WARBURG RETURNED TO Germany in good spirits. “America was a great adventure,” he wrote to an acquaintance in December 1949. “I really made a lot of friends there, and no one believed that I would ever leave.”1
Later that month, the same New York Times journalist who had written about Warburg’s cancer research the year before published a page-one story on his photosynthesis studies. The article stated as fact that only 3 or 4 photons are necessary to power photosynthesis and suggested that Warburg had overturned previous thinking on the subject by way of “highly ingenious new techniques.” The outrageous claim was presented in support of another: that Warburg, through a series of “epoch-making” photosynthesis experiments, had discovered a new way to grow algae that would vastly expand the world’s food supply.
Making it possible to grow food more efficiently had always been one of Warburg’s goals. The New York Times declaring that he had triumphed must have been enormously satisfying for Warburg, and more good news was soon to come. On May 8, 1950, the American military returned Warburg’s Dahlem institute to him in a ceremony attended by General Maxwell D. Taylor, the US military commander in Berlin. One of the few members of the Kaiser Wilhelm Society deemed untainted by the Nazis, Warburg received new equipment and funding at a moment when many German scientific labs were barely functional. “The Palace of Cell Physiology has emerged from the ashes, more beautiful than ever,” Warburg wrote to an American colleague in December 1951.
In June, when Martin Klingenberg, a physical chemistry student from Heidelberg, arrived at the institute, Warburg took him on a tour. Klingenberg was amazed by the state-of-the-art equipment. Compared with his lab in Heidelberg, Warburg’s institute seemed like “paradise.”2
At approximately the same time Warburg reoccupied his institute, he received a delivery from Sweden that would shape his thinking on cancer for the rest of his life. The shipment, sent by the scientist George Klein, contained a type of cancer cell that grows in abdominal fluid. Warburg had previously worked with razor-thin slices of tumors, but such samples inevitably included noncancerous cells as well. The cells from the abdominal fluid, by contrast, gave Warburg nearly pure cultures.
Warburg placed the new cancer cells in a glass vessel and attached it to his manometer. He had been studying the respiration of cancer cells for nearly 30 years, but what he measured this time was noticeably different from what he had measured before. In the 1920s, Warburg had found that respiration with oxygen could continue at a steady rate even as fermentation increased. And yet, those results never quite fit with Warburg’s theory—based on the conclusions of Pasteur—that fermentation and respiration always maintain a seesaw-like relationship, fermentation going up as respiration went down.
The new experiments made this problem go away for Warburg. The cells from the abdominal fluid hardly needed oxygen at all. They seemed to rely almost exclusively on fermentation. They fermented, Warburg wrote, like “wildly proliferating Torula yeasts.” As Warburg saw it, these new experiments were a huge advance, the long-awaited evidence that he had been right all along. When Klein’s boss later asked Warburg for a recommendation on Klein’s behalf, Warburg happily agreed. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.”3
In December 1950, Warburg and Heiss traveled to Stockholm for the 50th anniversary of the Nobel Prize awards, where Warburg was to give a speech about cancer research. Before Warburg’s lecture, he and Heiss set up four charts with data from experiments on the metabolism of cancer cells. As Warburg spoke, Heiss paced with a wooden staff and periodically pointed to the charts. When he was done speaking, Warburg informed his audience of Nobel laureates that he had just told them all they need to understand about the biology of cancer. The rest, Warburg said, was “garbage.”4
If it was increasingly rare for Warburg to doubt himself, as late as 1952 it was still technically possible. That year he traveled to Copenhagen to give a series of lectures at the Carlsberg Laboratory. The Danish biochemist Herman Kalckar took Warburg and another scientist on an outing to the castle in Elsinore where Hamlet is set. It was a beautiful day—sunny and “crystal-clear,” Kalckar recalled—and as they toured the famous castle, Warburg seemed himself. Peering through an iron grate into the dark expanse below, Warburg noted that it was “a perfect place” for the “Midwest Gang”—his nickname for Robert Emerson and the other scientists at the University of Illinois who disagreed with him about photosynthesis.
It was a typically Warburgian comment, but later that day Warburg turned to Kalckar and asked a question that was not at all characteristic: “Why do I encounter so much alienation from British and American biochemists?”
Kalckar, startled, tried to be diplomatic. He suggested that Warburg’s “opinionated footnotes” might be part of the problem.
“Give me one example,” Warburg said.
Kalckar obliged, pointing out that Warburg had called the legendary twentieth-century biochemist Sir Frederick Gowland Hopkins a “Romantic”—an insult suggesting that Hopkins would speculate beyond what the experimental data supported.
“Did I really?” Warburg asked. He seemed genuinely surprised that he had said such a thing. He told Kalckar that he had always admired Hopkins. “Warburg’s open confession was remarkable,” Kalckar wrote. “Perhaps Hamlet’s castle played its part.”5
Whatever came over Warburg that afternoon, it was a rare occurrence in the final decades of his life. The next year Warburg learned of new evidence that supported his understanding of cancer, and he grew still more certain that he had been right all along. In the 1920s, Warburg had been able to demonstrate only that an increase in fermentation is a basic feature of most cancers and that he could cause cells in a dish to ferment in the manner of cancer cells by poisoning them with chemicals that interfered with their use of oxygen. Warburg had never shown that depriving cells of oxygen could lead to an actual cancer in an animal. In 1953, the American researchers Harry Goldblatt and Gladys Cameron claimed to have done exactly that. Though Goldblatt acknowledged that the experiments couldn’t prove that oxygen shortages caused cancer in people, he pointed out that cancer is often found in places in the body where the blood supply is limited and cells have less access to oxygen.
Warburg was delighted with the finding of Goldblatt and Cameron and mentioned it often in his own articles and letters. He had long believed that chemicals and radiation caused cancer by damaging a cell and leaving it unable to use oxygen properly. The new research suggested that a disruption in the delivery of oxygen to a cell could cause cancer, even if the cellular machinery itself wasn’t damaged. The origins of a deadly cancer might be as innocuous as a plugged gland. However the use of oxygen was impaired, the result would be the same: a need for more energy from fermentation.
Goldblatt and Cameron’s discovery, and that of others in the early 1950s, helped Warburg fill in the sketch of cancer he had first proposed 30 years earlier. When cells turned to fermentation to generate enough energy to survive, he now claimed, it would lead to a “struggle for existence.” The cells least capable of replacing the power of respiration with fermentation might die quickly, but the more flexible cells would cling to life, even as they gasped for air.
The “struggle” to survive in the suffocating environment might be a prolonged process, which explained why cancers often arose years after someone had been exposed to carcinogens. But over time, as the cells took up glucose and divided, the best fermenters would win the Darwinian competition and multiply until they came to dominate. Alas, the victory of the superior fermenters, as Warburg had argued from the start, would come at a terrible price. Because the energy supplied by fermentation alone cannot maintain the structure of a “differentiated” cell—a cell that is specialized for a particular tissue—the survivors of the oxygen drought end up as primitive “undifferentiated” cells that eat and grow without pause. “[T]he differentiated body cell is like a ball on an inclined plane, which would roll down except for the work of oxygen-respiration always preventing this,” as Warburg once explained it. “If oxygen respiration is inhibited, the ball rolls down the plane to the level of dedifferentiation.”
Warburg believed that all cells had lived by fermentation alone before the earth’s atmosphere had filled with oxygen. The return to fermentation, as he imagined it, amounted to evolution in reverse. Cancer was a cell’s journey backward in time to its deepest origins. Even “Einstein descended from a unicellular fermenting organism,” Warburg noted.
Beyond Warburg’s original and most fundamental observation—that cancer cells swallow more glucose and ferment more than noncancerous cells—all of his arguments were speculative, precisely the type of theorizing Warburg would never have tolerated from others. But during the last two decades of his life, he presented this vision of cancer as though he himself were Einstein explaining a basic theory of physics. “If the explanation of a vital process is its reduction to physics and chemistry,” Warburg wrote, “there is today no other explanation for the origin of cancer cells, either special or general.”6
WARBURG WAS NOW so convinced he was right about cancer that the mere thought of considering other approaches seemed ridiculous to him. In 1953, the Nobel Prize–winning German biochemist Adolf Butenandt reached out to Warburg about founding a new cancer research center in Germany. Warburg told Butenandt that there was no point, given that he had already solved the cancer problem.
And so the events of the last week of 1953 could only have come as a terrible shock for Warburg. While most Americans were celebrating the holidays with family, a number of the nation’s leading scientists were huddled in Boston at a cancer symposium. One of the scientists in attendance was Sidney Weinhouse, an unassuming researcher working at a cancer institute in Pennsylvania. Weinhouse had recently studied respiration in cancer cells with a new tool, radioactive carbon molecules, that made it possible to make even more precise measurements.
When it was Weinhouse’s turn to present his data at the Boston symposium, he did not dispute Warburg’s most fundamental claim, that cancer cells ferment more. But he did dispute Warburg’s argument that fermentation was a cell’s response to a struggle to generate energy with oxygen. The cancer cells Weinhouse studied appeared to be breathing just fine.
Weinhouse’s conclusion was essentially a confirmation of what Warburg had found in the early 1920s—that respiration continued even as cancer cells fermented—but it was a stark refutation of Warburg’s more recent finding on the cancer cells taken from abdominal fluid. Warburg was claiming that fermentation replaced respiration in cancer cells, Weinhouse that fermentation accompanied respiration. The next week a science newsletter summarized Weinhouse’s findings under the headline “Cancer Theory Overthrown.” Dean Burk immediately wrote to Warburg to let him know about the insurrection. “Weinhouse,” Burk wrote, “is your ‘cancer Emerson.’ ”7
For Weinhouse, it might have been nothing more than a minor correction to an important scientific discovery. But Warburg couldn’t tolerate corrections. As far as Warburg was concerned, Weinhouse had declared war. A year later, Warburg proclaimed his victory in that war in a speech delivered in Stuttgart:
What was formerly only qualitative has now become quantitative. What was formerly only probable has now become certain. The era in which the fermentation of the cancer cells or its importance could be disputed is over, and no one today can doubt that we understand the origin of cancer cells if we know how their large fermentation originates, or, to express it more fully, if we know how the damaged respiration and the excessive fermentation of the cancer cells originate.8
The speech was translated by Burk and appeared in the February 1956 issue of Science. The next month, the New York Times published a story under the headline “German Physiologist Is Sure That He Has Discovered the Cause of Cancer.” The article began by describing Warburg as “probably the most distinguished figure in contemporary cancer research.” The remaining paragraphs read as though written by Warburg himself. Under the heading “Case Proved,” the article stated that when “fermentation has completely supplanted respiration, the normal cell has changed to a cancer cell.”9
Weinhouse, if lacking Warburg’s righteous passion, did not intend to back down. In August 1956, Science published Weinhouse’s response to Warburg’s speech. Weinhouse tried to soften the blow with a mention of “the great debt” biochemists owed to Warburg, but his insistence that the science did not support Warburg’s theory of how cancer begins could only be softened so much.
Science allowed Warburg to respond to Weinhouse in the same issue, and he was, predictably, less diplomatic. Warburg did make an effort to walk back his boldest claims, suggesting that “damaged” respiration could include cancers in which respiration continued but failed to “turn off” fermentation. Much of the disagreement, Warburg wrote, was “a dispute about words.”
What Warburg would not walk back was his deeper claim, that an increase in fermentation was the most fundamental characteristic of cancer. “The problem of cancer is not to explain life, but to discover the differences between cancer cells and normal growing cells,” he wrote in his usual mix of elegance and condescension. “Fortunately, this can be done without knowing what life really is. Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal. A man who knows nothing at all about engines, their structure, and their purpose, may discover the difference. He may, for example, smell it.”10
AS WARBURG RESTARTED his career in Dahlem in 1950, cancer therapy was stuck in the same place it had been decades earlier. Radiation was used to blast malignant cells, and surgeons wielded their knives against tumors, but the medical world still lacked the thing it needed most: cancer drugs that extended patients’ lives. In the 1950s, such drugs began to emerge. They are now known as chemotherapies, but they were far from the precision weapons Paul Ehrlich had imagined when he coined the term at the turn of the twentieth century. The drugs attacked rapidly dividing cells, cancerous or not. They ravaged the body, leaving patients frail and nauseated, sometimes barely clinging to life. Chemotherapy, Siddhartha Mukherjee writes, turned out to be “a ghoulish distortion of Ehrlich’s dream.”11
But then, it was not Ehrlich but another famed German scientist, Fritz Haber, who had prepared the way for modern chemotherapy. The director of the Kaiser Wilhelm Institute for Physical Chemistry, Haber initiated and oversaw Germany’s gas warfare program during the First World War. (While Warburg was at the Eastern Front, Haber’s gas unit took over the lab space that had been set aside for Warburg at the Kaiser Wilhelm Institute for Biology.)
Haber, said to be the father of modern biological warfare, is sometimes portrayed as an evil mastermind. With his shaven head and pince-nez, he looked the part. Though not considered as brilliant as some of his colleagues in Dahlem, Haber was a remarkably creative chemist with a Warburg-like belief in his ability to overcome technical obstacles. Warburg once told his sister that Haber purposefully woke himself in the night to think so he could continue to come up with new ideas. The ideas were frequently bizarre. After World War I, Haber spent years trying to extract microscopic gold particles from the ocean in a scheme to pay off Germany’s debts.12
If capable of villainy, Haber was a complicated villain. Beneath a gregarious exterior lay an anguished, almost Kafkaesque outlook—he once said that he felt as though he lived under “a great boulder” that was lifted every once in a while so that he could get a bit of air and sun. Though a “full Jew” according to Nazi criteria, Haber, widely considered a German hero after the war, could have held on to his job in 1933—at least in the short term. But unlike so many others in prominent positions, Haber was not willing to look away. Rather than fire his many Jewish employees, he resigned from the Kaiser Wilhelm Society and fled Germany.
Months later, the deeply patriotic Haber remained shaken and mystified by his sharp turn of fate. “I never did anything, never even said a single word, that could warrant making me an enemy of those now ruling Germany,” he wrote to a colleague in December 1933. Soon after, Haber died of heart failure. His work would outlive him, most infamously his research on gases. Intended to be used for insect control, it led to the development of Zyklon B, the gas the Nazis would later use to murder a number of Haber’s own relatives.13
Among the weapons to come out of Haber’s gas unit during World War I was an agent that smelled like garlic and that spread in a shimmering pale yellow mist. The weapon, which became known as mustard gas, was a source of terror for soldiers. It seeped into their uniforms and left their skin itching and burning and blistering, as though they were being cooked without heat. Gas masks were largely useless against it. And yet, most exposed to mustard attacks survived. Hitler himself had been hit with mustard gas in the last months of World War I. In Mein Kampf he described the experience as “a pain, which grew worse with every quarter hour.” “My eyes,” Hitler wrote, “had turned into glowing coals.”14
As early as 1919, a pair of researchers had noticed that soldiers who survived their encounters with the mustard agent often had more than scarred and pocked skin to remind them of their ordeals. The chemical poison obliterated the blood-forming cells of the bone marrow, leaving victims unable to rally the army of immune cells needed to fend off infections. The finding was published in an obscure journal and mostly ignored and forgotten.
Milton Winternitz, dean of the Yale School of Medicine from 1920 to 1935, didn’t forget about it. A chemist, Winternitz had worked on mustard compounds himself during World War I in a unit studying how to defend against Haber’s gases. During the next world war, Winternitz was appointed chairman of the Committee on the Treatment of War Gas Casualties. In that capacity, he asked two Yale pharmacologists, Louis Goodman and Alfred Gilman, to study mustard agents for their therapeutic potential.
While reviewing the literature on survivors of mustard attacks, Goodman and Gilman hit on something critical. For someone suffering from cancers of the blood, such as leukemia or lymphoma, in which immune cells will not stop multiplying, a limited supply of immune cells was the opposite of catastrophe. It was their only hope of survival.
As a first step, Goodman and Gilman injected a related mustard compound into mice with blood cancers. It quickly wiped out the animals’ immune cells and did so without eliciting the blistering caused by skin exposure. On August 27, 1942, not long after Zyklon B was first released into the Nazi gas chambers, the mustard compound was injected into a 47-year-old Polish immigrant known only as “J.D.” who had exhausted all other treatment options for his non-Hodgkin’s lymphoma. Within four days of his first injection, J.D. was moving more. He told a nurse that his throat felt better. He continued to improve over the following weeks. One month after his first injection, his medical records indicated that “all cervical and axillary nodes [of the cancer] were gone.”15
J.D.’s cancer returned within two months, and he died shortly thereafter. But his response to the mustard compound was a turning point in the history of cancer medicine. In defending his work on gas weapons, Haber had argued that poisoning soldiers with gases was no worse than shooting at them with bullets. The end result, painful injuries or death, was the same. Cancer scientists had now arrived at the inverse conclusion. The toxic effects of chemotherapy could be justified because the drugs achieved the same end result—saving a life—as a magic bullet.
Precisely how the first chemotherapies for cancer worked was not well understood at the time. Scientists now know that mustard compounds form bonds that prevent rapidly dividing cells from replicating their DNA. The chemotherapies that soon followed stop cells from dividing by interfering with their use of a particular B vitamin needed to synthesize new molecules. Though it is often overlooked even today, these drugs are metabolic therapies. They work on enzymes that Warburg understood to be central to cancer, and they disrupt the metabolic pathways that are turned on as a cell transitions to fermentation.
Weinhouse had shown that Warburg was wrong on the specifics, but chemotherapy turned out to be a validation of Warburg’s broader belief in the fundamental importance of metabolism.