had no sign of heart problems. Surgeons don't usually publicly criticize colleagues, but Dr. Steve Nissen, head of cardiology at the Cleveland Clinic, was scathing. "This is really American medicine at its worst," he said. "It's one of the reasons we spend so much on medicine and don't get a lot for it." II HOW MUCH BLOOD you have depends, as you might suppose, on how big you are. A newborn baby contains only about eight ounces, whereas a fully grown man will have more like five quarts. What is certain is that you are suffused with the stuff. Prick your skin any-where and you will draw blood. Within your modest frame are some twenty-five thousand miles of blood vessels (mostly in the form of tiny capillaries), so no part of you is ever far from the refreshment of hemoglobin, the molecule that transports oxygen throughout your body. We all know that blood carries oxygen to our cells--it is one of the few facts about the human body that everyone does seem to know--but it also does a whole lot more. It transports hormones and other vital chemicals, carries off wastes, tracks down and kills pathogens, makes sure oxygen is directed to the parts of the body where it is most needed, signals our emotions (as when we blush from embar-rassment or grow red with fury), helps to regulate body temperature, and even enables the complicated hydraulics of the male erection. It is, in short, a complex material. By one estimate, a single drop of blood may contain four thousand different types of molecules. That's why doctors are so fond of blood tests: your blood is positively packed with information. Spin a test tube of blood in a centrifuge and it will separate into four layers: red cells, white cells, platelets, and plasma. Plasma is the most abundant, constituting a little over half of blood's volume. It is more than 90 percent water with some salts, fats, and other chemicals suspended in it. That isn't to say plasma is unimportant, however. It is anything but. Antibodies, clotting factors, and other constituent parts can be separated out and used in concentrated form to treat autoimmune diseases or hemophilia--and that is a huge business. In the United States, plasma sales make up 1.6 percent of all goods exported, more than America earns from the sale of airplanes. Red blood cells (formally called erythrocytes) are the next most plentiful component, constituting about 44 percent of the total volume of the blood. Red blood cells are exquisitely designed to do one job: deliver oxygen. They are very small but superabundant. A teaspoon of human blood contains about twenty-five billion red blood cells, and each one of those twenty-five billion contains 250,000 molecules of hemoglobin, the protein to which oxygen willingly clings. Red blood cells are biconcave in shape--that is, disk shaped but pinched in the middle on both sides which gives them the largest possible surface area. To make themselves maximally efficient, they have jettisoned virtually all the components of a conventional cell--DNA, RNA, mito-chondria, Golgi apparatus, enzymes of every description. A full red blood cell is almost entirely hemoglobin. It is essentially a shipping container. A notable paradox of red blood cells is that although they carry oxygen to all the other cells of the body, they don't use oxygen themselves. They use glucose for their own energy needs. Hemoglobin has one strange and dangerous quirk: it vastly prefers carbon monoxide to oxygen. If carbon monoxide is present, hemoglobin will pack it in, like passengers on a rush-hour train, and leave the oxygen on the platform. That's why it kills people. (About 430 of them a year in the United States unintentionally, and a similar number by suicide.) Each red corpuscle survives for about four months, which is pretty good going considering what a jostling and busy existence it leads. Each will be shot around your body about 150,000 times, logging a hundred miles or so of travel before it is too battered to go on. Then these corpuscles are collected by scavenger cells and sent to the spleen for disposal. You discard about a hundred billion red blood cells every day. They are a big component of what makes your stools brown. (Bilirubin, a by-product of the same process, is responsible for the golden glow of urine as well as the yellow blush of fading bruises.) White blood cells (or leukocytes) are vital for fighting off infections. In fact, they are so important that we will treat them separately in chapter 12, on the immune system. For the moment, it is enough to know that they are much less numerous than their red siblings. You have seven hundred times as many red blood cells as white ones, which constitute less than 1 percent of the total.* Platelets (or thrombocytes), the final part of the blood quartet, also account for less than 1 percent of blood's volume. Platelets were for a long time a mystery to anatomists. They were first seen under a microscope in 1841 by a British anatomist named George Gulliver, but they weren't named or properly understood until 1910 when James Homer Wright, chief pathologist at the Massachusetts General Hospi-tal in Boston, deduced their central role in clotting. Clotting is a tricky business. The blood must be perpetually on alert to clot at a moment's notice, but equally mustn't clot unnecessarily. As soon as a bleed starts, millions of platelets begin to cluster around the wound and are joined by similarly vast numbers of proteins, which deposit a material called fibrin. This agglomerates with the platelets to make a plug. To try to avoid errors, no fewer than twelve fail- safe mechanisms are built into the process. Clotting doesn't work in the principal arteries, because the flow of blood is too fierce; any clot would be swept away, which is why major bleeds must be stopped with the pressure of a tourniquet. In severe bleeding, the body does all it can to keep blood flowing to the vital organs and diverts it away from secondary outposts like muscles and surface tissues. That's why patients who are bleeding heavily turn a cadaverous white and are cold to the touch. Platelets live for only about a week, so must be constantly replenished. In the last decade or so, scientists have realized that platelets do more than just manage the clotting process. They also play important roles in immune response and in tissue regeneration. For the longest time, almost nothing was known about the purpose of blood beyond that it was somehow vital to life. The prevailing theory, dating since the time of the venerable but frequently mistaken Greek physician Galen (ca. 129--ca. 210), was that blood was manufactured continuously in the liver and used up by the body as fast as it was made. As you will doubtless recall from your school days, the English physician William Harvey (1578-1657) realized that blood is not endlessly consumed, but rather circulates in a closed system. In a landmark work called Exercitatio anatomica de motu cordis et sanguinis in animalibus ( On the Motion of the Heart and Blood in Animals ), Harvey outlined all the details of how the heart and circulatory system work, in more or less the terms we understand today. When I was a schoolboy, this was always presented as one of those eureka moments that changed the world. In fact, in Harvey's day the theory was almost universally ridiculed and rejected. Nearly all Harvey's peers thought him "crack- brained," in the words of the diarist John Aubrey. Harvey was abandoned by most of his clients and died a bitter man. Harvey didn't understand respiration, so couldn't explain what purpose blood served or why it circulated--two pretty glaring defi-ciencies, as his critics were quick to point out. Galenists additionally believed that the body contains two separate arterial systems--one in which the blood is bright red and another in which it is much duller. We now know that blood traveling from the lungs is full of oxygen and therefore shiny crimson, while blood returning to the lungs is depleted of oxygen and thus rather duller. Harvey couldn't explain how blood circulating in a closed system could be of two colors, which became yet another reason to scorn his theories. The secret of respiration was deduced not long after Harvey's death by another Englishman, Richard Lower, who realized that blood dulls in color on its way back to the heart because it has given up its oxygen, or nitrous spirit, as he called it. (Oxygen wouldn't be discovered until the following century.) That, Lower reasoned, was why blood circu-lated, to continuously pick up and discharge nitrous oxide, which was quite a big insight and one that should have made him famous. In fact, Lower is remembered more now for another aspect of blood. In the 1660s, Lower was one of several eminent scientists who became interested in the possibility of saving lives through blood transfusions, and he became involved in a series of often gruesome experiments. In November 1667 before an audience of "considerable and intelligent persons" at the Royal Society in London, and without having any idea at all what the consequences might be, Lower transfused about half a pint of blood from a live sheep into the arm of an amiable volunteer named Arthur Coga. Then Lower and Coga and all the distinguished onlookers sat keenly for many minutes waiting to see what would happen. Happily, nothing did. One of those present reported that Coga afterward was "well and merry, and drank a glass or two of canary, and took a pipe of tobacco." Two weeks later, the experiment was repeated, again without ill effect, which is really surprising. Normally, when foreign substances are introduced in volume into the bloodstream, the recipient goes into shock, so why Coga escaped a miserable experience is puzzling. Unfortunately, the results emboldened other scientists across Europe to conduct transfusion tests of their own, and these took on an increas-ingly inventive, not to say surreal, cast. Volunteers were transfused with milk, wine, beer, and even mercury, as well as the blood of every species of domesticated creature. The results all too often were distressingly agonized, embarrassingly public deaths. Very quickly transfusion experiments were banned or fell into abeyance, and for about a century and a half they remained out of favor. And then followed a strange thing. Just as the rest of the scientific world was embarking on the outpouring of discovery and insight known to us as the Age of Enlightenment, medicine sank into a kind of dark age. You could hardly imagine more misguided and counter-productive practices than those to which physicians became attached in the eighteenth and even much of the nineteenth centuries. As David Wootton put it in Bad Medicine: Doctors Doing Harm Since Hip-pocrates , "Up until 1865 medicine was almost completely ineffectual where it wasn't positively harmful." Consider the unfortunate death of George Washington. In December 1799, not long after he had retired as America's first president, Washington spent a long day on horseback in foul weather inspect-ing Mount Vernon, his plantation in Virginia. Returning home later than expected, he sat through dinner in damp clothes. That night he developed a sore throat. Soon he had difficulty swallowing, and his breathing became labored. Three physicians were called in. After a hurried consultation, they opened a vein in his arm and drained eighteen ounces of blood, almost enough to fill a British pint glass (or overfill an American one). Washington's condition only worsened, however, so his throat was blistered with a poultice of cantharides--what is more commonly known as Spanish fly--to draw out bad humors. For good measure, he was given an emetic to induce vomiting. When all of this failed to produce any visible benefit, he was bled three times more. Altogether about 40 percent of his blood was removed over two days. "I die hard," Washington croaked as his well-meaning doctors relentlessly sapped him. No one knows precisely what Washington's complaint was, but it might have been no more than a minor throat infection that required a little rest. As it was, the illness and treatment together left him dead. He was sixty-seven years old. Upon his death, yet another doctor visited and proposed that they revive--indeed, resurrect--the deceased president by rubbing his skin gently to stimulate blood flow and transfusing him with lamb's blood, to replace the blood he had lost and refresh what remained. His family mercifully decided to leave him to his eternal rest. It may seem to us self-evidently foolhardy to bleed and pummel a person who is already severely ill, but such practices lasted an extraordinarily long time. Bleeding was thought to be beneficial not just for illness but to instill calm. Frederick the Great of Germany was bled before battle just to soothe his jangled nerves. Bleeding bowls were treasured within families and passed on as heirlooms. The importance of bleeding is recalled by the fact that Britain's venerable medical journal The Lancet , founded in 1823, is named for the instrument used for opening veins. Why did bleeding persist for so long? The answer is that until well into the nineteenth century most doctors approached diseases not as distinct afflictions, each requiring its own treatment, but as generalized imbalances affecting the whole body. They didn't give one drug for headaches and another for, say, ringing in the ears, but rather endeavored to bring the whole body back into a state of equilibrium by purging it of toxins through the administration of cathartics, emetics, and diuretics, or by relieving the victim of a bowl or two of blood. Opening a vein, as one authority put it, "cools and ventilates the blood" and allows it to circulate more freely, "without danger of burning." The most celebrated bleeder of all, known as the "Prince of Bleeders," was the American Benjamin Rush. Rush trained in Edinburgh and London, where he learned dissecting from the great surgeon and anatomist William Hunter, but his belief that all illnesses arose from a single cause--overheated blood--was largely self-developed during a long career back in Pennsylvania. Rush, it must be said, was a conscientious and learned man. He was a signer of the Declaration of Independence and the most eminent medical practitioner of his day in the New World. But he was a super enthusiast for bleeding. Rush drained up to eighty ounces at a time from his victims and sometimes bled them two or three times in a single day. Part of the problem was that he believed that the human body contains about twice as much blood as it actually does and that one can remove up to 80 percent of that notional amount without ill effect. He was tragically wrong on both counts yet never doubted the rightness of what he did. During a yellow fever epidemic in Philadelphia, he bled hundreds of victims and was convinced that he had saved a great many when in fact all he did was fail to kill them all. "I have observed the most speedy convalescence where the bleeding has been most profuse," he wrote proudly to his wife. That was the problem with bleeding. If you could tell yourself that those who survived did so because of your efforts while those who died were beyond salvation by the time you reached them, bleeding would always seem a prudent option. Bleeding retained a place in medical treatments right up to the modern age. William Osler, author of The Principles and Practice of Medicine (1892), the most influential medical textbook of the nineteenth century, spoke in favor of bleeding well into what we would consider the modern era. As for Rush, in 1813 at the age of sixty-seven he developed a fever. When it didn't improve, he urged his attending physicians to bleed him, and they did. And then he died. The beginning of a modern understanding of blood can perhaps be said to date from 1900 and an astute discovery by a young medical researcher in Vienna. Karl Landsteiner noticed that when blood from different people was mixed together, sometimes it clumped and sometimes it did not. By noting which samples joined with which others, he was able to divide the samples into three groups, which he labeled A, B, and 0. Although everybody reads and pronounces the last group as the letter O , Landsteiner in fact meant it to be taken as a zero, because it didn't clump at all. Two other researchers at Landsteiner's lab subsequently discovered a fourth group, which they called AB, and Landsteiner himself, forty years later, co-discovered Rh factor--short for "rhesus," from the type of monkey in which it was found.* The discovery of blood types explained why transfusions often failed: because the donor and the recipient had incompatible types. It was a hugely significant discovery, but unfortunately almost no one paid any attention to it at the time. Thirty years would pass before Landsteiner's contribution to medical science was recognized with a Nobel Prize in 1930. The way blood typing works is this: All blood cells are the same inside, but the outsides are covered with different kinds of antigens--that is, proteins that project outward from the cell surface--and that is what accounts for blood types. There are some four hundred kinds of antigens altogether, but only a few have an important effect on transfusion, which is why we have all heard of types A, B, AB, and O, but not, say, Kell, Giblett, and type E, to name just a very few among many. People with blood type A can donate to those with A or AB but not B; people with B can donate to B or AB but not A; people with AB can donate only to other people with AB blood. People with type O blood can donate to all others, and so are known as universal donors. Type A cells have A antigen on their surface, type B have B, and type AB have both A and B. Put A type blood in a B type person and the recipient body sees it as an invasion and attacks the new blood. We don't actually know why blood types exist at all. Partly it may be because there simply wasn't any reason for them not to. That is to say, there was no reason to suppose that any person's blood would ever end up in someone else's body, so no reason to evolve mechanisms to deal with such issues. At the same time, by favoring certain antigens in our blood, we can gain improved resistance against particular diseases--though often at a price. People with O blood, for instance, are more resistant to malaria but less resistant to cholera. By developing a variety of blood types and spreading them around among populations, we benefit the species, if not always the individuals within it. Blood typing had a second, unanticipated benefit: establishing parenthood. In a famous case in Chicago in 1930, two sets of parents, the Bambergers and the Watkinses, had babies in the same hospital at the same time. After returning home, they discovered to their dismay that their babies were wearing labels with the other family's name on them. The question became whether the mothers had been sent home with the wrong babies or with the right babies mislabeled. Weeks of uncertainty followed, and in the meantime both sets of parents did what parents naturally do: they fell in love with the babies in their care. Finally, an authority from Northwestern University with a name that might have come out of a Marx Brothers movie, Professor Hamilton Fishback, was called in, and he administered blood tests to all four parents, which at the time seemed the very height of technical sophistication. Fishback's tests showed that both Mr. and Mrs. Watkins had type O blood and therefore could produce only a type O baby, whereas the child in their nursery was type AB. So, thanks to medical science, the babies were swapped back to the right parents, though not without a lot of heartache. Blood transfusions save a lot of lives every year, but taking and storing blood is an expensive and even risky business. "Blood is a living tissue," says Dr. Allan Doctor of Washington University in St. Louis. "It's as alive as your heart or lungs or any other organ. The moment you take it out of the body, it begins to degrade, and that is where problems begin." We met in Oxford, where Doctor, a solemn but amiable man with a trim white beard, was attending a conference of the Nitric Oxide Society, a group that was formed as recently as 1996 because before that nobody realized that nitric oxide was worth getting together for. Its importance to human biology was almost entirely unknown. In fact, nitric oxide (not to be confused with nitrous oxide, or laughing gas) is one of our primary signaling molecules and has a central role in all kinds of processes--maintaining blood pressure, fighting infections, powering penile erections, and regulating blood flow, which is where Doctor comes in. His ambition in life is to make artificial blood, but in the meantime he would like to help make real blood safer to use in transfusions. It comes as a shock to most of us to hear it, but transfused blood can kill you. The problem is that no one knows how long it remains effective in storage. "Legally, in the United States," Doctor says, "blood can be kept for transfusion for forty-two days, but actually it is probably only good for about two and a half weeks. After that, nobody can say to what extent it is working or not." The forty-two-day rule, which comes from the Food and Drug Administration, is based on how long a typical red cell remains in circulation. "It was assumed for a long time that if a red cell is still circulating, it is still functioning, but we now know that that's not necessarily the case," he says. Traditionally, it was standard practice for doctors to top up any blood that was lost in trauma. Doctor continued, "If you'd lost three pints of blood, they would put three pints back in. But then AIDS and hepatitis C came along and donated blood was sometimes contaminated, so they began to use transfused blood more sparingly, and to their astonishment they found that patients often had better outcomes from not receiving transfusions." It turned out that in some cases it can be better to let patients be anemic than to give them someone else's blood, especially if that blood had been in storage for a while--and that is nearly always the case. When a blood bank receives a call for blood, it normally dispatches the oldest blood first, to use up aging stock before it expires, which means that almost everybody receives old blood. Worse still, it was discovered that even fresh transfused blood actually impedes the performance of existing blood in the recipient's body. This is where nitric oxide comes in. Most of us think of blood as being more or less equally distributed around the body at all times. Whatever amount is in your arm now is what is always there. In fact, Doctor explained to me, it is not like that at all. "If you are sitting down, you don't need so much blood in your legs because there is not a great requirement for oxygen in the tissues. But if you leap up and start running, you are going to need a lot more blood there very quickly. Your red blood cells, using nitric oxide as their signaling molecule, in large part determine where to dispatch blood as the body's requirements change from moment to moment. Transfused blood confuses the signaling system. It impedes function." On top of all that, real blood has some practical problems. For one thing, it must be kept refrigerated. That makes it difficult to use on battlefields or accident sites, which is a pity because that's where a lot of bleeding takes place. Twenty thousand people die every year in America from bleeding to death before they can get to a hospital. Globally, the number of bleeding deaths a year has been put as high as 2.5 million. Many of those lives would be saved if people could be transfused promptly and safely--hence the desire for an artificial product. In theory, it ought to be fairly straightforward, particularly because an artificial blood wouldn't need to do most of the many things real blood does except carry hemoglobin. "In practice, it's proved to be not so simple," says Doctor with a fleeting smile. He explains the problem by likening red blood cells to those magnets that you see picking up cars in junkyards. The magnet has to latch on to an oxygen molecule in the lungs and convey it to a destination cell. In order to do that, it has to know where to take the oxygen and when to release it, and above all it mustn't drop it en route. That has always been the problem with artificial bloods. Even the best- made artificial bloods occasionally drop an oxygen molecule, and in so doing release iron into the bloodstream. Iron is a toxin. Because of the extreme busyness of the circulatory system, even an infinitesimal accident rate will quickly mount up to toxic levels, so the delivery system has to be pretty much perfect. In nature, it is. For more than fifty years, researchers have been trying to make artificial blood but, despite spending millions of dollars, are still not there yet. Indeed, there have been more setbacks than breakthroughs. In the 1990s, some blood products made it into trials, but then it became evident that patients enrolled in the trials were having alarming numbers of heart attacks and strokes. In 2006, the FDA temporarily shut down all trials because the results were so bad. Since then, several pharmaceutical companies have abandoned the quest to make a synthetic blood. For now, the best approach is simply to reduce the volume of transfusions. In an experiment at Stanford Hospital in California, clinicians were encouraged to reduce orders for red blood cell transfusions except when absolutely required. In five years, transfusions at the hospital fell by a quarter. The result was not only a $1.6 million saving in costs but fewer deaths, quicker average discharges, and a reduction in posttreatment complications. Now, however, Doctor and his colleagues in St. Louis think they have nearly cracked the problem. "We have nanotechnology at our disposal now, which wasn't available before," he says. Doctor's team has developed a system that keeps the hemoglobin inside a polymer shell. The shells are shaped like conventional red blood cells but are about fifty times smaller. One of the great virtues of the product is that it can be freeze- dried, enabling it to be stored for up to two years at room temperature. At the time I met him, he believed they were three years away from trials in humans, and perhaps ten years from using it clinically. In the meantime, it remains a slightly humbling reflection that about a million times per second our bodies do something that all the science of the world put together so far cannot do at all. Excerpted from The Body: A Guide for Occupants by Bill Bryson All rights reserved by the original copyright owners. Excerpts are provided for display purposes only and may not be reproduced, reprinted or distributed without the written permission of the publisher.
