IN 1906, in yet another sign of the country’s dominant position in cancer science, Germany hosted the world’s first international congress of cancer research. The opening speaker, Professor Ernst von Leyden, provided an overview of the previous century’s cancer research, insisting that the statistics demonstrated a clear increase in cancer rates.
Much of the conference took place at the University of Heidelberg, where Warburg was then beginning his medical studies. While there is no record of Warburg’s attendance at the conference, he was almost certainly aware of it. Among the luminaries taking part in the event was Paul Ehrlich, a man surpassed perhaps only by Pasteur in Warburg’s hierarchy of scientific greatness. While Pasteur’s portrait would later occupy the central spot in Warburg’s library, a portrait of Ehrlich would hang only a few feet to its right.
Born in 1854, Ehrlich had been studying medicine in Strasbourg when he came across a monograph by Emil Heubel, of the University of Kiev, that would forever change his life. Though Heubel had once studied frogs thought to be in a state of hypnosis, it was his canine work that captivated Ehrlich. Along with their daily servings of a half-pound each of meat and bread, Heubel’s dogs received a considerable helping of pure lead. After a few months, the dogs would invariably die, at which point Heubel would cut them open and remove their organs to see how much lead each one had soaked up. What struck Heubel—and later Ehrlich—was how unevenly the lead would be distributed inside of the dogs. Some organs—the liver, kidneys, and brain—were quick to take up lead, but other organs were left virtually untouched. The heart, Heubel noticed, could not be poisoned by lead.
To confirm his findings, Heubel took some of the canine organs and placed them directly in a solution of lead only to see the same pattern repeat itself. Some seemed to soak up lead like a sponge; others could sit in a tub of lead forever and remain lead-free.
It wasn’t lead poisoning itself that fascinated Ehrlich but the underlying principle: lead solutions could only poison tissues where lead was able to form a chemical bond to specific types of cells. If Ehrlich could only figure out the secret of chemical attraction, why one molecule in the body will grab hold of another and never let go, medicine would no longer be “shrouded in darkness.”
Heubel had been curious about poisons, but Ehrlich was interested in cures. If a poison could attach to one type of cell yet not another, then so, too, could a medicine. The goal, Ehrlich said, was “to take aim, in a chemical sense,” to find a drug that would hit only its specific target. “It was a revelation to me,” Ehrlich later wrote, “and a sort of destiny.”1
Ehrlich, still a medical student, had arrived at the idea of chemotherapy—a term he himself would later coin. Though chemotherapy is now thought of as a general toxin that kills healthy cells along with cancer cells, leaving patients sick and often hairless, it began with Ehrlich’s dream of precision targeting. After reading Heubel’s monograph, Ehrlich dropped all other projects and spent his days gazing at slides of lead-poisoned brain tissues. The professor who was supposed to be Ehrlich’s examiner in chemistry at the time told another colleague that he couldn’t recall having seen Ehrlich at a single lecture.
Ehrlich’s medical training turned into a “disaster,” he recalled. He was ignoring his other work, yet making no progress in understanding why lead went into some tissues and not others. It was clear that lead bonded to something in the brain, but the brain was full of different types of cells, and any one of them might have been responsible for forming the link. Had he been a more typical student, Ehrlich might have given up on chemotherapy and returned to his studies. But Ehrlich had never been typical. As part of his high school exit exam, he had been assigned to write an essay in response to the prompt “Life—A Dream.” Ehrlich took the opportunity to argue that dreaming was merely a chemical process in the brain. (He almost failed to graduate.) Later in life, he carried pencils at all times so that he could quickly write down a thought or sketch out a molecule before it slipped his mind. If there was no paper nearby, Ehrlich would write on the nearest surface he could find: doors, tablecloths, and on at least one occasion, the cuff of a presumably stunned colleague.2
So, instead of retreating to his planned course of study, Ehrlich searched for a better way to investigate how cells form chemical bonds. The answer, he soon realized, had been staring him in the face the entire time. Like all medical students of the era, Ehrlich had learned how to stain tissue samples with dyes. (The little lines Boveri spent his life gazing at and drawing were called chromosomes, or “colored bodies,” because they would take up the dyes.) But why, Ehrlich now wondered, should the use of dyes stop with the staining of cells on microscope slides? Why not inject the dyes directly into an animal and then look to see where they end up—to which types of cells they bond—by observing which parts of the animal changed color?
Ehrlich’s idea was to redo Heubel’s experiments with dyes of every color. If he could determine the underlying principle—why a chemical will bond with one type of cell yet not another—he would be able to take aim at the targets he most wanted to hit: the living organisms that invade our bodies and cause diseases. By the late nineteenth century, Ehrlich had plenty of such organisms to choose among in the form of bacteria and parasites that had recently been linked to infectious diseases.
The first step was to identify chemicals that would attach to the invaders. But Ehrlich’s goal was not to make the unwanted organisms more colorful. He needed chemicals that could both bond to the invaders and kill them. What he needed, Ehrlich would say years later, were “magic bullets.”
The term “magic bullets” had been popularized by the nineteenth-century German opera The Marksman. In it, Max, a forester, is in love with Agathe. But before he can marry her, he must first beat his competition for her hand in a shooting contest. With so much at stake, Max is unable to resist when he is offered bullets that will hit whatever target he chooses. Max doesn’t realize that the magic bullets come at a steep price. Six of the bullets will hit whatever mark the shooter wants. The seventh bullet is guided by the devil.
If Ehrlich had alighted on his idea of targeted chemotherapies a decade earlier, he might have made little progress. But by 1878, the year he completed his medical studies, he had an array of different bullets to test. Germany was awash in new synthetic dyes. The dazzling new colors had emerged from the least likely of places: coal tar, the foul-smelling black gook that was left behind in gaslight lamps and gathering by the barrelful throughout Europe. William Henry Perkins, an English chemist, launched the synthetic dye industry when, at age 18, he discovered that a compound in coal tar could give rise to a pale purple solution. Yet it was a new generation of German technical school graduates who mastered the art of making chemical dyes.
Ehrlich became so lost in his dye research that the other students began to joke about him. A classmate recalled that Ehrlich “always went around with blue, yellow, red and green fingers.” His laboratory bench was said to “gleam in all colors of the rainbow.” Even Ehrlich’s face would sometimes show traces of the colors.3
Ehrlich’s initial plan had been to use the dyes to understand how chemical bonds form in living tissues. But in some cases, the dyes themselves appeared to be magic bullets. In the early 1890s, Ehrlich injected malaria patients with a variant of a dye known as methylene blue. The injections turned the whites of the patients’ eyes blue, but some also noticed that their fevers were improving. For Ehrlich the methylene-blue-derived malaria treatment was an early success—it would remain a malaria drug until the middle of the next century—but not the precision weapon he had in mind.
Ehrlich needed more powerful and more precise bullets, and he knew where to look for them. The immune system, Ehrlich had come to understand, is equipped with molecules that single out and execute invading germs while leaving the body’s own cells unharmed. His turn to immunology would lead Ehrlich to a new theory of how the immune system works and a series of breakthrough treatments for infectious diseases.
By 1899, the dreamy medical student with colored fingers had his own beautiful institute in Frankfurt and an entire team of scientists working under him. He had become the thing that Otto Warburg most wanted to become: a celebrated German and one of the most highly respected medical researchers in the world. Warburg could only read about Pasteur’s legendary feats of a generation past. Paul Ehrlich was Warburg’s living model.
GIVEN THAT EHRLICH WAS a famous medical researcher in Germany in the early twentieth century, it was inevitable that he would take aim at cancer. But while Ehrlich is celebrated by cancer scientists as the inventor of chemotherapy, it did not take him long to appreciate that treating cancer was a different challenge than treating an infectious disease. The entire point of chemotherapy, from the beginning, had been specificity, eliminating unwanted cells and only unwanted cells. But cancers form from our own cells. Borrowing another term from German folklore, Ehrlich called cancer cells “hostile brothers.” Whatever killed cancer cells, Ehrlich saw, would also kill the body in which the cells resided. Firing a bullet at cancer was like turning a gun on yourself.
Ehrlich needed a different approach for cancer, a way to undermine the hostile cells without poisoning their nonhostile siblings. He now turned to a new line of research pioneered by Leo Loeb, the younger brother of Warburg’s mentor Jacques Loeb. In 1897, after earning his medical degree from the University of Zurich, Leo Loeb moved to Chicago, where Jacques was then teaching. It was not a hard decision. He was repulsed by rising German nationalism, and there was no one left for him back in Germany: the Loeb boys had been orphaned when their father died from tuberculosis (Jacques was 16 at the time, Leo only 6).
Without an academic appointment, Leo Loeb started a private practice, but like Jacques, he lacked the temperament for the work. Beneath his quiet exterior, Leo, too, had a passion for bold experimentation, for pushing biology beyond its known limits. While in medical school, Loeb had experimented with transferring skin from one part of an animal to another. In Chicago, he rented a small room behind a drugstore and filled it with mice and guinea pigs purchased with his own money. Years later, Loeb was delighted to see his landlord, the owner of the drugstore, in the audience at one of his lectures. But at the time, the landlord likely couldn’t have imagined that the quiet young immigrant working behind his pharmacy would soon be among the most highly regarded cancer researchers in the world.4
In America, Loeb moved from transplanting skin to transplanting tumors. (His interest in cancer and cellular growth had been sparked, at least in part, by his familiarity with the studies done on sea urchin embryos at Naples.) Though others had worked on tumor transplants, it was Loeb who perfected the technique. In a paper published in 1901, he described transferring 360 fragments of thyroid cancers from a single white rat into some 150 host animals. Among Loeb’s many striking observations, one stood out: When the implants took hold and a tumor grew, the cells of the host animal did not become cancerous. Only the cells from the transplanted tumor multiplied. And if Loeb kept transferring these cancer cells from one animal to the next, they could live on and on, seemingly forever.5
It was one of nature’s cruel jokes: the possibility of immortality discovered not only by someone who had been orphaned at age 6, but in the very cells that kill us. Yet Loeb’s work on transplants and the immortality of cancer cells helped turn the study of cancer into a modern science. At the time, researchers had no reliable method for inducing cancer in animals. Thanks to Loeb, research labs—including Warburg’s—would fill with cancer-stricken animals, and countless new experiments would become possible.
Still, if Loeb’s transplantation studies were key to the rise of modern cancer science, his successful transplants weren’t the entire story, maybe not even the most important part of the story. What intrigued Loeb most were the transplants that failed, those that were immediately destroyed by their new hosts. Was it something in the host animal’s hereditary makeup, Loeb wondered, that caused it to accept or reject a cancer? Did the host’s immune system attack the tumor?
Loeb believed that if he could only figure out how a body eliminated a transplanted cancer, it might lead to a cure or, at the least, a new understanding of cancer prevention. But Loeb had more questions than answers. He soon moved on to chemotherapy studies, building on Paul Ehrlich’s work with chemical dyes. Ehrlich, meanwhile, had grown interested in Loeb’s work on transplanted tumors. He, too, tried to determine why many of the transplanted tumors never took hold. In some instances, he could implant a tumor into a rodent, and it would grow in the usual fashion. But when he tried to transfer additional cells from the very same tumor into the very same rodent, the second transplant would often fail. It was as if his experimental animals had a one-transplant limit.6
Ehrlich, among the world’s experts on the immune system, might have assumed that the body’s own defenses were eliminating the second transplants. But that assumption was far from obvious at the time. If the animal’s immune system had already accepted the tumor once, Ehrlich wondered, why should it reject it the second time? This puzzle led Ehrlich back to an outdated idea. Pasteur had once hypothesized that when a body eliminated an infection, it would destroy not only the invading organism itself but also whatever nutrients or chemicals the invading organism had relied on to grow. By the time Ehrlich took up the question, it was clear that Pasteur’s idea was wrong. “Yet,” Ehrlich wrote, “this old theory seems to me to contain a nucleus of truth, as is so often the case.”
As Ehrlich saw it, the “nucleus of truth” in Pasteur’s idea was that microbes will not grow without the right nutrients. He had seen that phenomenon in his own laboratory dishes. Some of his bacilli would not grow until he added hemoglobin to the cell culture. Perhaps, Ehrlich reasoned, the same principle held true for cancer cells inside of an animal body. Perhaps the second transplant couldn’t grow because the first transplant was using all of the nutrients it needed.
Ehrlich did not have every detail right, but he had arrived at a “nucleus of truth” of his own. In an extraordinary 1907 lecture in which he described his experiments, he came closer than any scientist of his time to anticipating today’s thinking on nutrition and growth factors in cancer. “[E]very proliferation,” Ehrlich said, “depends in the first place on the avidity of the cells for the nutritive substances.”7
Ehrlich, the man who brought the phrase “magic bullets” to medicine, had a knack for language. But the name he chose for his new metabolism-based theory didn’t help it catch on. He called the starving of transplanted tumors “athreptic immunity.” The term “athrepsia” comes from an ancient Greek word for malnutrition. At the time, it referred to a medical condition that caused newborn infants to waste away and die. The eccentric Ehrlich had looked at vanishing tumors and seen dying babies.
OTTO WARBURG MET Paul Ehrlich in 1912 during a visit to Ehrlich’s institute in Frankfurt. By then, Ehrlich had achieved international fame with his most successful magic bullet of all, the one capable of seeking out and destroying the organism responsible for syphilis. After their meeting, Warburg and Ehrlich rode together in a horse-drawn carriage to a nearby town. “It was a beautiful summer evening,” Warburg recalled. When Warburg told Ehrlich about his discovery that sea urchin eggs will take up more oxygen upon being fertilized, Ehrlich was unable to corral his excitement. As Warburg recalled, Ehrlich shouted “Yes, quantitatively!” again and again, growing so lost in the idea that “he seemed to see nothing of the mountains and valleys that surrounded us.”
The two men met only one other time, at an academic reception in Berlin, not long after their initial meeting. When Warburg spotted him, Ehrlich was standing alone and appeared to be lost in his thoughts. Ehrlich may have been depressed. His secretary claimed that Ehrlich had once confessed to her that when feeling down, he would sometimes stand before his cabinet full of dyes and say to himself, “These are my friends which will not desert me.” But Warburg saw no melancholy in Ehrlich’s isolation. What he saw, instead, was a scientific imagination hard at work. “Ehrlich lived in two worlds,” Warburg wrote, “and by putting into practice in this world what he saw in that world of his own, he arrived at one of the greatest scientific achievements of all time.”8
Ehrlich continued to pursue a cure for cancer even as his syphilis treatment was changing the course of modern medicine. In 1909, Carlo Moreschi, an Italian researcher then studying at Ehrlich’s institute, added a new twist to the study of “athreptic immunity.” Before carrying out the tumor transplants, he first put some of the mice on low-calorie diets. The results were striking: though it was sometimes possible to successfully transplant tumors into the underfed mice, the tumors wouldn’t grow nearly as well as those transplanted into mice that were able to eat all they wanted.
While Moreschi was studying the quantity of food consumed by rodents, other researchers began to wonder whether the type of food mattered as well. A number of studies found that diets free of carbohydrates, which break down to glucose, could protect mice from cancer in much the same way as low-calorie diets. In 1913, two Cornell University cancer researchers published a review of these studies in the Journal of Medical Research, concluding that enough experiments had been done on enough animals to eliminate any doubts that carbohydrate-free diets made rodents “more resistant to tumor growth.” The article made no claims about a cure, noting that the effect of the carbohydrate-free diet was observed not at the beginning of the tumor growth but on “its continued progress.” Yet the contrast between carbohydrate-free diet and standard diet was clear: “When the diet includes carbohydrate,” the authors noted, “the tumors grow luxuriantly.”9
Cancer, it seemed, had an unusual appetite. The question was why. A decade later, Warburg would observe cancer cells swallowing up enormous amounts of glucose and become convinced that he had arrived at the answer.