The Nobel laureate Otto Warburg―a cousin of the famous finance Warburgs―was widely regarded in his day as one of the most important biochemists of the twentieth century, a man whose research was integral to humanity’s understanding of cancer. He was also among the most despised figures in Nazi Germany. As a Jewish homosexual living openly with his male partner, Warburg represented all that the Third Reich abhorred. Yet Hitler and his top advisors dreaded cancer, and protected Warburg in the hope that he could cure it.
In Ravenous, Sam Apple reclaims Otto Warburg as a forgotten, morally compromised genius who pursued cancer single-mindedly even as Europe disintegrated around him. While the vast majority of Jewish scientists fled Germany in the anxious years leading up to World War II, Warburg remained in Berlin, working under the watchful eye of the dictatorship. With the Nazis goose-stepping their way across Europe, systematically rounding up and murdering millions of Jews, Warburg awoke each morning in an elegant, antiques-filled home and rode horses with his partner, Jacob Heiss, before delving into his research at the Kaiser Wilhelm Society.
Hitler and other Nazi leaders, Apple shows, were deeply troubled by skyrocketing cancer rates across the Western world, viewing cancer as an existential threat akin to Judaism or homosexuality. Ironically, they viewed Warburg as Germany’s best chance of survival. Setting Warburg’s work against an absorbing history of cancer science, Apple follows him as he arrives at his central belief that cancer is a problem of metabolism. Though Warburg’s metabolic approach to cancer was considered groundbreaking, his work was soon eclipsed in the early postwar era, after the discovery of the structure of DNA set off a search for the genetic origins of cancer.
Remarkably, Warburg’s theory has undergone a resurgence in our own time, as scientists have begun to investigate the dangers of sugar and the link between obesity and cancer, finding that the way we eat can influence how cancer cells take up nutrients and grow. Rooting his revelations in extensive archival research as well as dozens of interviews with today’s leading cancer authorities, Apple demonstrates how Warburg’s midcentury work may well hold the secret to why cancer became so common in the modern world and how we can reverse the trend. A tale of scientific discovery, personal peril, and the race to end a disastrous disease, Ravenous would be the stuff of the most inventive fiction were it not, in fact, true.
Ravenous will be available on May 25, 2021, and is currently available for pre-order.
Summary and excerpt courtesy of Sam Apple and Liveright Publishers.
Sugar is not the entire story of insulin resistance. Any carbohydrate that is rapidly digested—beer or bread, pasta, and cereals made with refined flour—will also spike glucose and insulin levels. If fat is eaten together with these carbohydrates, the insulin spike will lead that fat to be stored rather than burned, and that dietary fat, too, will contribute to the “overload” problem. But nothing appears to drive the first stages of the process quite like refined sugar. Drinking sugar—in soda or fruit juice—is thought to be worst of all.
Lewis Cantley, the scientist who pioneered the study of how insulin activates the pathways linked to cancer, is among the researchers who have grown alarmed about sugar. Cantley does not write popular books or articles. He has received several of the highest honors in his field, including the 2015 Canada Gairdner International Award, often a prelude to a Nobel Prize. Cantley, in other words, could hardly be more different from the diet doctors on TV or on the cover of magazines in the grocery store. But he has stopped eating sugar himself for a simple reason. His research has led him to the conclusion that today’s “high consumption of sugar” is “almost certainly responsible for the increased rates of a variety of cancers in the developed world.”
Cantley reached this conclusion based on the evidence connecting refined sugar to elevated insulin, and elevated insulin to cancer. But in Cantley’s mouse model of colorectal cancer, he found an even more direct relationship between sugar, in the form of high-fructose corn syrup, and cancer. Mice that were genetically engineered with mutations associated with colorectal cancer and then given a daily serving of sugar equivalent to the amount in a can of soda developed cancers that grew faster and bigger than mice that did not consume the sugar. The fructose in the sugar, Cantley saw, could both turn on the Warburg effect and provide the building blocks for fat molecules that the cancers use to grow. “The evidence,” Cantley said, “really suggests that if you have cancer, the sugar you’re eating may be making it grow faster.”
While most of the fructose in sugar ends up in the liver, Richard Johnson, a fructose expert at the University of Colorado, explained that fructose can be metabolized by other tissues. He said that fructose appears to be able to directly fuel not only colon cancer but also cancers of the breast, lung, and pancreas. Though Johnson does not argue, as Warburg did, that cancer stems from a problem of cellular breathing, he believes that fructose is the “perfect food” for a growing cancer precisely because it helps cancer cells to survive in the low-oxygen environments. This can be especially important when a cancer spreads to a new location and doesn’t yet have a reliable blood supply to provide oxygen. “If you want to make a cancer happy,” Johnson said, “feed it fructose.”
According to Johnson, the same phenomenon can be seen in animals, like the naked mole rat, that live in low-oxygen environments. In their underground homes, the mole rats have less air than most animals could ever tolerate. They manage by converting a portion of their meals into fructose, which in turn increases fermentation and makes the mole rats less dependent on respiration. For the mole rats, fructose is necessary for survival. And that we crave the taste of fructose suggests that our primate ancestors benefited from it as well. Johnson, in collaboration with the anthropologist Peter Andrews, has put forward a hypothesis that we evolved from prehistoric apes that migrated from Africa to Europe and back. In Europe, these apes initially managed to find fruit for much of the year, but around 12 million years ago, Johnson and Andrews suggest, a cooling period set in that left the apes facing long winters with very little food.
As the apes starved, the capacity to store even a little extra fat was the difference between life and death. Both genetic and fossil evidence suggest that it was during this period of starvation that a mutation arose in the gene coding for the enzyme uricase. While fructose could already be converted to fat in these apes, the uricase mutation made fructose all the more fattening. During a long period without food, survival of the fittest, Johnson wrote, became “survival of the fattest.”
Cantley and Johnson are only two of a growing number of researchers who are alarmed about sugar and cancer. Michael Pollak, who runs the Division of Cancer Prevention at McGill, is another. “Glucose or fructose-based drinks are really among the most unhealthy foods that you could imagine,” Pollak said. It’s okay to have a little sugar, but it should be consumed like a condiment, “in the same way we have pepper.”
Precisely how much sugar is too much may be different for each person, depending on one’s genes and age and exercise habits and capacity to store fat safely. But the path from the refined sugar added to our diets to insulin resistance, and from insulin resistance to cancer, is now well understood and based on widely accepted science. For that reason, the science journalist and author Gary Taubes believes that sugar can be thought of as “a primary cause” of cancer and other diseases linked to insulin resistance and elevated insulin.
Taubes, who studied physics at Harvard and engineering at Stanford, has spent the last 20 years researching and writing about the links between insulin, obesity, and the chronic diseases associated with the modern Western diet. He does not claim with absolute certainty that eating lots of sugar leads to these diseases, only that it is the simplest answer that fits with all of the available evidence and so, according to the principle of Occam’s razor, should be considered the most likely explanation.
“Too much sugar” might be the simplest explanation for the many obesity-linked cancers, but it is not a simple explanation. It is an idea built upon more than a century of science. Scientists had to figure out, among many other things, how fructose is converted to fat; how fat in our muscles and liver and other organs interferes with insulin signaling; how the pancreas responds by pumping out more insulin; how elevated insulin activates the Warburg effect and other molecular pathways within cancer cells; and how those pathways keep fledgling cancers alive and well nourished.
Warburg’s devotion to “simple” explanations was unrivaled. He liked to cite the wisdom of William Bayliss, an English physiologist who wrote in 1924 that the “truth is more likely to come out of error, if this is clear and definite, than out of confusion” and also that “it is better to hold a well-understood and intelligible opinion, even if it should turn out to be wrong, than to be content with a muddle-headed mixture of conflicting views, sometimes miscalled impartiality, and often no better than no opinion at all.”
Otto Warburg did not live long enough to see the most convincing evidence linking sugar to the strange metabolism of cancer cells that he discovered. Even if he had, it is unlikely he would have budged from his own oxygen-focused explanation. Warburg, alas, did not absorb another lesson from Bayliss that appears at the bottom of the very same page of his 1924 book: “It is not going too far to say that the greatness of a scientific investigator does not rest on the fact of his having never made a mistake, but rather on his readiness to admit that he has done so, whenever the contrary evidence is cogent enough.”
In the case of sugar and metabolic diseases, there is contrary evidence. Skeptics have argued that if sugar is truly the driving force behind America’s obesity and diabetes epidemics, the rates of these conditions should have gone down in recent years, given that sugar consumption has declined of late in response to warnings about the danger it poses. Whether this argument is “cogent enough” is worth exploring, but as Taubes has pointed out, Americans today are still eating sugar in quantities that would have been unthinkable a century ago—a time at which Haven Emerson was already pointing out that Americans were eating vastly more sugar than their grandparents ever had. As Taubes sees it, to suggest that sugar is not responsible for metabolic diseases based on current trends would be like cutting back from 20 to 17 cigarettes a day and then concluding that smoking could not be responsible for lung cancer if the rate did not fall.
The smoking parallel might also explain why the connection between sugar and cancer can be so hard to accept. Although the definitive studies linking smoking to lung cancer were only carried out in the 1950s, smoking should have been the most obvious suspect long before then. A British physician had connected inhaling snuff to cancer of the nose by 1761. By the end of the eighteenth century, it was known that chimney sweeps developed cancer of the scrotum and that cancer of the lip was more common among pipe smokers. Lung cancer, meanwhile, had become far more common after cigarette smoking had become far more common, and it was understood that cigarette smokers inhaled carcinogens more deeply into the lungs relative to pipe smokers.
As a medical student, Richard Doll himself had become interested in the connection between pipe smoking and oral cancers. And yet Doll—like most British and American doctors of the mid-twentieth century—couldn’t fathom that cigarettes were behind the emerging lung cancer epidemic until his own studies finally provided overwhelming evidence. As Doll once explained, the problem was that “cigarette smoking was such a normal thing and had been for such a long time.” It “was difficult to think it could be associated with any disease.”
In 2016, Cantley said that we may someday “view this era of massive addiction to sugar in America in the same way that we now view the period of massive addiction to tobacco.” In the meantime, almost everyone agrees that we need far more research on the health effects of sugar. Nearly 100 years ago, Elliott Joslin pointed out that if Americans were dying of infectious diseases like typhoid or scarlet fever at the rates they were dying of diabetes, there would be a rapid government response “to discover the source of the outbreak.” The same point could have been made about cancer.
Many different debilitating conditions appear together with insulin resistance. Our numbness to the suffering they cause might, in the end, be the most debilitating condition of all.
Sam Apple is the author of Ravenous: Otto Warburg, the Nazis, and the Search for the Cancer-Diet Connection. Apple is on the faculty of the MA in Science Writing and MA in Writing programs at Johns Hopkins. Prior to his arrival at Johns Hopkins, Apple taught creative writing and journalism at the University of Pennsylvania for 10 years. Apple has published magazine features, short stories, and personal essays on a wide range of topics. In recent years, he has primarily written about science and nutrition. His work has appeared in The New York Times Magazine, The New Yorker, The Atlantic, Wired, The Los Angeles Times, The Financial Times Magazine, ESPN The Magazine, The MIT Technology Review, and McSweeney’s, among many other publications.
This content was originally published here.