“A Chemical Laboratory of the Most Amazing Kind”
THE STORY OF modern cancer research begins, improbably, with the sea urchin. At the start of the twentieth century, the German scientist Theodor Boveri turned to sea urchin eggs to answer one of the central questions in biology: how are the instructions for making a new organism passed from one generation to the next? It was clear that a fertilized sea urchin egg knew how to grow from a single cell into a spiny round creature that could inch its way along the ocean floor. And yet, despite the countless hours Boveri and his colleagues spent looking, the instructions themselves were nowhere to be found.
Boveri was a kind, reserved man, serious and meticulous. He kept his research bench at the University of Würzburg pristine. When lecturing, he stood immobile before the chalkboard and spoke quietly, “his eyes boring into” his audience, a student recalled.1 Much of Boveri’s working life was spent hunched over his laboratory table, gazing into his light microscope. The rest of it was spent drawing the cells he observed. Even when photographic reproduction became possible, Boveri, an amateur painter, preferred to rely on his own hand.
The sketching of the cells wasn’t merely an act of reproduction. Boveri’s former student and biographer Fritz Baltzer wrote that when drawing, Boveri carried on “an undisturbed and intimate dialogue with nature.” For Boveri, drawing was a way of seeing, and he saw in a way that few others could: “One had the feeling,” Baltzer wrote, that Boveri “saw more in a few minutes than the students had perceived in hours or days.”2
Though he lived and taught in Würzburg, Boveri was happiest during his regular stays at the Naples Zoological Station. Opened in 1873 by Anton Dohrn, a wealthy German biologist, the zoological station became a major research site for Europe’s leading developmental biologists. The building, as Boveri once described it, was a “beautiful white edifice” flanked by “dark green oaks.” Standing in the second-floor corridor beneath the red arches, Boveri could look out onto the calm waters of the Gulf of Naples, where, hidden beneath the surface, lay the true treasures: the simple sea creatures that had become the preferred experimental subjects of physiologists and developmental biologists of the era.3
In the 1880s, Boveri was studying chromosomes, the little threads that had recently been discovered in the nucleus of the cell. At the time, scientists thought that chromosomes appeared anew in every cell. Through his careful examination and repeated drawings, Boveri saw that this was wrong. Cells grow by division: one cell becomes two; two become four; four become eight; and so on. Shortly before a cell divides, each chromosome is copied and pinned to its twin at the center. As a cell begins to split into two new cells, a quiet drama unfolds: the twins, pulled apart from their centers, fold inward at either end, appearing as if they’re reaching out for one another, as if they’re not quite ready to begin a new life alone.
That chromosomes are copied and passed from a cell to its progeny was a critical clue for Boveri, but it proved nothing in itself. He still needed a way to test whether chromosomes influence the development of a sea urchin. In 1901, while working in Naples, he found it, thanks to an experimental innovation that allowed him to create sea urchin eggs that lacked a complete set of chromosomes.
Some of the sea urchin embryos without the proper chromosomes would form hollow balls; others would grow half-formed parts and collapse in on themselves. Boveri had turned developmental biology into a theater of the grotesque, but the lesson was clear: each chromosome held a different part of the instructions for a new life. Without the right chromosomes, a fully formed and properly functioning sea urchin would never arise, just as a complete building can’t be built from a blueprint that is missing critical sections.
If Boveri had stopped there, his 1902 paper summarizing his findings would still be among the most significant in the history of biology. We now know that chromosomes are made of tightly coiled strings of DNA that contain the instructions for how to build an organism. Boveri’s mangled sea urchin embryos made possible the extraordinary genetic discoveries of the twentieth century.
Even though he was focused on how an organism develops normally, Boveri couldn’t resist ending his paper with one additional observation: some sea urchin embryos with the wrong number of chromosomes develop “tumorlike” growths. Since it was already known at the time that cancer cells often had abnormal chromosomes, Boveri couldn’t help but wonder if, in searching for how chromosomes shape the development of life, he had also found how chromosomes shape the development of cancer. Perhaps, he reasoned, cancer arises when the instructions for proper growth are jumbled.4
Boveri’s cancer theory received little notice during his lifetime. But by the end of the twentieth century, he would be celebrated as the first scientist to recognize that cancer is a disease of bad information, a disease of damaged DNA providing cells with the wrong instructions.
As it turns out, another scientist, Otto Warburg, was studying the growth of sea urchin eggs at the Naples Zoological Station at approximately the same time as Boveri. Though still a medical student, Warburg had already announced his desire to cure cancer. Because eggs, like tumors, grow by dividing again and again, they made for a logical place for Warburg to begin his experiments.5
Beyond a shared interest in sea urchin development and what it might reveal about cancer, Warburg and Boveri had little in common. Warburg didn’t need to see. As a chemist, he was at home in the world of the invisible, with what he could infer by measurement and calculation alone. And so while Warburg was also studying sea urchin eggs in Naples and also interested in what the eggs might teach him about cancer, he approached his research with an entirely different set of questions. Boveri wanted to understand how changes to chromosomes provide cancer cells with the instructions to grow. Warburg wanted to understand how changes to breathing patterns provide cancer cells with the energy to grow. If a cell’s path to cancer can be thought of as a building project gone awry, Boveri focused on what went wrong with the blueprint; Warburg on what went wrong with the power stations needed to run all of the construction equipment.
Warburg and Boveri weren’t only different types of scientists. They were also very different types of people. Boveri was a man of doubt. After suggesting in his 1902 paper that cancer could be explained by chromosomes, he waited over a decade before expanding on the idea for fear of how it would be received. Warburg, who spent his entire career feuding with other researchers, at times seemed constitutionally incapable of doubt. When Warburg, an avid equestrian, fell during one of his morning rides and fractured his pelvis, he blamed his horse. A glassblower who worked closely with Warburg for eight years couldn’t remember him ever admitting he was wrong on a single matter.6
Boveri once compared himself to a chandelier that had “ceased to give light” but “nevertheless decorated the room.” Warburg, in his own mind, illuminated every room he stepped into. And he expected those rooms to be well furnished. He collected antique British furniture and rugs and owned silver from one of the oldest noble families in Europe. When his sister sent him a clock while he was away in medical school, he thanked her in a letter but confessed that he didn’t like it. “It seems to be putting on airs,” Warburg wrote. “It wants to be a bronze clock on a marble stand,” but is made of “gilded wood that has been lacquered like a Berlin tenement.”7
There might be no better example of Warburg’s famed arrogance than his response after learning he had won the 1931 Nobel Prize: “It’s about time.” Eight years earlier, he’d been so sure he would win the Nobel Prize that he traveled to London to have a suit tailored for the ceremony. Warburg wasn’t delusional. He had good reason to expect the Nobel Prize at some point in his life. He was raised to win it. “I was so much encouraged to become a scientist,” Warburg once said, “that I deeply pitied every other occupation of men.”8
Warburg’s father Emil, himself nominated for a Nobel Prize in 1929, was among the leading physicists of his generation. (Warburg’s mother, Elisabeth, managed the household and cared for Warburg and his three sisters.) In 1895, Emil Warburg was named professor of physics at the University of Berlin, placing him at the pinnacle of German science at a time when someone of Jewish heritage rarely managed to attain such heights. The family moved from Freiburg to Berlin, and Otto Warburg’s childhood home became a gathering place for a circle of extraordinary German scientists, among them Max Planck, Fritz Haber, Walther Nernst, and Albert Einstein.
Given his parentage, it was little surprise that Otto Warburg would develop an almost pathological dedication to his science. According to the Nobel Prize–winning physicist James Franck, Emil Warburg’s proposition to his students was straightforward: if you aren’t prepared to dedicate “every bit” of yourself to science, it is best to keep your “hands off it.”9
When studying under Emil Warburg, Franck and his fellow students took few breaks. Emil would sometimes turn up at the university lab at midnight ready to discuss their experiments as though it were perfectly normal to be debating the finer points of gas laws in the middle of the night. And God help the student who wasn’t prepared for his unannounced arrivals. As Franck recalled, when a student couldn’t answer questions about his research, Emil would sometimes simply walk away without a word so that “the unfortunate sinner” might absorb “the full measure of his ignorance.”10
Otto Warburg may well have surpassed his father’s attachment to science. The biochemist David Nachmansohn compared Warburg’s passion for his work to “the religious fervor of some historical figures, whose whole life was almost exclusively devoted to their relationship with God.” Warburg himself liked to say that a scientist should be “ready to die for the truth,” and he expected everyone who worked in the lab to participate in his martyrdom.11
Still, it’s one thing to be a person who lives only for science and another to be the child of such a person. Warburg’s sister Lotte kept a diary, and Emil Warburg’s choice of work over family is among the dominant themes in it. (Einstein once condescendingly suggested that she had a “daddy complex.”) In her diary, Lotte describes Emil as “objective to the point of numbness.” He could be “selfless and friendly” with his students, but when it came to family, he was “loveless.” In another entry, Lotte remarks that her father wouldn’t have been able to find the bed he supposedly shared with her mother and that it would have been better had he never married. Emil’s thoughts, Lotte writes, led an independent life and “forced him to give up his own life.”12
So as not to interrupt Emil’s thoughts, the Warburg home ran according to strict dictates. The rules weren’t merely implied; Emil had written them out by hand. They included restrictions on tipping one’s chair onto its back legs while seated and putting one’s elbows down on the table. In fairness, his son may have required a bit of heavy-handed parenting. Though little is known about Otto Warburg as a young boy, when he was 12 his parents received a letter from the elite Berlin gymnasium he attended. While the letter notes that Warburg demonstrated “considerable talents and accomplishments,” there was bad news as well: “The pupil Warburg” the letter states, has “repeatedly taken part in gross misconduct and he has encouraged fellow pupils to join in.”13
Whether Warburg was disappointed by his father’s sternness or absence from family life is difficult to know. It is clear that Warburg saw his father as a competitor. Warburg had been a good violinist but gave it up when he saw that he would never be able to play music as well as Emil, a pianist who sometimes played chamber music with Einstein. The competitiveness might have been driven by spite. Emil was known for his frugality and resented his son’s opulent tastes. And he appears to have never quite fallen out of the habit of criticizing his son. In an exchange of letters in 1912—Warburg was 29 at the time and already one of the most promising scientists of his generation—Emil expressed genuine interest in Otto’s work, but also couldn’t resist pointing out that he found it “increasingly difficult to decipher” his son’s handwriting.14
Nevertheless, with his approach to science and insistence on repeated and meticulous measurements, Otto was practicing the ideals of his father, who once wrote that learning to measure accurately leads to the development of a “a serious, manly scientific character.”15
If Warburg strayed from the path set before him as a child, it was by journeying beyond the pure science of physics and chemistry into the realm of the living. Emil Warburg had found new ways to understand the laws of the universe. For his brilliant son, that would not be enough.
AFTER TWO YEARS studying chemistry at the University of Freiburg, Warburg moved back to Berlin in 1903 to train in organic chemistry under Emil Fischer, one of the luminaries in his father’s circle. Fischer was then the most distinguished organic chemist in the world. Tall and stern, he would stand perfectly straight in the lab in his formal black hat and pince-nez. The moment a student turned a conversation in a more personal direction, Fischer turned it right back to science. Warburg recalled that even after he had crystallized a molecule numerous times, a decidedly unimpressed Fischer would say, “Now go ahead twenty-five times more.”16
Fischer had won the Nobel Prize a year earlier for his work on the chemical structures of sugars and purines. When Warburg arrived at his lab, he was studying proteins. Most researchers at the time believed that proteins were little more than unstructured clumps of smaller molecules. Fischer knew better. Proteins, he recognized, were built from simple molecules, amino acids, but they weren’t the amorphous clumps other researchers described. They were intricately structured micro-machines, each one designed to perform a unique job inside of the cell based on its unique form.
To decipher the structure and function of a protein was a Herculean task in its own right, but Fischer wasn’t interested in merely understanding how proteins work. He hoped to one day make proteins from scratch. It was, he knew, an ambitious goal, but by 1903, he had already managed the very first step: synthesizing amino acids into short strings. Warburg wrote his dissertation on the process, and had he devoted the rest of his life to studying only the structures of organic molecules, he might still have become one of the most important scientists of his generation. But after receiving his degree, Warburg realized he didn’t want to stop at organic chemistry.
The problem wasn’t that Warburg’s research under Fischer was too dull. On the contrary, the science felt revolutionary. Science, in Emil Fischer’s words, was coming to seem like “the true land of unlimited possibilities.” If a strand of amino acids could be synthesized in the lab, how long would it be until scientists could piece together an entire protein? And how long after that until organic molecules might be “tricked,” as Fischer once put it, into doing the scientist’s bidding so that the cell itself could function as “a chemical laboratory of the most amazing kind”?17
In the early twentieth century, Fischer anticipated a future, if only “half in a dream,” when scientists would reinvent “the living world” itself. Warburg did not even need to dream to see that future. In 1906, just as Warburg was completing his training in organic chemistry, the German American physiologist Jacques Loeb published two popular monographs in German that made Fischer’s grandiose visions seem almost modest.18
Though largely forgotten today, in the first decades of the last century, Loeb may have been the most famous scientist in America. Regularly featured in newspapers and magazines, he was the inspiration for the character of Max Gottlieb in Sinclair Lewis’s novel Arrowsmith. Loeb, too, spent time at the Naples Zoological Station, where he performed a series of Frankenstein-esque experiments on the sea creatures that lived in the shallow waters of the gulf. He discovered that if he took tubularias, plant-like animals that spring from the ocean floor, and grew them upside down, he could “produce at desire a head in place of a foot.” By cutting away a piece of the animal and suspending it in an aquarium, Loeb could even grow a two-headed tubularian. In another experiment, Loeb suspended a starfish in water by attaching its “arms” to small pieces of cork. A starfish, if turned upside down, will flip back over. But with no surface to orient itself, the suspended starfish could no longer distinguish up from down and would flip again and again, the suspended sea creature itself a metaphor for the dizzying state of the biology of the age.19
Loeb left Germany in 1891, convinced that his Jewish background would make a university appointment impossible. He first settled in Zurich, finding work as an ophthalmologist. It didn’t go well. The philosophically minded Loeb was almost laughably unsuited to caring for patients. One night, while walking along a wooded hill on the outskirts of the city, he confessed to his American wife, Anne, that he was miserable. He had so many big questions that he couldn’t explore while rubbing yellow ointment into people’s eyes all day. By that point, Anne had likely already come to terms with her husband’s obsessions. The couple had honeymooned in Naples the year before so that Loeb could immediately return to work at the zoological station. The Loebs immigrated to the United States, where Loeb found a position at Bryn Mawr. Less than a decade later, he would carry out the experiment that would make him famous around the world.20
Once again it was the sea urchin that played the starring role. Loeb found that if he placed a sea urchin egg in a jar of water mixed with minerals and then returned the egg to seawater, something utterly strange happened: the egg began to grow and develop as though it had been fertilized by a sperm. It was a simple experiment, but through Loeb’s visionary gaze, it would come to seem like the start of something much bigger and more profound. On November 19, 1899, the Chicago Sunday Tribune announced Loeb’s discovery with a detailed sketch of a sea urchin and a blaring headline across the top of page one: “Science Nears the Secret of Life.” Loeb could already see the day, he told another newspaper, when a scientist might mix chemicals in a test tube and end up with a “substance” that would “live and move and reproduce itself.”21
As a young researcher, Loeb had argued that scientists didn’t necessarily need to understand every last mechanism of life so long as they succeeded in engineering living organisms to meet humanity’s needs. He absorbed this belief from German plant physiologists of the era who were intent on securing Germany’s food supply by creating better crops. But for all his claims about pragmatism, Loeb hungered for deeper knowledge. With each new discovery, he would find himself in need of another scientific explanation. What Loeb really wanted, he would eventually state, was to explain all “life phenomena” in terms of the “motions of electrons, atoms, or molecules.”22
At the height of his fame, the New York Times compared Loeb to Copernicus, calling him “undoubtedly one of the greatest experimental geniuses of whom we have any knowledge.” It might have helped that Loeb spoke in a thick German accent and looked the part of the eccentric genius—or that he was conducting experiments that seemed straight out of science fiction: “I wanted to go to the bottom of things,” Loeb once said of his research program. “I wanted to take life in my hands and play with it . . . to handle it in my laboratory as I would any other chemical reaction—to start it, stop it, vary it, study it under every condition, to direct it at my will!”23
To his critics, including many of Germany’s leading biologists, Loeb’s quest to understand life at the level of the chemical reaction seemed hopelessly naive. Perfect knowledge of any given cellular function, according to this view, would never provide real insight on the organism as a whole. A dismissive piece in the New York Times in 1905 questioned the significance of Loeb’s research and suggested that biologists see him as “a man of lively imagination” as opposed to a flawless “investigator of natural phenomena.” But for his admirers, including Mark Twain, who responded to the attack with an essay in defense of Loeb, the bold futuristic claims were irresistible.24
Loeb made it seem as if science would soon achieve full mastery over life, and few scientists of the era were hungrier for mastery than the young Otto Warburg, who already regarded himself as something of a deity. But if Warburg was going to take life into his own hands, he would first have to learn how life worked. In 1906, Warburg moved on from Fischer’s Berlin lab to the University of Heidelberg to study medicine. Two years later, on break from his medical classes, he traveled to the Naples Zoological Station and measured the breathing rates of sea urchin eggs. When his paper was published, he sent it to Loeb, who had already taken an interest in the topic. Loeb responded by thanking Warburg and inviting him to America. The two would continue to exchange letters until Loeb’s sudden death in 1924. Though the 24-year-old Warburg had initiated the correspondence, Loeb would fall into the role of fawning admirer, praising Warburg’s “stunning” work again and again. In one instance, Loeb apologized profusely out of fear he had offended Warburg by suggesting a mistake in his work.25
Loeb’s deference to Warburg was likely rooted in his fear of criticism and his sense that Warburg was an ally. His fame and success notwithstanding, Loeb took each new attack on his science as a personal affront. Anne Loeb once recalled that her husband had spent the first months of their marriage pacing the Gulf of Naples in fits of frustration over what he perceived to be unfair criticisms. Given that nothing bothered Loeb more than the failure of German physiologists to appreciate his physiochemical approach to the study of life, nothing would have pleased him more than Warburg’s emergence as a supporter of his work. Who better to demonstrate the superiority of his approach to biology than the son of a world-class physicist, a man who, furthermore, had studied under the world’s most distinguished organic chemist? Had Loeb ventured to create a new champion for his science in a test tube, he could hardly have done better than Warburg.26
If the relationship meant more to the mentor than the mentee, Loeb, nevertheless, had an immense influence on Warburg’s career. Near the end of his life, Warburg said that the goal of his work had always been, and still remained, “to find out to what extent the processes in living organisms can be resolved in terms of physics and chemistry.” And so while Warburg’s early work on sea urchin eggs is typically explained as a first effort to understand cancer, he was also exploring questions Loeb had raised years earlier, questions aimed at even deeper mysteries.27
As Loeb makes clear in the introduction to The Mechanistic Conception of Life, his best-known book, he was interested in how sea urchin eggs begin to breathe because he saw it as a path to answering one of biology’s greatest puzzles: how life itself begins. Loeb was in search of the on switch for life. Warburg’s earliest studies of sea urchin eggs in Naples were designed to help him find it.
IN THE YEARS AHEAD, Warburg, like Boveri, would build on what he had learned from studying sea urchin eggs at Naples to arrive at an entirely new understanding of cancer. Boveri would become the father of the genetic approach to cancer; Warburg, the metabolic approach. Modern cancer science itself would, in a sense, develop from the eggs of the sea urchin.
But at the end of the first decade of the twentieth century, Warburg’s cancer breakthrough was still more than a decade away. In the meantime, he had other great scientific problems to solve. Fischer and Loeb had taught Warburg that science could reveal every secret of life, and Warburg wanted to know them all. He planned to figure out not only how much oxygen a cell breathed but which hidden molecules inside of a cell made breathing possible. It was an extraordinarily ambitious goal, and while he was at it, Warburg was going to unravel the mysteries of photosynthesis as well.
Though journalists sometimes referred to Loeb as a modern Faust intent on pushing science to once unthinkable places, Loeb, for all his scientific hubris, was a humble man. If there was a true Faust in the first decade of the twentieth century, it was not Loeb but his mentee.
Warburg was even following the same academic path as the original Faust. The character is thought to be based on the sixteenth-century German physician and alchemist Georgius of Helmstadt, who called himself Doctor Faustus and who, like Warburg, studied at the University of Heidelberg. Helmstadt is believed to have died violently in the mid-1500s. By the end of the century, his legend was already the subject of a hugely popular book of tales and had inspired Christopher Marlowe’s play Doctor Faustus, the first great literary treatment of the story.
As the classic version of the legend goes, a brilliant scholar, longing for deeper knowledge of the world, arrives at a deal with the devil. In exchange for greater scientific powers, he will give up his soul. Warburg, in his mid-20s, was already ravenous for knowledge and power. The devil’s offer was still to come.