Ravenous

WHILE IN MEDICAL SCHOOL in Heidelberg in his late 20s, Otto Warburg, as always, found much to complain about. In 1907, he sent a letter to his sister Lotte in which he noted that his recent experiments had been “ruined by two jackasses.” “Medical doctors,” Warburg added, “can really botch things up.”¹

Still, Warburg had plenty to be grateful for at Heidelberg. The well-known physician overseeing his studies, Ludolf Krehl, was an ideal mentor for him. Krehl believed that good medicine began with foundational science, and as a result, Warburg’s medical training was almost entirely devoted to research.

Krehl, like Emil Fischer and Emil Warburg, saw no reason to take breaks from science—students were expected to be at work when Krehl stopped by the laboratories on Sunday evenings. When Warburg went on vacation, it was to the Naples Zoological Station for more research. Under the influence of Jacques Loeb—and with cancer seemingly already in mind—Warburg had begun his work at Naples with a basic question: how much oxygen did growing cells consume? But over time, Warburg shifted from the question of “how much” to the question of, simply, “how.” For all the scientific advances of the era, one of the most important questions in biology—how food and oxygen combine inside us to sustain life—remained unanswered.²

That nutrients we eat are burned with something in the air was clear even to Galen, the Roman physician to the gladiators who remained the most influential medical thinker for much of the next two millennia. Galen was convinced that food and air came together in the heart, which burned with the heat of a flame. Some 1,600 years later, the great French chemist Antoine Lavoisier alternately placed a guinea pig and a burning piece of charcoal inside a chamber of ice and demonstrated that Galen had been at least partially right in conceiving of animal breathing as a burning fire. The ice around the animal and the ice around the charcoal would melt at different rates, but in both cases, the amount that melted (a measure of heat) was in direct proportion to the carbon dioxide given off. Respiration, wrote Lavoisier in 1790, is “similar in every way to that which takes place in a lamp or lighted candle.”³

Lavoisier also grasped another critical fact about respiration: the carbon we breathe out in the form of carbon dioxide comes from our food. But Lavoisier, guillotined during the French Revolution, never had the opportunity to solve the rest of the puzzle. Our bodies might burn food in much the same way a lamp burns oil or a candle burns wax, but oxygen reacts with lamp oil or candle wax only when we raise the temperature with the heat of a flame. The question left for scientists after Lavoisier was how the same reaction could take place in the absence of that flame. Why does a slice of bread that won’t burn when sitting on a table begin to burn once it is inside of us? Food and oxygen were clearly the fuels needed to sustain a cellular fire, but the match inside of our cells remained elusive.

In 1910, Warburg still had only a vague notion of how oxygen reacts with molecules from our food. He knew there had to be a molecule that made the reaction possible. Such molecules were already known as enzymes, though Warburg, distrustful of the enzyme science of the time, preferred the older term, “ferment.” Since chemicals that damage cell membranes were known to slow respiration, he reasoned that the key molecule was likely attached to the cell’s surface. But Warburg had little idea of how that molecule—he called it the “respiratory ferment”—worked or how it interacted with a membrane. As Warburg wrote to Loeb, the membrane’s role in respiration remained “a total mystery.”⁴

Three years later, Otto Warburg completed his medical studies in Heidelberg. Though he had not solved the mystery of cellular breathing, he had already written some 30 scientific papers and distinguished himself as one of Germany’s best young scientists. He graduated magna cum laude, missing the rank of summa cum laude not because of the quality of his work, but rather, one adviser noted, because of the “dictatorial certainty” with which he had spoken during his dissertation defense.⁵

Warburg returned to Berlin. His timing was perfect. Germany might have been at the forefront of international science in the first decade of the new century, but the German scientific establishment was not resting easy. England and the United States were both threats to German hegemony. The individual scientist causing Germans the most anxiety was none other than Jacques Loeb. In 1910, the Rockefeller Institute had lured Loeb away from academia with the promise that he would be free to pursue his scientific interests without the obligation to teach. Loeb, already the most prominent figure in the world of cell biology, was poised to usher in a new scientific era in which Germany would be unable to compete.

What their nation needed, prominent German scientists argued, was a Rockefeller Institute of its own, a place where that nation’s best researchers could work on whatever matters they chose without distraction. In 1911, the Kaiser Wilhelm Society, a joint venture of the German state and private donors, was founded. Emil Fischer, the famed scientist who taught Warburg organic chemistry, was one of the leading fundraisers and advocates for the new society. Fischer told one scientist he recruited to the Kaiser Wilhelm Society that he would have so much freedom he could choose to spend years simply walking in the woods, perhaps pondering “something beautiful.”⁶

The first two institutes were devoted to chemistry. A third Kaiser Wilhelm institute, devoted to biology, was scheduled to open in 1914 with Theodor Boveri as its director. Boveri’s most important task, at the outset, was to select the leaders for the various departments within the new institute. He soon found himself trapped in a thicket of political negotiations. Boveri was already in poor health, and the stress of staffing the institute only made things worse. “I am at the end of my forces,” he told a friend in January of 1913. “For four months this inner struggle has torn me.”⁷

Boveri finally gave up. He would never direct the new institute. But the department heads he chose would remain in place. To lead the cell physiology department, he had tapped the most promising German scientist in the field: Otto Warburg. In so doing, Boveri, then in the midst of writing the famed monograph that would lay the foundations of the genetic understanding of cancer, also helped further the metabolic view of cancer.

Not yet 30 when Boveri made his decision, Warburg now had among the most envious positions in all of science—his own lab in an elite scientific institute in the world’s most advanced scientific country. Warburg was free to study photosynthesis or respiration or any other topic he cared to. Loeb had taught him that a scientist could remake the biological world. Thanks to Boveri, Warburg now had everything he needed to achieve his grand ambitions.

Because the Kaiser Wilhelm Society Institute for Biology had not yet been built in 1913, the one thing Warburg lacked, in the near term, was a place to conduct his experiments. But finding a laboratory bench would not prove difficult for the son of Emil Warburg, whose influence on German science had only grown since Otto had left home. In 1905, Emil became the president of Germany’s Imperial Physical and Technical Institute, then one of the premier physics institutes in the world. The campus, located in the posh Charlottenburg district, included an elegant two-story villa for the president’s family. Otto once said the home was “like a palace.”⁸

Warburg continued working on cellular respiration in the laboratory of Walther Nernst, a future Nobel laureate and friend of the family. Whether Warburg was able to appreciate his good fortune is difficult to know. He may still have suffered from the distress he had alluded to in his 1912 letter to Otto Meyerhof, his medical school classmate. Meyerhof had sent a sympathetic response and recommended a doctor, but if Warburg was feeling better upon his return to Berlin, it was likely Meyerhof’s science, rather than his kind words, that made the difference.⁹

Only months after Warburg completed his research on cellular respiration at Heidelberg, Meyerhof brought a surprising finding to his attention: certain acids could slow the breathing of growing sea urchin embryos. Since the same acids were known to bind to metals, Warburg wondered if metals played a role in allowing a cell to breathe by making oxygen more reactive. Specifically, he wondered if the respiratory ferment (enzyme) he was searching for worked because it contained a metal. Perhaps, like a dancer stepping in to swoop away someone else’s partner, the acids were slowing respiration by grabbing on to the metal and preventing it from reacting with oxygen as it normally would.

Warburg wasn’t the first to suspect that metals might play a role in respiration. That iron, when wet, would react with something in the air and turn to rust had been understood for thousands of years. And iron was already known to carry oxygen in the blood, where respiration was once thought to take place. Asking whether iron might be the key to breathing required little in the way of scientific brilliance. The hard part was providing conclusive evidence. Warburg had a hunch that iron was critical for respiration and thus life, but he could not be certain.

To learn more, Warburg sprinkled iron salts on breathing sea urchin eggs. More iron, he saw, increased the amount of oxygen taken up. Next Warburg wanted to know if iron compounds could trigger reactions in a model system—a system outside of living cells. To find out, he heated hemoglobin from blood, which he knew contained iron, until it turned into charcoal. He then added the charcoal to a solution containing amino acids and oxygen. The charcoal worked precisely as Warburg pictured a respiratory ferment working on the surface of a cell. Before the addition of the charcoal, the oxygen wouldn’t react. The iron-rich charcoal was like a love potion. As soon as Warburg added it to the solution, the oxygen sprang to life and instantly attached to the surrounding amino acids.¹⁰

More revealing still, whether in living cells or in his model system, the iron compounds would lose their catalytic magic when cyanide was added to the solution. Cyanide was understood to be the world’s deadliest poison due to its ability to interfere with how our bodies use oxygen. Now Warburg saw why. It reacted with the iron in his respiratory ferment that would otherwise be available to react with oxygen. Cyanide, Warburg realized, is like a pillow being pressed down on the face of a cell. It kills by suffocation.

Even with these findings, Warburg still didn’t have anything close to proof that respiration is dependent on iron. Cyanide can react with other metals as well, and copper was also known to be present in cells. But the evidence was growing. Galen, it seemed, had turned to the wrong artifact of ancient life in trying to understand why we breathe. The most revealing clue hadn’t been fire, but the rusting iron swords of the gladiators he had once treated.

IN TURNING TO BIOLOGY, Otto Warburg had moved beyond his father’s physics. Now, having returned to Berlin, he would pause to look back. Less than a decade earlier, Einstein had pondered what happens when light hits a metal surface and arrived at one of the most startling insights in the history of science: Light wasn’t simply a wave as every physicist believed. It could also behave like a particle. It was an idea so outrageous that hardly any physicists accepted it. Even Planck, whose own calculations had laid the groundwork for Einstein’s breakthrough, dismissed the notion as a youthful mistake of an otherwise promising physicist.

But not everyone thought Einstein was wrong. In 1907, Emil Warburg conducted his own investigations of light’s energy. In the following years, he would provide the first experimental evidence for Einstein’s theory of how light particles interact with molecules. “You are making real,” Einstein wrote to Emil Warburg, “that which for years I had only vaguely dreamed about.”¹¹

Otto Warburg, too, would become fascinated by the transfer of energy from light to matter. He began to study the phenomenon at Emil Warburg’s institute. But rather than shining light at metal, he would aim light at living cells to understand how photosynthetic organisms use energy to make glucose. With that simple redirection, Warburg had arrived at the perfect bridge between his own research and the research of his father. In a letter that Emil Warburg sent to his son, he even mentions an experiment the two intended to work on together, a surprising plan given the tension in the relationship. While it appears that the joint experiment was never carried out, Otto Warburg would go on to revolutionize the field of photosynthesis over the next decade, becoming the first to truly grasp the process in the context of Einstein’s new understanding of light.¹²

Otto Warburg won the Nobel Prize for his research on cellular respiration, and he is best known today for his cancer research; but for all of the many bitter scientific disputes he engaged in, none was more personal to him than the dispute over photosynthesis. Though accepted as scientific fact for several decades, Warburg’s finding that only 4 photons were necessary to release one molecule of oxygen would be overturned in the second half of the twentieth century. The revised figure—8 to 12 photons—took little away from Warburg’s critical contributions to the field, and yet Warburg was never able to acknowledge that he was wrong or let go of his indignation. His hope, he wrote of the photosynthesis researchers who disputed his findings, was that they would be “punished already in this world.”¹³

Warburg’s obsession with the number of photons required to power photosynthesis was a mystery to some of his colleagues. They failed to grasp that photosynthesis wasn’t just another area of interest for Warburg; it was his inheritance.

They may have also failed to grasp that Warburg saw photosynthesis as a natural extension of his study of cellular breathing. Photosynthesis is essentially respiration in reverse, and Warburg understood the two processes as different aspects of the same underlying phenomenon. In his early work on photosynthesis, he picked up almost exactly where he had left off in his respiration studies by investigating the role of metals in sparking reactions. When another researcher complained that the study of animal physiology was overtaking the field of plant physiology, Warburg told his sister Lotte that he found the objection ridiculous. “This all belongs together,” he said.¹⁴

Cancer, from Warburg’s perspective, belonged with both photosynthesis and respiration. Warburg had not yet discovered that cancer cells ferment glucose, but his work on sea urchin eggs started with the assumption that cancer was a problem of growth and so must have something to do with the way a cell uses energy. The legendary twentieth-century biologist Theodosius Dobzhansky famously wrote that it was impossible to make sense of any aspect of biology without examining it through the lens of evolution. Warburg might have said the same of energy processes. Now back in Berlin, he was poised to establish his own scientific identity in the new Kaiser Wilhelm Institute, but even when studying cancer, he would remain Emil Warburg’s son.

THAT GERMANY’S NEW scientific society had been named after Kaiser Wilhelm II was more than an obligatory show of respect. Wilhelm was an enthusiastic supporter of the society and its institutes and was said to have personally designed the organization’s flag and court uniform. Though his interest was less in the substance of the science than in the prestige it conferred on him, Wilhelm did once attend a lecture Ehrlich gave on chemotherapy. As the story—which may be apocryphal—goes, Wilhelm later called Ehrlich to a special audience and asked him when he was going to cure cancer. When Ehrlich could not provide the answer he wanted to hear, the kaiser lost interest and turned away.¹⁵

Wilhelm had good reason to be concerned about cancer. By 1901, both of his parents had been killed by it. His father, Kaiser Friedrich III, was the first to succumb. In early 1887, Friedrich, then still the crown prince and heir to the throne, complained of a sore throat. It seemed he had only a cold. By the end of the month, Friedrich’s throat was so swollen he could barely speak. Upon examining the crown prince, his doctor noticed a small growth and cauterized it with an electric wire. This didn’t help. Over the course of the year, as Friedrich deteriorated, his treatment devolved into a dark comedy of errors as his British and German physicians bickered over whether to operate.

For the many Germans who loved Friedrich, his demise was painful to witness. He was a fundamentally decent man who detested war and favored democratic reforms—he once attended a synagogue service in his Prussian military uniform to show his solidarity with Berlin’s Jews. By November 1887, Friedrich’s doctors were desperate, which probably explains why they listened when a Bavarian duke told them about a new cancer therapy he had heard about from his sister, Empress Elizabeth of Austria. Elizabeth had supposedly learned of the new experimental therapy during a visit to a hospital in Vienna.¹⁶

The new therapy was the creation of Ernst Freund, a 23-year-old Jewish doctor in Vienna who had just earned his medical degree. Two years earlier, while still a student, Freund had published an obscure five-page paper describing the elevated glucose levels he had detected in the blood of patients with carcinomas (cancers that arise in the epithelial cells that line the surfaces of our organs). A full 62 of the 70 carcinoma patients Freund had examined appeared to have too much glucose in their blood. Since the link “can hardly be considered accidental in so many cases,” Freund wrote, “I believe that the presence of an abnormal of amount of sugar or glycogen in the blood is necessary for the existence of the carcinoma.”¹⁷

Newspaper reports from late 1887 offer conflicting reports of what happened after Friedrich’s doctors took an interest in Freund’s research. It appears that the crown prince had blood drawn from his neck and that his physicians confirmed that he did, in fact, have elevated levels of glucose. The physicians then introduced Freund’s experimental glucose-lowering treatment, which involved both dietary changes and an unspecified medication. It may have been the first cancer ever treated with a modern metabolic therapy.

According to some accounts, the treatments helped. On December 23, 1887, the New York Times reported on the crown prince’s therapy under the headline, “The Crown Prince’s Malady: A new theory regarding the treatment of cancer.” The very next day, the paper published a second story, citing a clearly perturbed cancer authority: “The theories of Dr. Freund of Vienna concerning the cause of the cancer in the German Crown Prince’s throat are generally discredited by New-York medical men,” the article stated. The article added that there was “no relation whatever between cancer and sugar in the blood.” For readers of the New York Times, at least, the new metabolic understanding of cancer was dead within 24 hours of its arrival.¹⁸

It is possible that Freund’s dietary regime made a difference. When Wilhelm I died in March 1888, Friedrich was well enough to assume the throne. But if the treatment helped, the effect was short-lived. Friedrich died that June after four months in power, leaving the throne—and the German military—in the hands of his notoriously foolish and aggrieved 29-year-old son, Wilhelm II. Wilhelm read little outside of newspaper clippings about himself and would erupt into angry fits when portrayed in an unflattering light. “In order to get him to accept an idea you must act as if the idea were his,” Wilhelm’s closest friend once explained. Worst of all, he surrounded himself with warmongers who were skilled in the art of manipulating his rage. Wilhelm’s hatred of England was so fierce, a New York Times reporter noted in 1908, that “his eyes snapped” when the subject came up.¹⁹

It is impossible to know how a living Kaiser Friedrich would have changed the course of the twentieth century, but Germany would almost certainly have followed a different path had he survived. While countless different social and economic factors played a role, the critical turning point for Germany was the start of the First World War, a war that left 20 million dead and set the stage for the Second World War. And the First World War would likely never have happened if not for the ascension of the recklessly militant and volatile Wilhelm. John Röhl, the celebrated British historian who spent nearly 30 years writing a three-volume biography of Wilhelm, concluded that even though he was not acting alone and was not the principal advocate of war in the summer of 1914, Wilhelm nevertheless had “perhaps the heaviest overall” responsibility “for having brought about Europe’s great catastrophe.”²⁰

Friedrich was only 56 at the time of his death, and his own father had lived into his 90s. The cancer that killed Friedrich and put Kaiser Wilhelm II in charge of the German military might have been the most consequential in history, a mass of overeating cells in the throat of one man that led to a half century of hell.