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Preface

The drama ended, as do so many these days, in a courtroom. This particular chamber was long and low-ceilinged, with a wide dais at its front for the eight black-robed judges. Each of the four defendants sat flanked by tall policemen who gazed impassively from under the brims of their trademark pillbox hats. In keeping with the formality of French courts, the prosecuting and defense attorneys wore flowing black robes, which would dramatically sweep behind them as they rose to make a point. The only visible flaw in the decorum appeared among the audience members, some of whom wore T-shirts bearing inflammatory slogans. There were audible exceptions to decorum as well, as people would moan or shout "Non!" at a defendant's response, or when one man, the most vocal of the plaintiffs, would, as his doctor walked past, loudly hiss "Assassin!"

    The plaintiffs in this trial were dying of AIDS. They charged that they had been infected through the negligence of the defendants--high officials in the French national transfusion service. In France, where the government until recently held a monopoly on blood and its derivatives, these men were supposed to ensure the safety of blood products. Instead, they allowed thousands of the nation's hemophiliacs to inject blood-derived clotting factors they knew to be contaminated. The defendants had done so because of a complicated mixture of paternalism, economics, and to some extent the limits of science, but the victims saw the incident more starkly. To them the affair was a matter of betrayal. The doctors on trial in the summer of 1992 were supposed to have embodied all that was noble in the French transfusion tradition--altruism, medicine, business, and technology. Instead, during the years of the "contaminated-blood affair" they came to symbolize the cynicism and expediency of a money-driven age.

    The sense of betrayal surfaced in many places beyond the courtroom in Paris. For more than a decade the theme has been sounded in one locale after another throughout the world. In America, patients have filed hundreds of civil suits against doctors, drug companies, and even their own patient organizations, for abandoning their health to the expediency of the marketplace. In England, AIDS-infected hemophilia patients castigated their national transfusion service with reacting too slowly to the threat of emerging viruses. In Japan, patients charged that the government and drug companies criminally concealed the contamination of blood products; as a result, some of the nation's most revered doctors have gone to jail. In Canada, the scandal of contamination spread so wide that the government held a series of hearings across the country that convulsed the nation with anger and shame.

    Why those scandals erupted is one of the underlying questions of this book, a history of human blood as a resource and humanity's attempts to understand and exploit it. Blood is one of the world's most vital medical commodities: The liquid and its derivatives save millions of lives every year. Yet blood is a complex resource not completely understood, easily contaminated, and bearing more than its share of cultural baggage. Indeed, the mythic and moral symbolism of blood, which has been with us since ancient times, subtly endures. It clouded professional judgments and public perceptions in the AIDS scandals of France, Canada, and Japan, among others.

    If one considers blood a natural resource, then it must certainly rank among the world's most precious liquids. A barrel of crude oil, for example, sells for about $13 at this writing. The same quantity of whole blood, in its "crude" state, would sell for more than $20,000. Crude oil, as we know, can be broken down into several derivatives, including gasoline, distillates such as diesel, and petrochemicals. Blood can be separated into derivatives as well. Spun in a centrifuge, it divides into layers--red cells on the bottom, a thin intermediary layer of platelets and white cells, and an upper tea-colored layer of plasma. Each layer, in turn, can be used as various therapeutic products. Red cells can be transfused directly. White cells and platelets can be used to restore resistance or clotting ability to patients undergoing chemotherapy. Plasma, a resource in its own right, yields albumin for restoring circulation, clotting factors for patients with hemophilia, antibodies for vaccine production, and several other reagents and pharmaceuticals. Taken as a whole, the value of the derivatives in a forty-two-gallon barrel of crude oil would raise its price to $42. The price of the same quantity of completely processed blood would increase its value to more than $67,000.

    Of course, blood is not processed by the barrel or handled in quantities anywhere near those of oil. (Only about sixteen million gallons of blood and plasma are collected annually worldwide--the equivalent of thirty-two Olympic-size swimming pools.) Indeed, the world market for blood and its derivatives probably does not exceed $18.5 billion per year, versus $474.5 billion for petroleum. Yet one cannot avoid comparing the two resources. Just like the oil industry, the blood trade involves collecting a liquid resource, breaking it into components, and selling the products globally. Red cells, being perishable, tend to remain within national borders, but certain portions of blood--plasma in particular--are traded among multinational companies and on a worldwide spot market. Just as with oil, one region has become the premier harvesting ground, providing much of the resource for the rest of the world. The United States, with its liberal rules regarding collection, has become known as the OPEC of plasma.

    No wars have been fought over blood as they have been for oil, but the movement of blood has played an important role in our wars. A major anxiety about D-Day, for example, was whether enough blood could be stored to supply all the wounded that military planners had projected. In preparation for the Persian Gulf War, the military shipped massive quantities of blood to the battle zone for what they thought would be thousands of casualties. (Good fortune proved them wrong.) Such collections have always been secret, since intelligence services know that the mobilization of blood is a sure sign of an impending attack.

    If the analogy between blood and oil is provocative, it is where the comparison breaks down that the story of blood becomes especially compelling, and life-changing to those who have been caught in its sweep. For one thing, oil does not transmit disease, a critical consideration in the blood trade. A slip in quality control at a refinery may result in the loss of a few dollars, but a mistake in blood processing can infect thousands of people. Second, whereas oil companies pay handsomely for drilling rights, blood collectors pay nothing or very little for their raw material, since donating is thought of as an act of human kindness. Such an arrangement, however admirable, can distort people's judgments. Think, for example, how the leaders of the oil industry would react if Saudi Arabia provided crude oil for free: They would bend over backward (even more than they currently do) never to offend their benefactors. So it had been with the blood collectors: When faced with the necessity of refusing blood from certain people to minimize the spread of viral disease, they found themselves reluctant to offend their cherished donors. As a result, public safety was compromised.

    The most telling difference between the two resources, however, is the one that reaches into our cultural past. Though oil serves as a critical resource, it carries no particular cultural baggage. Blood, in contrast, is laden with meaning. The descriptive cliché, "the elixir of life," barely touches on the liquid's mystical, religious, and patriotic significance. The Bible mentions blood more than four hundred times: "The life of the flesh is in the blood," says Leviticus, equating blood with life itself. Blood is considered so holy in the Old Testament that the law specifically forbids its consumption, which is why Jehovah's Witnesses, who interpret the Bible literally, refuse transfusions. The Egyptians saw blood as the carrier of the vital human spirit, and would bathe in the liquid as a restorative. It is because blood conveyed strength to the Romans that gladiators were said to have drunk the blood of fallen opponents. Doctors from the medieval to the Victorian era assumed blood to have fantastical powers, draining it to remove evil humors, transfusing it to pacify the deranged. Our own culture attaches great value to blood, with the blood of Christ as among the holiest sacraments, blood libel as the most insidious slander, the blood-drinking vampire as the most odious demon.

    The symbolic power of blood does not confine itself to mythology, for it has affected the behavior of doctors in modern times. The Nazis, in their perversity, refused transfusions from non-Aryan blood donors--condemning their armies to chronic shortages--and composed intricate charts of the presumed blood-related traits of the various races. Even the democracies were tainted by blood prejudice: During World War II, as America fought a racist enemy, the military maintained separated blood stocks from black and white donors for fear of offending white soldiers' sensibilities. Most recently, the persistent belief that blood products collected among their countrymen had to be inherently pure contributed to bad decision-making in the tainted-blood scandals of France and Japan.

    Thus, the story of blood cannot be limited to the twentieth century, when doctors began to use it for transfusions. The narrative reaches back into antiquity, as an undercurrent to the history of medicine and civilization. It spans the globe over the course of several centuries, periodically surfacing in dramatic ways, from the first blood experiments, during the Age of Enlightenment, to the genetic-engineering labs that one day may render transfusion obsolete.

    The story of blood is one of metamorphosis, of a liquid that became symbolically transformed as society learned how to deconstruct and manage it. As such, the history divides itself into three eras, each reflecting the spirit of its age.

    The first period, described in the section "Blood Magic," involves the transformation of blood from a magical substance to a component of human anatomy, capable of being isolated and studied. This section covers the period from antiquity to the early twentieth century, the time when the concept of blood moved from the magical to the biological; when blood became recognized as a therapeutic liquid transfusible from one creature to another. It is a measure of the symbolic power of blood that the first transfusions were used to treat not blood loss or anemia but insanity.

    The second era, covered in the section called "Blood Wars," describes the transformation of blood from a scientific curiosity to a strategic materiel. During the first few decades of the twentieth century, medical scientists began to master the resource, learning the techniques of mass collections, storage, and the separation of plasma. These advances occurred just in time for World War II, the greatest spilling of blood that the world has ever known. That conflict decisively altered blood's cultural significance--from the mother liquid of all health and disease, to a strategic resource, devoid of mystical overtones yet essential to human enterprise. The change became irreversible when Dr. Edwin J. Cohn of Harvard, working under a military contract, found a way to fractionate plasma into its many constituents. This technology, analogous to the "cracking" of oil, along with the freeze-drying of plasma, gave the Allies an enormous advantage over the Axis powers, whose blood-related technology was primitive. It also set the stage for a postwar global blood industry.

    The final section, "Blood Money," describes how the liquid that saved so many lives became the basis for a global industry. A small group of drug companies dominates the plasma business, analogous to the "Seven Sisters" of oil. In their quest to harvest the resource, those drug firms set up "plasma mills" in America's skid rows, buying from the residents, who often included drug addicts and indigents. Later, seeking new sources of raw material, they imported plasma from the Third World, notably Central America--a practice of dubious safety and morality. So politically explosive was the idea of harvesting the resource from the poorest of the poor that in one Central American country the populace rose up, destroying the facility and sparking a revolution. Meanwhile, the business of whole blood boomed as surgical advances such as open-heart surgery and organ transplants required ever-larger transfusions. (A single liver transplant may require fifty units of red cells.) Whole blood, collected on a nonprofit basis by the Red Cross and community blood banks, became the target of fierce competition as the "benevolent" collectors struggled for dominance.

    If the global blood business has been tainted by an element of exploitation, it must also be seen as tremendously beneficial. Countless lives have been saved by transfusions, not to mention plasma-derived pharmaceuticals. People with hemophilia, who have been using clotting factors since the late 1960s, have seen their average life expectancy double. Yet the same therapeutics that brought life to so many have also transmitted disease: If blood and plasma products could be routinely distributed among millions, so too would any pathogens they harbored. During the blood-products boom of the 1970s, blood-related hepatitis rates soared, killing tens of thousands of hemophiliacs and transfusion recipients. By the end of the decade, doctors thought they had solved the hepatitis problem, only to be confronted by another virus that spread in an identical pattern--HIV. Though tainted blood products only caused a small portion of the AIDS epidemic (the disease was mainly spread through sexual contact and intravenous drug use), they took an enormous toll. More recently, another public health crisis has begun to unfold--the silent epidemic of blood-borne hepatitis C. It is ironic that, after all the transformations of blood wrought by modern medicine, HIV and other viruses revived the medieval image of blood as the bearer of evil humors and death.

    Today we confront a resource simultaneously safer and more threatening than before. Many nations, having learned from the AIDS crisis, have instituted virus screening-and-removal procedures. This has made blood more expensive, an ominous development in an era of shrinking health budgets. Furthermore, we can no longer complacently assume safety, since new diseases threaten to emerge. Meanwhile, poor nations, with little access to modern equipment, face unprecedented risks of blood-borne diseases. In order to address the inherent risks of the resource, some companies are creating artificial blood substitutes, immune to the pathogens that afflict humans. Even if those products someday appear, they will likely be expensive, prolonging the disparity between nations that have modern blood products and those that do not. Thus blood distribution, like that of other critical resources, will continue to raise questions of equity and social justice.

    This, then, is the story of blood--the chronicle of a resource, the researchers who have studied it, the businessmen who have traded it, the doctors who have prescribed it, and the lay people whose lives it has so dramatically affected. The book is also a challenge to those who distribute, regulate, and use the resource. Indeed, a lasting tension in the history is how we view this most human of commodities. Is it a gift of charity or simply a pharmaceutical? Can a single resource be both, and if so, what are the safest and most ethical ways to manage it? The answers to such questions will determine the future of this precious, mysterious, and hazardous material.

Chapter Twelve

BAD BLOOD

The blood business boomed in the 1960s and '70s. The enterprise had become so decentralized by now that no one knew how much was collected, although most estimates put it well above six million pints a year in the U.S. alone, easily surpassing peak collections during the war. The liquid's uses multiplied as well, as Cohn's dream of component therapy approached realization. Rather than using whole-blood transfusions, doctors increasingly administered individual components such as red cells, white cells, platelets, and plasma. Plasma itself was giving way to an increasing number of fractionation products, including albumin, gamma globulins, blood-typing sera, and clotting factors for people with hemophilia. Doctors used more blood in more ways than ever before.

    At this point the blood business divided. Hospitals and blood banks continued collecting whole blood, but plasma became an industrial affair. A new process called plasmapheresis propelled the separation. The system involved removing blood from the donor, centrifuging it to separate the plasma, and then re-infusing the red cells. The procedure was uncomfortable and could take a couple of hours (at least until it was automated in the mid-1980s), which made it necessary to pay the donors.

    Plasmapheresis proved invaluable to the drug industry, allowing manufacturers to harvest greater volumes of the raw plasma they desired. The process was safer than harvesting whole blood, since removing only plasma did not lead to anemia. Furthermore, while it takes weeks for the body to regenerate red cells, plasma can be replenished in a couple of days. All this meant that drug firms could collect more often than before: Previously they had had to wait a couple of months between purchases of blood from a given donor; now they could buy from him twice a week--104 times a year instead of 6.

    What happened next can best be envisioned by imagining that someone invented a very fast and cheap way of drilling for oil at the same time that the industry discovered petrochemicals. Almost overnight, the collection business boomed. Hundreds of new plasma centers sprang up to meet the demands of the burgeoning "biologics" industry, as it came to be called. Some belonged to the drug firms that had pioneered fractionation under Cohn; others belonged to small independents, specializing in collecting and selling the raw material. Like drilling rigs at an oil field, they sprouted wherever the resource seemed promising--around army bases and college campuses, in downtrodden neighborhoods, and along the Mexican-American border. From there the "source plasma" was sent to the nation's biologics manufacturers, who, in order to process it economically, pooled it in vats containing thousands of pints.

    New classes of people became involved--shadier buyers, more desperate sellers. Experts had warned about the potential for abuse. During a 1966 conference at Cohn's Protein Foundation, Dr. Tibor Greenwalt, a leader in nonprofit blood banking, cautioned against "exploiting for its proteins a population which is least able to donate them"--yet that gave little pause to commercial entrepreneurs. Tom Asher, a fifty-year veteran of the plasma industry who worked as a manager for the Hyland division of Baxter Laboratories, ruefully recalled that his company set up its first center at Fourth and Town streets in Los Angeles--"absolute dead center, Skid Row. We'd immunize donors with tetanus to increase their antibodies for tetanus gamma globulin. When hurried, our doctor, who was also the bouncer, would occasionally give them shots of tetanus antigen right through their trousers." Later the company took to "bankrolling all sorts of characters" to meet the booming demand for source plasma, many with questionable ethics. Another Los Angeles center, called Doctors Blood Bank and run by two local pathologists, paid donors in chits redeemable at a local liquor store.

    Stuart Bauer, a writer for New York magazine, investigated the world of down-and-out plasma sellers by becoming one himself. After a loved one died of transfusion-related hepatitis, Bauer went undercover, donning old clothes and selling his plasma thirteen times over a period of seven weeks. His tale was a bleak one of hardened collectors and avaricious doctors, and of the winos, addicts, malnourished, and destitute whose plasma they "farmed" at the center in Times Square. Among the chilling scenes in his article is one about the experience of donation:

The pain of insertion comes in three overlapping waves. The first two waves--the puncturing of the skin and the piercing of the radial vein--are dicey enough, but stubbing a toe or biting the tongue are really worse. It is the third wave, the least painful part, that carries the freight. For when the body of the catheter is fitted inside the vein, distending it, it catches you--of all places--in the heart, which registers the intrusion with a chilly ping. When the next beat comes the heart's resumption has a choked rhythm . . . and you resolve from here on in to cater to your heart. But the only favor it occurs to you you can do is not to breathe too deeply. So you take in air in miserly little sniffs. And root for your heart as you would for a long-distance runner who had stumbled. . . .

    "Ever wonder what it's like?" [he asks the nurse].

    ". . . Wonder what what's like?"

    "Being on the other end of a hollow needle the size of a swizzle stick? . . . It's like being impaled on the antenna of a car radio, that's what it's like."

    Later he describes a scene in which the doctor at the center finds an elderly donor lying quite still with his mouth and eyes open. "How are we today, Sydney?" he asks the old man. But Sydney is dead. After the body is removed, the doctor remarks that during his years of association with the center the man had donated almost half a million cubic centimeters of blood. " 'One always hates to lose a veteran donor with a gamma globulin like his. . . .' "

    Not all those who sold their plasma were exploited. Some donors, with rare blood types or immunity factors, could sell their plasma at a premium. This was especially true of women who had developed a sensitivity to the Rh factor, the condition in which a baby with Rh-positive blood triggers an immune reaction in its Rh-negative mother. Two disciples of Karl Landsteiner, Drs. Philip Levine and Alexander Weiner, had shown that an Rh-negative woman could be immunized against the disease by injecting her with Rh antibodies immediately after the birth of her first Rh-positive child, and by the late 1960s this injection became commercially available. The source of this rare antibody--called "Big D" in blood-banking circles--was other Rh-negative mothers who had given birth to an Rh-positive child. The women most prized for plasma donation were "high-titre" mothers whose antibody concentrations were unusually high. A woman with such a rare combination of biology and circumstance could become wealthy from selling her plasma several times a month. One such woman, Dorothy Garber of Miami, Florida, had such a high concentration of the Big D antibody that she was able to earn more than $80,000 a year.

    For every Dorothy Garber, however, there were thousands of less fortunate sellers--the unemployed, indigent, and substance-addicted--who would line up outside the centers in ragged neighborhoods to sell their plasma for $10 a pint. A "high percentage of our donors are either illiterate or functionally illiterate," the director of a South Carolina plasma center run by Cutter Laboratories wrote in an undated memo. "They have great difficulties reading words with more than two syllables and even more trouble understanding the meaning [of] those words. I am fairly sure most of the other Plasmacenters have the same problems."

    The most disenfranchised group of donors was prisoners, who became an important source of plasma-derived products, mainly gamma globulin. Gamma globulins can be fractionated from anybody's plasma, but the best way to gather them is to find someone who has been exposed to a disease and has produced a high concentration of the antibodies in question. One way to collect gamma globulins would be to comb the population for survivors of diseases such as rabies or tetanus. A far more practical method is to inject a donor with a light dose of the pathogen and wait a few days for his immune system to gear up. This "hyperimmune" plasma can be fractionated to produce a highly concentrated and specific gamma globulin.

    Prisoners proved ideal for this procedure. They were desperate enough to need the money (or furlough time, the reward in some prisons) but not likely to disappear, as were the transients from Skid Row. Soon prisons became an important source of gamma globulins for pharmaceutical firms such as Cutter and Hyland and the subcontractors who served them. Unfortunately, they operated in a regulatory vacuum. Under so-called short-supply provisions governing vital resources, drug companies could buy certain materials from unlicensed, uninspected vendors. Plasma was one such vital material. So, although federal health and safety rules covered the drug companies that processed the plasma, they exempted the smaller firms that merely collected it. A dangerous situation developed in which drug companies maintained reasonably safe and hygienic prison centers but the subcontractors who supplied them often did not.

    The most notorious of these cases involved a chain of prison facilities owned by an Oklahoma physician named Austin R. Stough. Stough was a prison doctor for the Oklahoma State Penitentiary when he became aware of the emerging market for plasma. He opened a plasma center in the penitentiary, then expanded to institutions in Arkansas and Alabama. There he injected volunteer prisoners with the antigens for several diseases, collected their hyperimmune plasma, and sold it as raw material to the major biologics firms. By the mid-1960s, Stough had set up centers in five prisons in the South and was supplying the raw material for a quarter of the nation's hyperimmune gamma globulin.

    Soon the prison donors started getting sick. One man nearly died when a technician reinfused him with someone else's red cells; another expired after a series of injections designed to boost his antibodies to whooping cough. Hepatitis rates jumped at several of the prisons. Five months after Stough's center opened in Kilby Prison in Alabama, the hepatitis rate among inmates soared from zero or one case a month to fifteen, then entered a sustained rate of twenty to thirty cases a month, including four deaths. Then forty-two men became sick at two other prisons in Alabama. "They're dropping like flies out here," said a penciled note from an inmate at Kilby. By the time the epidemic had run its course, the National Communicable Disease Center in Atlanta (the forerunner to the Centers for Disease Control) reported that 544 cases could firmly be linked to Stough's operation and that the real number probably approached a thousand. They could not make an exact estimate, because many health records had been lost or destroyed.

    There was no doubt as to the cause of the infections. Stough ran a sloppy operation, with poorly trained technicians and unsanitary equipment. Even his customers knew it--an inspector for Cutter Laboratories reported that he was "appalled" by the conditions. Yet, right until the time that Stough was forced to abandon his plasma business, the major drug firms remained a loyal clientele. To them it was a question of supply. Having cultivated corrections officials with generous retainers, Stough had gained unparalleled access to the resource. Besides, reasoned the companies and federal officials, gamma globulins did not transmit hepatitis--as far as they could tell, the products derived from prison plasma were safe. Coldly and legally speaking, what happened to the prisoners was not really their concern.

    Such indifference could not last for long. Dark stories were emerging about commercial blood and plasma in America, about a system that was poorly regulated and out of control. It also became evident that American blood products were not entirely safe. They had become tainted by a virus that, spread through transfusions and contaminated plasma, was killing hundreds, perhaps thousands, per year.

Hepatitis (the word derives from the Greek hepatikos, "liver") has a history touching the highs and lows of medical practice. Often known as "jaundice," because in advanced cases the patient turns yellow, the disease had been described since Babylonian times as a cause of fever, malaise, lassitude, stomach problems, and sometimes death. Hepatitis caused frequent pandemics in Europe, ranking only behind cholera and plague. Like the other medieval diseases, it seemed especially likely to break out in crowded, dirty conditions. A disease known as "campaign jaundice" plagued armies and civilians during medieval wars, and remained a scourge of the military for centuries. The French called the disease jaunisse des camps; to the Germans it was Soldatengelbschut; scientists called it icterus, in reference to a yellow bird from Greek mythology, the sight of which was said to cure the disease. Jaundice decimated Napoleon's army during its Egyptian campaign, struck tens of thousands of soldiers during the American Civil War, and broke out among millions of soldiers and civilians during the Franco-Prussian War and World Wars I and II.

    Despite the obvious patterns of the disease, it was centuries before doctors realized it was contagious. Autopsies of jaundice victims had revealed a swelling of the bile duct. Confusing the symptom with the cause, doctors decided that the jaundice arose from a blockage in the duct emerging from the liver. They called it "catarrhal jaundice," referring to the mucous lining that they found to be swollen.

    The earliest evidence that jaundice could be spread by injections came in the late nineteenth century, when nearly two hundred workers at a shipbuilding company in Bremen, Germany, came down with the disease. A public-health officer named Dr. Lürman went to the factory to determine what caused the outbreak. In his introduction to a subsequent study, he wrote: "The etiology of these epidemics is obscure. Some believe the causes to be from noxious vapors. Others think the disease is a form of gastrointestinal catarrh. In only one case . . . does [a physician] state that the epidemic had the appearance of an infectious disease."

    Like any good public-health official, Lürman began examining one possible source after another. The outbreak was not connected to the patients' socioeconomic status, since all classes of workers were affected, from laborers to supervisors to office personnel. Fumes could not have caused the disease--the factory, perched on a bluff overlooking the Weser River, was well ventilated--nor could the water have spread the disease, since many of the victims did not drink from the company wells. He ruled out nutrition: The patients came from a large assortment of families with a broad variety of food; even "the schnapps drunk by most of the workers came from various sources." Indeed, "none of the etiological events leading to an icterus epidemic thus far described fit this picture."

    One possibility, however, intrigued him. A few months preceding the outbreak, in August 1883, nearly thirteen hundred workers at the factory had been inoculated against smallpox. The inoculant was prepared in the manner of the time: Doctors would prick the blisters of patients who had contracted cowpox, a relatively mild disease, drain off the discharge, mix it in pools, and add glycerine as a stabilizer. They would then vaccinate new patients by scraping the skin and applying the inoculant with a quill. Lürman wondered whether the doctors had transmitted other unknown factors as well. Working through the records of the victims at the factory, he found that, regardless of which building they had worked in or which among six doctors had given the vaccination, they all had been inoculated with vaccine from the same pharmacy. In contrast, none of the workers who were hired subsequent to the vaccination became jaundiced, nor did any who had been vaccinated elsewhere. Eliminating every conceivable possibility, he found himself left with exactly one. "Considering the distribution of cases," he concluded, ". . . one must take into account the [vaccination] . . . as the etiological source of the icterus epidemic."

    Outbreaks of injection-induced hepatitis continued to appear well into the next century. Sometimes they took place at the newly emerging clinics for syphilis, diabetes, and arthritis, where doctors would inject their medications with insufficiently sterilized needles, or in which they prepared the medications in pools of human plasma. It was not until after World War I that researchers had gathered enough evidence to show that an infectious agent caused jaundice, and only during World War II that they identified that agent as some kind of virus. In fact, the worst single-source outbreak in history occurred during World War II. The U.S. Army had contracted the Rockefeller Institute to produce millions of doses of yellow-fever vaccine, which the institute produced in a solution of pooled human serum (that is, plasma from which the clotting factors had been removed). Evidence had already surfaced by then that plasma might carry a risk of hepatitis, so the institute took precautions. They bought the plasma from two unimpeachable sources--the Blood Transfusion Betterment Association in New York and the Johns Hopkins Medical School in Maryland--and heated it for an hour at 132 degrees Fahrenheit. But that was not enough. Shortly after the vaccinations began, hepatitis broke out at several army bases, in such widely separated locations as California, Hawaii, Iceland, and England. The infection rate was so high in the Third Armor Division at Camp Polk, Louisiana, that the entire unit was unable to go abroad. By the time the epidemic had run its course, 28,585 soldiers had been stricken and sixty-two had died. Doctors traced the infection to nine lots of serum pooled from the medical students, nurses, and interns at Johns Hopkins. No one had thought to ask at the time whether the blood donors had ever had jaundice.

    It was difficult to link hepatitis and transfusion during the chaos of war. Battlefield conditions made record-keeping difficult--especially in the front lines, where plasma was most used. One field surgeon, attempting to track the rising rates of hepatitis, was able to divide his patients into groups no more precise than "Probably Transfused," "Possibly Transfused," and "Probably not Transfused." It was unusual when a physician could clearly document a direct correlation. One such case, of a blood donor directly transferring a severe case of hepatitis to a recipient, was reported by a physician in the Mediterranean Theater late in the war:

The sergeant who made the donation was a 235-lb., strong, well-muscled member of a general hospital medical detachment, with an entirely negative previous history. On 8 May he played a game of baseball and knocked a home run. On the next day, he acted as a donor, and, on 10 May, his blood was given to a 19-year-old rifleman who had sustained a gunshot wound of the right lower abdomen. . . .

    On the next day, 11 May, the donor reported to sick call, and he died on 14 May, of fulminating infectious hepatitis, confirmed by the clinical course, the laboratory findings and the necropsy findings. There was no doubt of the diagnosis. . . .

    As soon as it became known that the donor had hepatitis, the recipient was transferred to a special ward, where he was kept under close observation. He remained perfectly well . . . until 21 May, when he began to complain of lower abdominal pain and generalized discomfort. The temperature was 99.4' F. On 23 May, a blood smear showed a few of the abnormal toxic lymphocytes ordinarily seen in early infectious hepatitis. Thereafter, the clinical course, as well as the laboratory findings, were entirely typical of infectious hepatitis, except that jaundice did not appear until 1 June. The patient was critically ill for the next several days, but, after 8 June, his condition gradually improved and he went on to an apparent normal recovery.

    Few case reports were so dramatic or direct. More typically, doctors would get a sense after a time that hepatitis was rising in proportion to transfusions. In an effort to get a handle on the problem, the army conducted a single-day survey of all the hepatitis patients in its hospitals in the United States on June 1, 1945. This one-day snapshot of the disease revealed that, of the 1,762 patients in hospitals with hepatitis that day, five hundred reported that they had recently been transfused with blood or plasma. It also became obvious that soldiers who had received plasma were more likely to get sick than those who had received whole-blood transfusions. The difference was due to the methods of preparation: Whole blood was prepared one unit at a time, whereas plasma was collected in pools of fifty units or more in order to make freeze-drying economical. A soldier who received one unit of blood found himself exposed to one donor; he who received one unit of plasma found himself exposed to the equivalent of fifty.

    The Red Cross attempted to limit the problem by rejecting any donors who had a history of hepatitis during the previous six months. It was a laudable but inadequate precaution. Carriers might not exhibit clear symptoms and would not realize they had the disease. The British took another approach, limiting their plasma pools to ten units each in order to minimize the risk of contamination. But the Americans, driven by the need to provide massive quantities of medical supplies, found they could not conform to such limits, and used more and more freeze-dried plasma made from ever-larger pools. As Douglas Kendrick, by now a general and chief of the army's blood service, wrote, "Saving the patient's life was obviously more important than protecting him against the remote possibility of his contracting hepatitis."

    After the war, when the army gave the surplus plasma to the American Red Cross, they knew the material carried a risk of hepatitis, but the army surgeon general, Norman T. Kirk, downplayed the concern. "I am writing you concerning the questions recently raised as to the possible risk of jaundice and hepatitis following the administration of the Army and Navy plasma declared surplus and accepted by the Red Cross for distribution for civilian use," he wrote to Red Cross President Basil O'Connor on February 13, 1946. "Some apprehension has arisen as a result, and it is feared that it may spread and thus jeopardize the whole program which the Red Cross has formulated for the proper distribution . . . of this surplus plasma." Kirk asserted that, though the "causative agent" of hepatitis "can be transmitted by plasma," it could also be carried by blood or any other biologic product. Besides, the benefits of pooled plasma outweighed the threat.

    Kirk, who had earlier miscalculated when he opposed the shipment of whole blood to Normandy, did so again in pushing for the civilian use of the war-surplus plasma. Locked in the paradigm of battlefield medicine, he saw the issue as survival with contaminated plasma versus certain death. But civilian patients had other options available. Furthermore, death by hepatitis in a civilian hospital attracted more attention than a similar death in the chaos of the battlefield--in some cases it was followed by lawsuits. And so, immediately after the first cases appeared, the Red Cross recalled the thousands of cans of yellow freeze-dried powder.

    During the Korean War, doctors looked at a variety of techniques to make plasma safe. One method involved treating the plasma with ultraviolet light to destroy a still-unidentified pathogen that was causing the disease. Assumed to be effective, this treatment failed miserably. Nearly 22 percent of the soldiers who received plasma transfusions during the Korean War contracted hepatitis, almost triple the rate in World War II. Part of the increase was attributable to a new, more sensitive way of detecting the disease; but part arose from the fact that plasma pools had now grown to four hundred units. In 1952, the National Institutes of Health recommended that the pools be reduced to World War II levels of no more than fifty units. The following year, because of the continuing high rates of hepatitis, the Department of the Army directed military doctors that, unless other solutions were unavailable, plasma should not be used "to support blood volume" in wounded soldiers. Not that all plasma products carried hepatitis; indeed, albumin, because it was heated, and gamma globulin, because of its antibody content, remained essentially hepatitis-free. It was only the whole plasma--pooled, freeze-dried, and reconstituted--that seemed to carry the disease.

    By the early 1950s, doctors had learned that two strains of virus were causing hepatitis. The first strain, hepatitis A, causes a specific disease called "infectious hepatitis," a relatively mild form of the disease. It corresponds to the "campaign jaundice" of old, and is spread through contaminated water and food such as meat, salad, and shellfish. The symptoms appear quickly, generally do not progress to the jaundice stage, and linger for a few weeks or months. Another strain, hepatitis B, causes a more serious form of the disease. Known as "serum hepatitis" or "homologous serum jaundice," it spreads through bodily fluids--sexual contact, contaminated needles, and blood and plasma transfusion. The virus can lie dormant for months, and then afflicts its victim with a terrible lassitude, fever, appetite loss, vomiting, and a striking revulsion for alcohol or tobacco. A small percentage of those who contract hepatitis B develop long-term liver damage, and of those, anywhere from 1 to 3 percent die. The disease strikes tens of thousands in America and kills hundreds each year. Yet even after doctors identified the virus--they could take its mug shot with an electron microscope and its fingerprint by testing for a protein in its shell--they found themselves virtually powerless to prevent it.

By all accounts, Dr. J. Garrott Allen was an agreeable individual. Tall and genial, with sandy hair and a mild disposition, Allen, a surgeon at Stanford University Medical School, generally was admired by his colleagues, except for one tiny character flaw: He tended to be obsessive. This was not just in the manner of your everyday scientist, who enjoys pursuing an idea. No--once Allen got hold of a notion, he found it impossible to let go. He would gnaw on it, worry about it, and inject it into every social interaction. Family members who hadn't heard from him in a while would find it the topic of their phone conversation: A dinner date that started conventionally enough inevitably arrived at the problem at hand. For upward of three decades, Allen's obsessiveness--low-key but constant--made him a key player in the blood-banking drama. The subject that obsessed him was hepatitis in blood.

    Allen did not set out to mount a jeremiad on the subject of hepatitis--the subject, as with most crusaders, seems to have found him. Born in West Virginia and trained in medicine at Harvard, Allen had been performing blood-related research since the war, when he was a surgeon at the University of Chicago. There, as part of the Manhattan Project, he performed army-sponsored research on how radiation affects blood. (His findings, critical in the use of postwar blood supplies, showed that people were much more susceptible to whole-body exposure to radiation than previously thought.) After the war, in addition to his surgical duties he managed the blood bank serving the University of Chicago Clinics. Cognizant of the problems with the war-surplus plasma, he experimented with new ways to make plasma hepatitis-free, and accidentally came upon a method. He drained the clear liquid from outdated bottles of whole blood, mixed it into pools of up to thirty units, and stored the bottles on a shelf. The shelf was rather warm, being near the ceiling, and the bottles would sit for months at a time.

    Allen found that none of his patients who received this aged plasma contracted hepatitis. Scientists knew that viruses were highly resistant to cold and desiccation--that was why freeze-drying plasma preserved the viruses instead of killing them, and why the war-surplus plasma remained contaminated. They also knew that heat could destroy viruses, which was why Cohn was able to make albumin safe. What prevented them from treating whole plasma this way is that heat denatures complex proteins in plasma. Allen, however, found that long-term gentle heating--just above room temperature--eliminated the viruses without wrecking the proteins. The process destroyed the clotting factors, he noted, but aside from that left the plasma intact.

    Allen used the technique for several years, and found that no one who received this liquid alone came down with hepatitis. Yet his method was never widely adopted. Even if effective, storing plasma for months would be an inconvenience, and probably an expensive one. Furthermore, other studies failed to replicate his findings. One, by the U.S. Division of Biologics Standards, found only a 50 percent hepatitis reduction using Allen's method. Another, by Dr. Allan G. Redeker at the University of Southern California, found almost no reduction at all. Allen contended that both studies were inadequate. In the government study, researchers used plasma they had stored not at the warm conditions Allen had specified, but only at room temperature--"a full 10∞ C. lower than our published reports," he wrote. "Unfortunately . . . they did not appear to appreciate the importance of duplicating the temperature at which our plasma had been held." In Redeker's study, the researcher used plasma that two pharmaceutical firms, Hyland and Courtland Laboratories, had collected from highly infectious Skid Row populations, under storage conditions that no one had carefully examined. Allen made a surprise visit to the companies. "I found numerous cases of plasma sitting outside in parking lots at a time when they were scheduled to be under incubation," he wrote. Allen complained, "It does no good to carry out a plasma study in which the conditions of storage of the plasma cannot be certified. . . ." He argued that the government should re-examine his methods under only the most scrupulous conditions. If they wanted to reject them at that point, so be it.

    But no such examination was to take place. By the time Allen published his critique, the National Research Council had concluded that Redeker's results raised "serious doubt . . . on the safety of all pooled human plasma preparations." That, as well as some shortcomings with plasma--the destruction of clotting factors using Allen's method, and the ready availability of an alternative in albumin--made a persuasive case against using whole, pooled plasma. In 1968, the government revoked all licenses for the sale to consumers of whole plasma prepared from multidonor pools.

    The experience frustrated Allen. It was not the rejection of his method that most bothered him, but his impression that people had not listened to the facts. "He just felt that, if he did his scientific work and kept at it, the truth would finally come out," said Dr. Edward Stemmer, a longtime colleague and friend. It would take him decades to vindicate this belief.

    When Allen conducted his research on plasma storage, no method existed to directly detect the hepatitis virus. All scientists could do to understand the efficacy of their methods was to conduct what are known as retrospective studies. In these studies, researchers would gather statistics on the incidence of hepatitis among various groups of patients. Then, working backward through medical records, they would look for hints as to the source of the disease. In this way they might find certain correlations--that patients who had received prison plasma, for example, seemed to have high rates of hepatitis. Conversely, they might find that patients who had received disinfected plasma remained free of the disease. Such studies could take years, and ideally suited a personality like Allen's. During his nearly twenty years of research, he patiently conducted a series of surveys comparing the recipients of his plasma with those who had received whole blood and freeze-dried plasma from his blood bank. Each survey was larger than the one that preceded it, as more and more patients came through his blood bank. By the end, he had surveyed more than twelve thousand people who had received whole blood or plasma.

    Like many blood bankers, Allen had found that his job had gotten more difficult after the war. By the late 1940s, in order to maintain supplies he had to buy blood and plasma from a local prison. (By the mid-1950s, in fact, prison blood constituted 69 percent of his product.) In the course of his surveys over the years, Allen found that the overall rate of hepatitis had grown almost in lock-step with the proportion of prison blood. In other words, there were two critical factors determining whether plasma transmitted hepatitis: the source of the plasma and the size of the pools. (The same would have been true with blood, except that, because red cells were not pooled, the second factor never became an issue.) This was no surprise--doctors had long worried about blood that came from prisoners or paid donors--but no one had conducted so large a survey or seen such a dramatic correlation.

Allen first detected the prison effect in a survey he reported in 1958, and it immediately prompted him to conduct several more. Enlisting the help of a statistician and of credit bureaus to track former patients (privacy laws were less restrictive than today), he studied a representative sample of 12,598 patients who had received a total of 42,407 units of blood in Chicago over a period of ten years, his tables filling more than 250 pages of a book he wrote about his work with hepatitis. He had moved to Stanford University Medical School, and in 1966 published his findings in California Medicine. The results were unnerving. Doctors had long known that professional blood carried somewhat higher risks of hepatitis, but "somewhat" turned out to be hardly the right word. Allen found ten times more hepatitis in recipients of professional blood than in those who had received blood from volunteers. And that involved only single transfusions. Recipients of multiple pints of professional blood would risk correspondingly higher levels of the disease. Extrapolating his results from prison donors to all paid donors of blood, Allen warned that plasma and blood centers would have to change their modes of operation rapidly. Doctors should limit their use of blood products "by giving one transfusion instead of two, two instead of three," and by avoiding all prison and Skid Row donors. In cases where no other source of blood products could be found, the bottles should be labeled as containing blood products collected from high-risk populations. After all, "when the source of blood is not known, the patient cannot be informed of the magnitude of the potential risk of hepatitis from the blood he is to receive."

    Allen's recommendations did not sit well with certain members of the blood-banking establishment. In fact, a few months after he published his study, the California and Los Angeles Medical Associations denounced his suggestions as "impractical, unworkable, and cause for concern." Blood bankers recognized the danger of hepatitis, but worried more about their problems of supply, which, if the paid donor was eliminated, could escalate into a national crisis. Nor did his suggestion about labeling comfort them, for along with rising rates of hepatitis had come a rising level of damage litigation. Can you imagine, they asked, what would happen to the physician who used a bottle labeled as coming from a Skid Row or prison donor? The case would be a litigator's dream. As one blood banker told a reporter from Science, the journal of the American Association for the Advancement of Science, "If you label it paid you may as well pour it down the drain."

    Yet Allen was not alone in making the link between commercial blood products and hepatitis. Other researchers had shown that commercially obtained blood carried at least three times the risk of volunteer blood. Eliminating paid donors, according to some estimates, could reduce the hepatitis rates by 85 percent.

    Allen, meanwhile, continued his surveys. He wrote about the residents of Skid Row, whose use of alcohol, drugs, and unsterilized needles made them prime hepatitis carriers. In a letter to a colleague who had also linked paid blood to hepatitis, Allen described some time he spent in San Francisco interviewing young people who sold their blood and plasma for drug money:

In 1967 and 1968, I spent a few afternoons in the Haight-Ashbury with the then "flower children." The pattern of events was fairly consistent for each one that I interviewed. Most had come from middle class or upper middle class homes, and were runaways. By about the fourth month, they had lost contact with their families, or vice versa. Money had become an acute problem, not only to support their drug habits but also for food. They freely admitted selling their blood in the Bay area and, when turned down by one blood bank, were generally accepted by another. . . . Putting this together with your data suggests that as their drug habits became more important to them, this group has been readily preyed upon by those dealing in paid blood and plasma. Again, according to your data, it would appear that nearly 80 percent of posttransfusion hepatitis . . . comes from carrier donors with an active self-injection addiction, or at least a drug habit in the past.

    It became clear to Allen that the question of paid blood had moved beyond the realm of science inquiry and into the arena of action. And so, while maintaining his surgical duties at Stanford (and serving as editor of the medical journal Archives of Surgery), he began to churn out a volume of correspondence, writing to everyone he thought could influence public policy. He wrote to the U.S. Food and Drug Administration; to the nation's largest labor union, the AFL-CIO; to the American Red Cross; to the American Medical Association; and to congressmen in whose districts hepatitis had been publicized by the media. In clear, patient, yet passionate prose, he explained why the nation must convert to an all-volunteer blood supply, and institute the labeling of blood in the meantime.

    Soon the media caught on to the problem. In 1970, The New York Times asserted that the blood-and-plasma industry was engaging in a game of "transfusion roulette" with blood products that might transmit hepatitis. In another investigation, a young Chicago Tribune reporter named Philip Caputo (who later became known for his Vietnam memoir, A Rumor of War) disguised himself as a vagrant and peddled his blood. Defying all conventions of good medical practices, several centers in a row bought his blood "even though the scab on [my] arm was still fresh from the day before." In another exposé, a popular NBC television-news program, Chronolog, portrayed the "procurement of blood plasma on an assembly-line basis." Millions of viewers saw images of what had been disturbing people like Allen for years: derelicts lining up to sell plasma in the Skid Row neighborhoods of Los Angeles. They also saw the faces of the victims--not only the destitute who felt compelled to sell their blood, but the transfusion patients who unwittingly and innocently had contracted hepatitis.

One group of patients who merited special concern was the nation's twenty-six thousand hemophiliacs. Their lot had improved since the famous case of the Tsarevich Alexis. In the course of a mere generation, their treatment had progressed from ice packs and blood transfusions to home-based infusions of fresh-frozen plasma, and their life expectancy had jumped from twenty or so years to well into the fifties. Their lives, however, could not be called easy. Huge volumes of plasma were required to quell an episode of bleeding, sometimes more than the patient's circulatory system could take. (One doctor, in order to get enough clotting factor circulating through the body, resorted to draining blood from one arm while infusing plasma into the other.) Even in the best cases, treating the hemophiliac could mean hours of infusing the plasma as he writhed in pain from internal bleeding.

    Robert K. Massie, who told the story of the Tsarevich Alexis's hemophilia in Nicholas and Alexandra, later wrote a memoir with his wife, Suzanne, about raising Bobby, their hemophiliac son. (It was his experiences with Bobby that prompted Massie to research the story of Alexis.) In this book, Journey, the Massies recounted the experience of being a family with hemophilia. They described the shock of learning their baby had hemophilia (there had been no trace of the disease in either family) and life in a perpetual state of emergency. They told about minor accidents that escalated into crises, shattering the routine of everyday life. Once, when Bobby was two and a half, he began bleeding spontaneously in the brain. With a police escort, his parents raced him to the hospital. He stayed there for a week and a half while doctors gave him constant transfusions.

    Later, during his growth years, he suffered crippling joint bleeds, like most hemophiliacs. When blood flows into the confined space of a hip, knee, wrist, or other joint, it causes stiffening and twisting as the limb contorts to provide a larger space for the fluid. The liquid presses on the nerves, causing almost unendurable pain. In time the blood corrodes the cartilage and bones, causing premature arthritis and crippling. (This deterioration, common in the hip, causes a characteristic symptom known as "hemophilia limp.") Joint bleeding kept Bobby in and out of a wheelchair for years, and in some ways was the worst of the ordeal. Suzanne Massie wrote of their endless nights sitting up with the child as he thrashed and screamed, "'No more pain! No more pain!' . . . Through those sleepless nights, I sat by Bobby's bed. I soothed his forehead. I held his hand while he moaned, asking him to tighten his hold on my hand so as to forget the pain. . . . He would do this and, although he was a child, his grip would nearly crack the bones in my hand. . . . Impotence, helplessness, choked my throat. I sat there numbly, hour after hour, as if the very act of witness would somehow help; but the pain continued implacably." The Massie family's experience typified those of tens of thousands of others touched by hemophilia.

    The circulatory system uses several overlapping systems to seal itself after an injury. Immediately after the wound is inflicted, muscle fibers in the blood-vessel wall contract to limit the tear. Then platelets move into the opening to clog it temporarily. Some platelets rupture, releasing a chemical that combines with proteins and enzymes in the plasma to form a tough, fibrous, long-lasting clot. All this happens in a series of steps known to hematologists as the clotting cascade--once it begins, it is virtually unstoppable. (That was why Richard Lewisohn's work with anticoagulants in the early part of the century represented such a breakthrough.) Yet in other ways blood clotting is a fragile process: If only one element of the sequence is missing, the rest of the process cannot take place.

    Bobby, like most other severe hemophiliacs, lacked a single protein in the cascade known as Factor VIII, or Antihemophilic Factor (AHF). (A much smaller percentage lack Factor IX, which causes an identical form of the disease.) Scientists had spent decades trying to find a replacement for these components. The men in Cohn's lab had produced a concentrate of fibrinogen, a substance rich in clotting factors that did not prove effective enough to justify its expense. In 1965, Judith Graham Pool of