The Demon Under the Microscope, page 12
On July 5, news of Calvin Jr.’s condition hit the newspapers. Even the Republican president’s political opponents rallied behind him: Attendees at the Democratic National Convention then under way in Madison Square Garden received regular bulletins on Calvin Jr.’s health and sent their sympathies to the White House. Phone calls and telegrams of support—more than ten thousand of them—began flooding in. The president seemed stunned, unable to concentrate on his work. He stopped what he was doing a dozen times that day and made his way to the boy’s room. Journalist William Allen White told the story of the president’s finding a rabbit in the White House garden, coaxing it close enough to catch, and trotting it up to his son’s room. He got a smile in return. A Coolidge family friend told White that the president “would have carried him the whole of the White House grounds, a handful at a time, if it would have done any good.”
Blood transfusions were sometimes tried in cases like this, although they were risky—blood-typing technology was crude, and the patient’s own immune system could react against the transfusion. The next day, July 6, White House staffers began offering their blood. But by then Boone had decided to get the boy out of the White House. Calvin Jr. was taken in an ambulance to Walter Reed Hospital, with the pale First Lady following in a car behind. There, seven of the world’s best physicians went to work, giving the boy injections of saline, blood transfusions, artificial respiration, a last-ditch operation. The chief justice of the Supreme Court wrote his wife, “The whole county is at the deathbed of young Calvin Coolidge.” He then told her that he had talked with a physician who told him it had been hopeless from the start: Once a S. pyogenes infection hit the bloodstream, it was as bad as being bitten by a poisonous snake.
The president and the First Lady stayed at the hospital through the night while their son passed in and out of delirium. Toward the end he thought he was leading troops into battle and they were winning, a positive sign, his father thought. But then Calvin Jr.’s body went limp, and he murmured, “We surrender.” Dr. Boone said forcefully, “No, Calvin, never surrender.” The boy slipped into a coma. On July 7, five days after Boone first looked at a blister on the boy’s toe, the president’s son died. Calvin Coolidge fell into a deep depression that some historians believe marked his entire second term, turning the once-energetic politician into a man known to everyone afterward as “Silent Cal.”
STREP WAS EVERY doctor’s nightmare. The organisms could be found everywhere, in dirt and dust, in the human nose, on the skin, and in the throat. Most strains of strep were harmless. But a few were deadly, and when they got into the wrong place—beneath the skin, through a wound, into the blood—they could cause at least fifteen different human diseases, each so different from each other that in the 1920s researchers had still not untangled them. The worst strains of strep could secrete three poisons, wipe out red blood cells, raise fevers, eat through tissue, fight their way through the body’s natural defenses, and create a bewildering variety of different diseases as they went. A strep-infected scratch could lead to the burning rash of erysipelas, the old St. Anthony’s Fire; a bit deeper it became cellulitis, a potentially fatal infection of the subcutaneous tissue; if it got into the bloodstream, it caused septicemia, a blood infection; in the spinal fluid, meningitis. Some strep diseases were relatively mild, others vicious. There was no containing it. A sore throat, infected with strep, could progress to quinsy, a throat abscess that had to be opened and drained before it suffocated the patient, which could lead to “bull neck,” with enormous gland swellings, often linked to a severe strep ear infection, sometimes a precursor to strep’s breaking into the bloodstream or, worst of all, into the spinal cord, causing strep meningitis. Blood infections with this germ usually killed the patient; spinal fluid infections—strep meningitis—always did. Strep was responsible, they said, for half the white hairs on every physician’s head.
By the time Domagk started working at Bayer, scientists had firmly identified strep as the cause of boils and abscesses, fevers and rashes, infections of wounds and of the heart, lungs, throat, blood, spinal cord, and middle ear. It had been identified as the cause of childbed fever. It was suspected—and later proved—to cause scarlet fever and rheumatic fever. Infections could start from something as minor as a pinprick, a sliver, or a burn; surgeons could die from a strep infection after nicking themselves during an operation. An artist had died of a strep infection after a model scratched his face. Worse, many of the diseases strep caused were capable of flashing into epidemics, passed on the hands, in nasal secretions, or through the saliva of carriers. Some strains could live for weeks in dust. If a deadly strain of strep took up residence in a hospital—and this happened all too often—it could be almost impossible to eradicate. Strep was a major reason doctors and nurses started wearing surgical masks. But even the most scrupulous precautions were often not enough. In 1930, the top four most serious hospital infections (those that threatened patients during hospital stays) were cellulitis, erysipelas, wound infections, and childbed fever. Every one was caused by strep. Taken together, strep diseases in Europe and North America alone during the 1920s were estimated to kill about 1.5 million victims a year. That same number adjusted for today’s population would total more than current worldwide annual deaths from cholera, dysentery, typhoid, and AIDS combined.
Under the microscope all strains of strep look like twisted strings of beads (streptós is Greek for “twisted”; coccus is a round bacterium). Pasteur had tied them to human disease as far back as the 1870s. The earliest names given to the organisms were based on what they did: S. pyogenes meant pus-forming strep, S. pneumoniae was pneumonia-causing strep, S. erysipelatus caused erysipelas. As more diseases were tied to strep, it became clear that this was not a single killer but a clan of cousins, a rogue family within a much larger universe of mostly harmless strep. Each strain had a slightly different growth pattern, a slightly different set of identifying marks, a different way of causing disease. Sometimes a single disease could be caused by more than one member of the clan. Sometimes a single member of the clan could cause more than one disease. It was, to say the least, confusing.
And in the 1920s it made the only effective weapon they had for treating bacterial disease once it started in the human body—serum therapy—impossible. That was proved during an epidemic of pneumonia in army training camps in Texas. Nothing was helping the young soldiers, who were coming down with the disease by the hundreds. Many were dying. It got so bad that officials called in outside medical experts to figure out how to stop it. The scientists tried serum therapy—gathering samples of bacteria from the lungs of infected soldiers, shooting the strep into test animals, harvesting the anti-strep serum, shooting it into the soldiers—and failed. Any single serum was active against only a single strain of strep, and there appeared to be too many different strains at work in Texas. Like every bacterial epidemic, this one eventually flared out on its own. The pressure was off, but the researchers kept trying to figure out why their efforts had failed. To untangle the strep mess, they hired a bright young Wellesley woman, a former French major who switched to microbiology when her roommate told her how interesting the classes were. Her name was Rebecca Craighill, but she became famous in the annals of science under her married name, Rebecca Lancefield. The switch from romance language to research lab was a lucky one for science. Lancefield was happy to get a job as a lab assistant and happy to take on what a more experienced researcher might have seen as the impossible task of unknotting the relationships within the strep family. She turned out to be a phenomenon—tireless, skillful with her hands, patient, meticulous, and insightful. She figured out how to separate different strains of strep, how to grow them in the lab, and how to use the antibodies of animals as exquisite sensors able to differentiate minute variances between one kind of strep and another. She would isolate a strain of strep, grow it in quantity, then puree the bacteria and inject the resulting soup into animals. The injection was not an infection—the puree contained no live bacteria, only bits and pieces—but the animal would still sense the injected material as foreign and mobilize its immune system to fight it, producing antibodies highly specific to the particulars of the invading substance. If one strain of strep differed even slightly from the last, the antibodies would sense it. Lancefield harvested the antibody-containing blood, spun it down in a centrifuge, and collected the yellow serum. Each serum was matched precisely to a single strain of strep. She slowly built a library of serums that she could use as highly specific probes. If the serum responded strongly to an unknown strep, then the unknown strain was closely related to the one used to make the serum. If the reaction was weaker, they were not closely related. She used the serum probes to explore the world of strep and identify its members with pinpoint accuracy.
Through the 1920s she found that the strep causing erysipelas was slightly different from the one causing childbed fever, which was slightly different from the one causing meningitis, and so on. For a time she studied “green” strep, which some people thought caused rheumatic fever. Her work helped to show that green strep was a large and varied family of related strains, mostly harmless (although some green strep could cause a form of heart infection).
Her real passion was the study of another large group of strep, the most dangerous, the strains that caused most strep diseases—the ones that killed Calvin Coolidge Jr. Once again the bacterial world proved far more complex than anyone had thought. These disease-causing strep were part of a larger group called hemolytic strep, named for their ability to destroy red blood cells. Lancefield discovered that hemolytic strep could be divided into three large subgroups, which she named simply alpha, beta, and gamma. Not every hemolytic strep was a danger to human health, however. The alphas and gammas were relatively harmless. It was the beta hemolytic strep that included most of the killers. She studied the betas intensively, breaking them into subgroups—A, B, C, all the way through O—based on differences detected by antibodies. Then she focused on Group A, where again the worst killers seemed to be concentrated. She identified many of them, but she never did find them all. Researchers eventually discovered more than forty separate strains of Group A beta hemolytic streps, each different enough from the others to cause unique diseases and reactions. A serum raised against one did not work very effectively against another. No wonder serum therapy had not worked in Texas. No wonder Sir Almroth Wright’s serum had failed to stop strep-caused wound infections in Boulogne.
Lancefield’s results, her list of strep types and subtypes lengthening through the 1920s, offered little hope that any medicine would ever be found to stop them. There were just too many types.
LANCEFIELD’S FINDINGS also made life more difficult for Domagk. Strep, he knew from the work of Sir Almroth Wright and others, were the single most important cause of the wound infections that had given him his mission in life. If strep existed in so many forms, each a bit different from the others, what were the chances of finding a single chemical that would work against all of them? He faced a more immediate practical problem as well. Domagk wanted to include strep in his test panel of germs, the group of microbes he used to screen chemicals at Bayer, but he could not economically test every chemical against forty strains of strep, or twenty, or even five. He needed a single strain, one that could kill both mice and men, a superstrep with which he could reliably infect test animals.
“Reliably,” for his purposes, meant a strep that, when injected into a mouse, always grew, always spread quickly, and always killed. Mice were his test animals of choice, because they reproduced rapidly and could be bred into uniform strains, lessening mouse-to-mouse variations that could throw off his results. He did not want simply to make his mice sick. He wanted them dead. Within a few days was best. Death was definite and unarguable, a certain end point for a test, a plus or minus in his lab book, a precise point in time; any lab assistant could assess it without any doubt or personal opinion. That made for reliable science.
He began sampling and isolating strep from human patients and found that most strains did not kill mice the way he wanted. Strep, in addition to their other qualities, were fastidious germs, able to survive in a number of environments but flourish in few. Most of the strains of interest to health workers were so well adapted to the human body that the temperature and composition of growth broth had to closely mimic that of human blood. Domagk’s lab used an egg- or meat-infusion bouillion containing serum or blood and 0.1 percent glucose, in an atmosphere ranging from 5 to 10 percent carbon dioxide. Any deviation and the microbes refused to grow. Domagk learned the tricks.
Then he went looking for his superstrep. He made contacts in local hospitals, asked physicians to keep an eye open for particularly vicious strep infections, collected samples of bacteria from the bodies of the dead. The strep he gathered varied terrifically in their ability to kill mice. None seemed to provide consistent results over time. It was months before he isolated a strain of strep from a patient who had died from a particularly aggressive case of blood poisoning. This particular strep was so powerful that a fraction of a drop from a bacterial culture diluted to one part in one hundred thousand killed every mouse he gave it to within two or three days. Most died within twenty-four hours. This superstrep might not be representative of all strep—what strain was?—but at least it provided Domagk with a reliable germ to use in animal tests, a peerless killer. It was the best he could do.
Test system in place, he made anti-strep experiments part of his standard disease panel. By 1929, when he moved into the newly completed laboratory Hörlein had promised, Domagk had made a fine art of animal testing. It was now possible for him, his growing group of six assistants (all of them women), and his animal-care support staff to thoroughly test more than thirty new chemicals per week, both in vitro (in test tubes) and in vivo (in animals), delivered three different ways (intravenously, subcutaneously, and by mouth), plus the occasional addition of a nonfatal disease like gonorrhea or other germ of interest, plus tests against cancer cells. Not every new chemical sent to Domagk’s lab got the full battery—some were given fewer tests for initial screening, and on some days a particular culture of germs might not be ready for injection—but in every case every chemical was tested against a variety of diseases in living animals. It was just what Hörlein wanted: a smooth-functioning, reliable machine for discovery. He signed Domagk to a permanent contract. The months went by, the chemicals came in for testing, the mice died in batches of six or ten at a time, thousands upon thousands as the years passed. There were no quick discoveries, but they did not expect that. Domagk perfected and refined his system. Even the dead animals had their function. Domagk did postmortem exams once a week, running his scalpel down each animal’s abdomen, peeling back the skin and muscle, examining the organs, looking for swelling, discoloration, abscesses. Then he took fluid samples and removed organs, carefully sliced paper-thin sections, stained and mounted his samples on slides, examined them under the microscope, gauged where and how the bacteria had caused death. He trusted this work to no one else, making every exam of every animal himself. During these times he shut himself off and refused visitors and phone calls. Domagk’s system raised the testing of prospective drugs to a new level of precision and a vastly expanded scale. By 1929, that system was working at peak capacity.
The only thing missing was a positive result.
CHAPTER NINE
SIR ALMROTH WRIGHT’S research group had found strep involved in roughly three-quarters of all wound infections in the hospital at Boulogne. It was the primary cause of the most grievous cases, including gas gangrene, where the strep acted as a first wave of infection. There was strep everywhere at Boulogne; the germs were blown into wounds along with the dirt and torn bits of uniforms, grew in tissue easily, invaded the body readily, weakened the patients with poisons, and soaked up oxygen in the wound. Sir Almroth had learned everything there was to know about strep wound infections—except how to stop them.
Now, in the late 1920s, he had grown dispirited and increasingly cranky. He had thought that serum therapies or vaccines would stop wound infections. He had been proved wrong. But he was also certain that drugs would never solve the problem. That had been proved to his satisfaction back in 1911 during his ill-fated trip to South Africa. The Optochin disaster had turned him forever against the Germans and their fascination with using laboratory chemicals to cure disease, a quixotic endeavor, Sir Almroth thought, a field of failure that was now being called chemotherapy (used today only in relation to cancer treatment, the word “chemotherapy” in the 1920s referred to treating any infectious disease with chemicals).
Leonard Colebrook was not so sure. Sir Almroth’s second-in-command at the St. Mary’s Inoculation Department in London—the scientists that called themselves the House of Lords—Colebrook had been with Sir Almroth in both the diamond mines and the casino at Boulogne. He had seen the same horrors, the blinded miners, the soldiers with yards of rubber tubing stuck into their abdomens, the wounds bathed in bleach. He had heard the men crying out as their injuries were treated. Colebrook had always done whatever Sir Almroth asked, but now he was beginning to grow weary of the Old Man’s constant railing against chemical cures. Colebrook quietly and respectfully disagreed. Optochin might have been a fiasco, but Colebrook placed more emphasis on the fact that Ehrlich’s Salvarsan had been a success. Salvarsan worked against only one disease, it was true, syphilis, an unusual malady caused by an unusual germ, and even then only with excruciating side effects. But it worked. To Sir Almroth, Salvarsan was an anomaly. To Colebrook, Salvarsan was a signpost. It proved that chemicals could stop disease, and it pointed the way to more cures. All of the failures that followed—the chemicals that cured mice but not people, the chemicals that made patients sicker than their disease did—failed to dissuade him. Many researchers in the 1920s gave up looking for drugs to cure infectious disease. But Colebrook—like Hörlein and Domagk—continued to believe.
