GIVEN HIS INCREASINGLY erratic behavior, the most surprising aspect of Warburg’s life in the late 1950s and the 1960s might be that he was still capable of sound, sometimes even groundbreaking, research. Though he was wrong about the source of the oxygen released by photosynthesis, Warburg’s explanation involved a new mechanism he had discovered, known as the bicarbonate effect, that would continue to be studied for decades.
During the same period, Warburg discovered that cancer cells typically have less of an antioxidant enzyme known as catalase. It was an important observation that helped explain why cancer cells are especially vulnerable to the highly reactive molecules formed by radiation. Warburg soon proposed a catalase-focused therapy that would leave cancer cells still more vulnerable to reactive molecules. Warburg’s specific treatment was far-fetched, and his contribution to this area of research has been forgotten. But it would prove to be another example of his remarkable foresight. A 2017 review paper on catalase noted that many new drugs are now being investigated with the hope of treating cancer by targeting the balance between reactive molecules and antioxidants in cancer cells. Some 60 years after Warburg proposed the idea, the article stated that “modulating catalase expression is emerging as a novel approach to potentiate chemotherapy.”1
Warburg even made efforts to keep up with new science on occasion. One colleague recalled meeting with Warburg in the early 1960s and telling him about his recent work on proteins. Warburg, who would have been about 80, peppered this colleague with detailed questions, continuing the conversation long after Heiss had announced that lunch was ready.
The questioning may have been as much a show of dominance as of interest. A researcher working under Hans Krebs in England recalled the day in 1965 that Krebs arrived at his lab in a pin-striped suit. Krebs tried to deny that his attire was unusual but finally showed the young researcher a telegram he had received from Warburg. As the researcher remembered it, the telegram said, “I want you to come to Berlin. I have a new theory. I do not want your opinion. I want an audience.” Krebs, then in his mid-60s, flew to Berlin, spent a day listening to Warburg, then immediately got back on a plane and flew home.2
Warburg made his dominance known in other ways as well. Peter Ostendorf recalled that when not at his laboratory bench, Warburg could be found in his library, sitting before his typewriter at the head of the long wooden table in the center of the room. If the door was closed, it was understood that Warburg was not to be bothered. But even if the door was open, you could not interrupt Warburg, who would sometimes be gazing out the window at his institute’s garden. The only thing to do was wait. “You would stand there,” Ostendorf recalled, “rustling your papers or clearing your throat, hoping to get noticed.”3
This was the man Warburg had always been. He was sitting in the same spot in his Dahlem institute he had sat in during the 1930s, when he had refused to change his ways even when his life was in danger. But when Warburg looked out of the window of his library in the 1960s, there was one difference to the scene. After the war, Warburg had erected a statue of Emil Fischer, the man who had taught Warburg organic chemistry.
BY THE TIME Warburg arrived in Fischer’s Berlin lab in 1903, the older man had already made one of the greatest discoveries in the history of science: he had unlocked the secrets of carbohydrates.
Carbohydrates are formed from sugars. Glucose, a simple sugar, is the most ubiquitous and most central to life. It is the sugar made by plants during photosynthesis, and it is kept within a carefully regulated range in the body of every animal at all times. But the driving force behind Fischer’s interest in sugars was not glucose. In the late nineteenth century, virtually all Germans were interested in sucrose, or “table sugar”—the sugar that sweetens so many of our foods and drinks. (Both glucose and sucrose were—and still are—colloquially referred to as “sugar.” In the pages that follow, “sugar” will refer to sucrose unless otherwise indicated.)
The German sugar story can be traced to the middle of the eighteenth century, when the Berlin chemist Andreas Marggraf gazed down at a solution of pulverized beets under his microscope and noticed something intriguing. The crystalline structures he observed looked remarkably similar to the crystalline structures found in pulverized sugarcane. It wasn’t a total surprise. The juice from the beets, Marggraf knew, tasted like the sweet juice from sugarcane. But knowing that the two different plants contained the identical chemical was an important breakthrough. Cane sugar was already an enormous global industry. If sugar could be extracted from beets, it had the potential to change the world economy.
Only there was a problem: Marggraf could obtain very little sugar from each beet. It took decades of technological advances before beet sugar could be extracted and refined efficiently. Napoleon, who hoped to wean his empire off of sugar exports from the British colonies, would become the first great champion of the beet sugar industry. (A satirical cartoon from 1811 depicts Napoleon haughtily squeezing a beet over his coffee.) But over the course of the nineteenth century, the Germans would come to dominate the beet sugar industry. Prussian Saxony, it turned out, had the ideal soil for growing beets.4
As German beet sugar production increased, so, too, did German sugar consumption. In 1800, a typical German ate about 1 pound of sugar a year. When Fischer turned to sugars in the 1880s, Germany was supplying almost a third of the world’s sucrose supply, and the typical German was consuming 15 pounds a year. (The English and Americans were already eating far more sugar than the Germans.) Once a luxury item, sugar—in coffee and tea and cocoa and jam and pastries—became a daily indulgence and sometimes a substitute for meat and fats. The candy, ice cream, chocolate, and soft drink industries all stem from the mid-nineteenth century, as does the expectation of a sweet dessert at the conclusion of every lunch and dinner.5
But though sugar was suddenly everywhere, it was still not well understood. Chemists mistakenly thought that all sugars were merely carbon atoms attached to molecules of water—hence the name “carbohydrates.” By Fischer’s day, it was known that sugars were formed out of varying arrangements of carbon, hydrogen, and oxygen atoms. Chemists even knew the basic recipe of glucose: 6 atoms each of carbon and oxygen and 12 of hydrogen. But how, precisely, the atoms of carbon, hydrogen, and oxygen were arranged in each different sugar was still anyone’s guess. Sugars had been lumped together as a group simply because they tasted sweet and could support fermentation. As late as the 1870s, a leading chemist referred to theories of how molecules are arranged in space as “fancy trifles” that “are completely incomprehensible to any clear-minded researcher.”6
To make any progress, Fischer would need to isolate pure crystals of the different sugars, but neither he nor anyone else knew how to do that. The problem chemists of the era faced is familiar to anyone who has eaten pancakes: crystals are solids, but sugars tend to form syrups. Fischer’s first breakthrough involved some luck. Like so many of the great German chemists of his generation, he had begun his career working on dyes. While doing so, he synthesized a compound, phenylhydrazine, that gave him a pale-yellow solution. It looked like urine. Fischer moved on, never imagining he would return to the seemingly worthless liquid in his glass beaker.7
But in the mid-1880s, Fischer discovered that phenylhydrazine was able to do one very important thing: it could react with sugars and give rise to the pure crystals he needed to move ahead with sugar chemistry. It was only a first step. And in the hands of an ordinary chemist, such crystals would have been far less significant. But Fischer—a man who turned to chemistry only after his father declared him “too stupid to be a businessman”—was far from an ordinary chemist. With the pure crystals at his disposal, Fischer could subject them to a litany of chemical tests to glean new insights about the nature of the bonds. Soon he was synthesizing new sugars from scratch. Out of a sticky goo emerged an entire class of organic molecules. As Yale chemist Frederick Ziegler once put it, Fischer’s work on the structure of sugars was to organic chemistry “what Newton and Einstein were to physics.” Another chemist once compared Fischer’s analysis of sugars to “Shakespeare.”8
Among the many sugars Fischer worked on was fructose, a sugar, as the name indicates, that can be found in fruits. Chemists before Fischer had already determined that fructose was similar, but not quite identical, to glucose. The two simple sugars rotated light waves in opposite directions, and fructose was slightly sweeter than glucose. Fischer could now explain why fructose and glucose were so similar and yet so different. The two molecules have the identical number of carbon, oxygen, and hydrogen atoms. The difference between glucose and fructose is only a matter of how the atoms are arranged.
Though glucose and fructose can be found apart, the two molecules can also bond to each other. When that happens, the result is sucrose, the sugar we add to our foods and drinks. Fischer could not figure out exactly how glucose and fructose bond to form sugar. That discovery would be left to other scientists after Fischer committed suicide in 1919. Though he had cancer, it is also believed that Fischer was dying from his long-term exposure to phenylhydrazine. The molecule that revealed the true nature of sugars turned out to be a poison.
Fischer’s poisoning is not the only sad irony of his story. His work on sugars changed his field, and yet the full implications of his findings would be absorbed only slowly into the bloodstream of modern medicine. When it came to nutrition and disease, sugars would remain a sticky mess for decades to come.
WHILE FISCHER AND others worked to understand how fructose and glucose bonded to form sugar, some medical thinkers of the era were taking note of something else having to do with sugar: the more refined sugar that people ate, the more likely they seemed to develop diabetes and cancer. In 1902, the British biochemist Robert Plimmer spent a year in Fischer’s Berlin lab, leaving just before Warburg arrived. Two decades later, Plimmer and his wife, Violet, published Food and Health, a popular nutrition guide. “Not so very long ago sugar was a rare luxury kept under lock and key in the tea caddy,” the Plimmers wrote. But with the rise of German beet sugar and falling prices, the consumption of sugar had “increased enormously” and was “still increasing in all civilised countries.” They added, “Incidentally, cancer and diabetes, two scourges of civilisation, have increased proportionately to the sugar consumption.”9
The possible connection between sugar and diabetes was always more apparent than any connection between sugar and cancer. Hindu physicians discovered that the urine of diabetics was sweet as far back as the sixth century CE. In the United States, the person who saw the emerging diabetes epidemic most clearly—and connected it to sugar most convincingly—was Haven Emerson, the father of Warburg nemesis Robert Emerson and the onetime commissioner of the New York City Department of Health. Diabetes was not only on the rise, Emerson wrote in 1924, but over the previous 50 years it had increased more rapidly than any disease for which there were records.
Though he was not certain whether refined sugar from cane and beets was dangerous because of its unique impact on metabolism or because it was merely a source of excess calories, Emerson was certain that Americans were endangering their health: “Do we need to eat three times as much sugar each year as our grandparents did?”10
Emerson was able to show that sugar consumption in the West had risen together with diabetes beginning in the nineteenth century and also that when sugar consumption fell during World War I, diabetes rates in the following years fell as well. But no matter how closely the trends overlapped, it was still only a correlation. Elliott Joslin, the leading American authority on diabetes, looked at the same evidence as Emerson and remained unconvinced. Joslin understood that diabetics needed to avoid sugar and other carbohydrates to keep their blood sugar (glucose) under control, but that didn’t mean that sugar was responsible for causing the disease in the first place.
Joslin’s skepticism was largely based on a single observation. The Japanese diet, he noted in 1923, consisted “largely of rice and barley,” and yet diabetes was “not only less frequent but milder in that country.” The Japanese example, Joslin said, “would seem to save us from [the] error” of blaming sugar for diabetes.
It was a simple point, but Joslin himself had made a critical error. The Japanese were consuming lots of glucose in the form of rice and barley, but not lots of sugar, or sucrose—glucose bonded to fructose. It was a strange oversight, given that Joslin knew that fructose comprised half of sugar. If Joslin was glossing over the difference between sucrose and glucose, it was likely because he believed that the fructose half of sugar was harmless.11
Elliott Joslin would prove far more influential than Haven Emerson or anyone else who believed that refined sugar might be causing diabetes. And if the leading medical thinkers of the era were not ready to tie diabetes to sugar, it was all the less likely that they would be ready to tie cancer to sugar. The doctors most inclined to make the connection tended to be those who had traveled to faraway regions to treat indigenous populations. Sir Robert McCarrison, marveling over the absence of cancer and other ailments among the Hunza of the Himalayas, noted in 1921 that the amount of sugar coming into the country in a single year was seemingly less than what was consumed in a single day in a “moderately sized hotel” in Pittsburgh.12
A handful of researchers continued to point out the suspicious correlations between sugar and cancer deaths in the second half of the twentieth century. The British physiologist John Yudkin would prove the most outspoken. (Though his 1972 book, Pure, White and Deadly, is only about sugar and nutrition, Yudkin, who served in the Royal Army Medical Corps during World War II and whose wife escaped Nazi Germany in 1933, perhaps couldn’t resist a title that sounded like a warning about Nazism.)
Yudkin’s own research found that both breast and colon cancer rates in a given country would rise in accordance with how much sugar the population consumed. As Yudkin readily acknowledged, such comparisons say nothing about cause and effect, but “only provide clues as to possible causes.” But the clues were gradually piling up. More arrived in 1975 when Richard Doll looked into the relationship between cancer and sugar consumption across different countries and found that sugar could be tied to a number of other cancers, including those of the prostate, ovaries, uterus, rectum, testicles, and kidneys. A few years later came a review of sugar consumption and breast cancer deaths in women over 65. The five countries with the most deaths turned out to be the very five countries that consumed the most sugar. The five countries with the fewest deaths, in turn, were the five countries that consumed the least amount of sugar.13
These studies, however inconclusive, might have led to a sugar scare, given that far less compelling evidence would regularly lead to panics over synthetic chemicals. At approximately the same time the evidence linking sugar to cancer was emerging, the United States cracked down on artificial sweeteners based on studies that found that rats consuming extraordinary quantities were more likely to develop bladder cancer. (The studies were later found to be irrelevant to humans.)
When it came to the natural ingredients in the Western diet, it was not the refined sugar added to our diets but meat and animal fats that would be singled out as potentially dangerous. Mice fed high-fat diets did develop cancer more readily, but the evidence said to support the relationship in humans—for instance, that migrating to the United States made Japanese women much more likely to develop breast cancer—might just as easily have been used in support of the sugar hypothesis. Americans, after all, typically ate both far more sugar and far more animal fat than the Japanese.
The animal fat hypothesis faced other problems as well: up until the early twentieth century, there were societies across the world—the Inuit of the Arctic, various Native American tribes of North America, the Maasai of Africa—where cancer was rare even though meat and fat were staples of the diet. Much later, a series of large-scale studies in the 1980s and 1990s failed to turn up evidence that dietary fat caused cancer.
Though some, like Yudkin, would continue to sound the alarm about sugar, it made little difference. The belief that animal products were the true threat had crystallized into accepted wisdom as readily as if it had reacted with Fischer’s phenylhydrazine. Consumption of refined sucrose from sugarcane, beets, and corn (in the form of high-fructose corn syrup, which is essentially identical to sugar from cane and beets) would continue to increase in one country after another, decade after decade. By the first years of our current century, the average American, by conservative estimates, was swallowing more than 90 pounds of sugar a year—not including the natural fructose from fruits. (The glucose and fructose consumed together in whole fruits, though potentially still fattening, are generally considered less problematic than refined sucrose because the molecules are absorbed more slowly and lead to less dramatic spikes of glucose and insulin in the blood.)14
Given the evidence already available in the 1970s, it’s difficult to understand why sugar was not considered at least as likely to cause cancer as animal fats. But then, Joslin and others had long ago cleared sugar of any metabolic wrongdoing based on evidence concerning only glucose. Once again, it seemed, everyone had forgotten that glucose and sugar were not the same thing, that glucose had a twin.
Otto Warburg, around 1965.
Otto Warburg and West German President Theodor Heuss by statue of Emil Fischer, 1953.
