An Old Idea, Revived: Starve Cancer to Death
Published by Tim Ferris This post is very exciting for me.
It covers a subject I care deeply about (cancer), and it’s exclusive, unpublished material from a New York Times Magazine feature entitled “An Old Idea, Revived: Starve Cancer to Death.” Written by Sam Apple, this piece got a lot of attention.
Now, here on this blog, you can read what didn’t make it in.
First, some context and definitions are in order, as I can’t reproduce the NYT piece in full. Let’s set the tone with a few paragraphs from a previous cancer-related post with Peter Attia, MD. These words are mine:
Moving on to definitions, the most important is the “Warburg Effect.”
Below is a summary from the same Dr. Attia piece, and the words are his this time. Citations can be found in the original:
How can we capitalize on these apparent defects?
Researchers will continue to debate the causes of cancer and best treatments, but–in the meantime–there appear to be promising dietary interventions we can use with little to no downside. I’m no doctor, nor do I play one on the Internet, but that’s my current conclusion.
I’ll let Sam pick up the thread from here. Any comments in brackets are mine. Enjoy!
Enter Sam Apple
Hello, Tim Ferriss readers. I’m writing here today because I recently wrote a feature for The New York Times Magazine on Otto Warburg and the revival of cancer metabolism research.
I’m happy about how the piece turned out and very flattered by the kind responses I’ve received. But, as is almost always the case when I publish magazine articles, a significant portion of what I wrote never made it into print. That’s the bad news. The good news is that Tim has been nice enough to offer to publish some of the snippets that the Times didn’t have enough space for. As his loyal fans will know, Tim has been at the forefront of this story for a long time, so I’m really delighted to be able to contribute to this blog.
Another bit of good news: I’ve recently heard from some editors at publishing houses who are interested in a book on this topic. If you’d like to be notified if and when the book becomes available, please email me at samapple.update [at] gmail.com with “book” as the subject.
Okay, enough chitchat. Let’s get to the science…
The Ketogenic Diet
I’ve received a number of emails asking why I didn’t mention the ketogenic diet in my article. After all, if the aim of metabolic therapies is to disrupt cancer’s use of nutrients, it follows that a diet that lowers glucose and insulin levels may be beneficial. In fact, I had discussed the ketogenic diet and the fascinating research being carried out by Thomas Seyfried and Dominic D’Agostino, among others, in my original draft. Here’s a passage that got lost along the way:
On the surface, the strategy of using drugs to cut off a tumor’s supply of nutrients is not unlike the strategy advocated by Thomas Seyfried, at Boston College, who is the author of Cancer as a Metabolic Disease. Seyfried is among the few researchers who believe Warburg got the whole story right and that cancer originates with the cell’s inability to produce sufficient energy with oxygen. Other researchers aren’t seeing the damage to respiration, Seyfried argues, because they’re looking at cancer cells outside of the body and failing to appreciate that cells in culture behave differently. Warburg “had this thing pegged,” Seyfried says.
Unlike most cancer metabolism researchers, Seyfried is primarily focused on non-toxic therapies, particularly the ketogenic diet, which has been used as a therapy for epilepsy for decades. The ketogenic diet is a high-fat, very low-carbohydrate diet, though Seyfried believes the diet also has to restrict calories to be effective against cancer. Without access to carbohydrates, which breakdown to glucose, the liver turns to fat and produces ketone bodies, an alternative fuel source that very few cancers are able to use.
[TIM: On such a diet, 95%+ of the ketones produced are derived from beta-oxidation of fatty bodies. A small % comes from ketogenic amino acids (AAs) such as leucine and lysine. That said, a high-protein diet doesn’t work well for inducing ketosis, as the liver will convert AAs into glucose via the process of gluconeogenesis.]
Seyfried, together with Dominic D’Agostino of the University of South Florida College of Medicine [TIM: Dom’s advice has led me to conduct monthly fasting experiments], is now investigating the combination of ketogenic diets and non-toxic therapies. When Seyfried, D’Agostino, and colleagues combined a ketogenic diet with hyperbaric oxygen treatment (HBOT) in a mouse model of aggressive metastatic brain cancer, they were able to dramatically shrink tumors and increase the average survival time from 31.2 days for mice on a standard diet to 55.5 days, a significant increase for an advanced cancer.
[TIM: For HBOT protocol, Dominic used 2.5 Atmospheres (2.5A) for 60 minutes on Mon, Wed, and Fri. Including pressurization and depressurization, each session was ~90 minutes.]
When they did the experiment again and added synthetically made ketone supplements to the non-toxic therapies, the results were even better [TIM: Here’s the study. Dominic adds, “Therapeutic ketosis with hyperbaric oxygen targeted tumor metabolism while simultaneously inducing oxidative damage in cancer cells by triggering an overproduction of oxygen free radicals”]. “Everybody’s always saying, ‘We want something that targets the cancer cell but spares the normal cell,’” Seyfried says. “The ketogenic diet does that.”
More on Diet, Glucose, and Insulin
Insulin, among its other roles in the body, tells a cell to take up glucose, a fact that makes it a natural suspect for a connection to the Warburg effect. When insulin resistance develops, cells are no longer as responsive to insulin, and the pancreas responds by producing more and more, at least until it wears out and diabetes begins to develop.
Too much insulin signaling and glucose uptake aren’t necessarily a problem for all cells, at least when it comes to cancer. Muscle and fat cancers may be extremely rare because the cells of those tissues have a way to store excess glucose and don’t need to metabolize it right away. Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, thinks the same would be true of liver cancer, if not for inflammation from hepatitis infections. Breast, endometrial, and colon cells, by contrast, are rarely exposed to insulin signaling under normal conditions. “It’s a little scary to think that those pathways are getting turned on by 50 times higher insulin in your serum, 24-hours a day,” says Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College.
It was Cantley who brought the worlds of insulin signaling and cancer metabolism research together with his discovery of the of the enzyme phosphoinositide 3-kinase (PI3K) in the mid-1980s. PI3K is part of a pathway of proteins that regulates the effects of insulin and IGF-1 (a closely related hormone) inside of a cell. When Cantley made his initial discovery, it wasn’t immediately obvious that it had implications for cancer, though by the end of the decade Cantley had become convinced he was onto something significant. The rest of the cancer community began to pay attention in the late 1990s, when other researchers discovered that PTEN, the tumor suppressor gene that has the job of slowing the PI3K pathway down — Cantley calls it “the braking system for PI3K” — is one of the most commonly deleted genes in many cancers. Mutations in the PI3K pathway have since been found in up to 80 percent of all cancers. These are the same cancers that use the Warburg effect and show up on PET scans.
According to Cantley, the PI3K pathway can be activated by mutations even when there is no extra insulin around or by extra insulin even when mutations haven’t yet appeared. But there’s reason to think that long-term elevated insulin, driven by diet, is often the first step in the process. Once the cells begin to take up more and more glucose, Cantley explains, they also produce more and more reactive oxygen species, or free radicals, which can lead to mutations — including mutations in the PI3K pathway. These mutations can further accelerate glucose uptake until the cell no longer even needs the insulin to obtain its steady influx of glucose.
Thompson found his interest turning to PI3K pathway upon his discovery of the role of AKT in regulating glucose uptake. AKT is part of the same pathway as PI3K, which is now also referred to as the PI3K/AKT pathway. That insulin signaling could be driving many cancers fit perfectly with Thompson’s research. Thompson had discovered that cells are supposed to be able to carefully control when other cells eat. The bombardment of insulin and IGF-1 signaling makes a mockery of that delicate regulation.
It’s also possible that, in some cases, insulin resistance contributes to cancer only indirectly, by causing the pancreas to peter out and stop producing enough insulin. When that happens, glucose levels rise in the blood and diabetes begins to set in. Whether it’s the elevated insulin or the elevated glucose that follows that’s driving the growth of tumors can be difficult to tease out. Matthew Vander Heiden, a leading cancer metabolism researcher at MIT, says that whether insulin or glucose is playing a more important role may depend on the given cancer. “Both probably contribute,” he says.
[TIM: This is one reason I tend to avoid not only high glycemic-load foods (the usual carb-rich suspects), but also insulinemic (insulin-spiking) foods that fly under the radar due to low glycemic load/index, including many types of dairy and non-caloric sweeteners. Explanations for the latter range from bitterness to microbiome impact.]
Other Top Cancer Metabolism Researchers and a Note of Caution
Writing an article of this nature is always a bit of a balancing act. On the one hand, I’m genuinely enthusiastic about the Warburg revival and think it holds enormous promise for cancer treatment, and, in particular, the role of diet in cancer prevention. But with respect to treating most cancers, there remains a long way to go before we’ll know if metabolic therapies live up to their promise. Many of the researchers I spoke with see a future of metabolic therapies used in conjunction with other therapies. And while almost everyone I talked to was optimistic about the future of metabolism drugs, a number of the researchers stressed the challenges ahead.
Matthew Vander Heiden of MIT (mentioned above), studies the biochemical pathways that cells use to fuel their growth. He believes that targeting metabolism might leave tumors with fewer opportunities to evade treatments than targeting mutations, but also stresses that metabolism is extremely complicated. “I really push the idea that there’s not one cancer metabolism,” says Vander Heiden, noting that a liver cell that becomes a tumor might require different metabolic changes than a lung cell that becomes a tumor.
David Sabatini of MIT’s Whitehead Institute, also struck a note of caution during our conversation. Sabatini discovered the mechanistic target of rapamycin (mTOR) while still a graduate student at Johns Hopkins. The mTOR pathway is a critical regulator of growth in many species, but despite — or perhaps because of — his significant contribution to the field, Sabatini has come to appreciate the many challenges cancer metabolism researchers still face: “Pathways,” according to Sabatini, “can go in many, many different directions and change very, very quickly.” Sabatini says that he currently sees the most hope for therapies that are able to target cancer cells where they differ from other proliferating cells, which can also turn to the Warburg effect when growing.
Peter Attia, a prominent doctor who spent two years as a surgical oncology fellow at the National Cancer Institute [in Steve Rosenberg’s immunotherapy lab] and served as the president of the Nutrition Science Initiative, has been publicly drawing attention to the promise of metabolic therapies for a number of years on his blog, The Eating Academy. But Attia also told me that it’s naïve to assume that metabolic therapies are going to be “the Holy Grail.” “We have to give cancer a hell of a lot more respect than that,” Attia says. Attia sees a future where chemotherapy, and perhaps also radiation for local control, remain in the arsenal but are accompanied by immune-based therapies, possibly hyperbaric oxygen, and “huge amounts of metabolic therapy” — including dietary changes. “I think that at that point you can turn cancer into a chronic disease,” says Attia [TIM: I spoke with Peter and he added “Basically, think of HIV. You die with it, perhaps, but not necessarily from it.”]. “You’ve got to be able to exploit every weakness.”
I was also sorry that I didn’t have more room to discuss the work of Peter Pedersen, a biochemist at Johns Hopkins, who was among the relatively few cancer researchers who continued to pursue Warburg’s ideas about tumors and energy long after they fell out of fashion. Pedersen still remembers the day, around the time he came to Johns Hopkins in 1964, that he spotted parts of a device known as a Warburg apparatus left out in the hallway with the trash. The Warburg apparatus, which measures respiration, had already been replaced by more modern technology, but the symbolism was hard to miss. According to Pedersen, there was already “little or no interest” in Warburg at the time. (Pedersen also wanted me to flag that the critical research on 3-bromopyruvate was carried out by Dr. Young Ko.)
More on Otto Warburg and the Nazis
While working on the history portion of my article, I received extremely valuable assistance from Petra Gentz-Werner, who has written several books about Warburg in German. Here’s a bit more detail on Warburg, including the story of how Hitler’s inner circle protected him:
Warburg was a short, handsome man with penetrating blue eyes. He had a deep knowledge of literature and history and became a lifelong Anglophile after a visit to Cambridge as a young man — he collected antique English furniture and would travel to England to buy his suits. In his written reflections on meeting Warburg at his institute in Berlin, the German biochemist Theodor Bücher recalled Warburg’s elegant woolen waistcoat, gray tweed trousers and carefully polished Scottish shoes.
Why Warburg took an interest in cancer as a young man is not entirely clear. In his slim biography of Warburg, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab as a young man, writes that Warburg first became interested in cancer while still a medical student after becoming aware of the “ravages” of the disease and the lack of successful treatments. But cancer was likely on Warburg’s mind for the same reason it was likely on Boveri’s mind at the time. In the early 20th Century, the prevalence of cancer in Germany was greater than in almost any other nation and rising rapidly
That Warburg believed he would be the one to cure cancer was an early sign of what would later become an almost legendary arrogance. Dr. Richard Veech, a metabolism researcher at the National Institutes of Health, who did his doctorate at Oxford in the lab of Hans Krebs, remembers the day the then 65-year-old Krebs, a world-renown scientist, showed up in the lab in his pinstriped suit. Warburg had just sent Krebs a telegram telling him to come to Berlin. “I do not want your opinion,” Warburg wrote. “I want an audience.” Krebs spent two days listening to Warburg’s theory then flew back to England.
Of course, Warburg was the rare megalomaniac whose belief in his own greatness was fairly well founded. Warburg enlisted in the Germany military upon the outbreak of World War I, serving as a physician and an assistant to a senior officer in a cavalry regiment that fought on the front lines. In 1918, Einstein, prompted by Warburg’s mother, sent Warburg a letter in which he urged him to come home. In making his case, Einstein suggested to Warburg that his survival was important to the future of German physiology, and Einstein, as usual, turned out to be right. Warburg would return to Berlin and go on to become perhaps the greatest biochemist of the 20th century, making enormous contributions not only to the study of cancer, but also to the study of photosynthesis and metabolic enzymes.
[Skipping ahead here so as not to republish material from The Times] Still, the most remarkable fact was not that the Nazis prevented Warburg’s award but that Warburg was alive and well in Nazi Germany in 1994. The Nazis began purging universities and academic institutes of Jewish scholars as early as 1933, but Warburg, despite his Jewish ancestry, was left almost entirely unbothered. Worse yet for Warburg’s prospects in Nazi Germany, he lived with another man, Jakob Heiss. After serving in World War I, Heiss, according to Krebs, moved in with Warburg to “keep house” and then never left. Krebs writes that the two were “virtually inseparable.”
It certainly helped that Warburg was already a famous scientist and that the Rockefeller Foundation had funded the institute he ran in Berlin. And Warburg was well connected in German society. But fame and connections had not been enough to make other German scientist of the era untouchable. The most common explanation is that that Warburg was kept alive because a number of leading Nazis, including Hitler, were thought to be terrified of cancer. Hitler’s mother died from breast cancer in 1907 and Hitler believed his stomach cramps could be an early sign of the disease. So it’s easy to picture the bind Warburg must have created for the Nazis. In a country where cancer was genuinely dreaded, and where Jews were regularly referred to as tumors in the German body, Nazi leaders likely had come to see their best hope for a cure not only in a man of Jewish descent, but in a Jew who happened to have one of the most famous Jewish last names in the world and who lived with another man.
In 1941 Warburg’s scientific rivals did manage to have him dismissed from his position as director of Kaiser Wilhelm Institute for Cell Physiology on the grounds that he had non-Aryan blood. At this point Warburg appeared to be in great danger and was likely saved by several influential connections who persuaded Philipp Bouhler, the head of Hitler’s private chancellery, to reconsider Warburg’s case. Bouhler, who oversaw the euthanizing of more than 70,000 disabled adults and children, wasn’t likely to be sympathetic. He reached out to a number of German scientists to assess Warburg’s importance before coming to the conclusion that Warburg should be returned to his position. After the war, Warburg said that Bouhler’s chief of staff, Viktor Brack who had directly intervened on his behalf, told him, “I did this not for you or for Germany, but for the world.” As part of the process of reinstating Warburg at his institute, his ancestry was reexamined. Despite his father’s two Jewish parents, Warburg was reclassified as only one-quarter Jewish.
Why the Nazis left Warburg alone is only half of the mystery. The other half is why Warburg stayed when he might have fled in the early 30’s like so many other Jewish scientists. Petra Gentz-Werner, a German scholar who has written books and articles about Warburg is convinced he had no sympathies for the Nazis. Gentz-Werner cites the book written by Warburg’s sister, Lotte, which highlights Warburg’s disgust for the Nazis.
The rest of the narrative picks back up in my published article for The New York Times Magazine.
The Last Word
Finally, because he has done so much to draw attention to the research of Otto Warburg and the metabolic roots of cancer, I was hoping there would be enough space to give Thomas Seyfried the last word on Warburg. Here is the ending I’d used in the longer version of the story, which, even if there had been space, probably would have been inappropriate for The Times:
With respect to his hypothesis that cancer begins with a problem of oxygen consumption, the mainstream scientific community has concluded that Otto Warburg was wrong. But in his recognition that cancer is deeply rooted in how our cells obtain and use energy, Warburg has been redeemed. Or, as Thomas Seyfried of Boston College puts it, “We found out that the son of a bitch is right!”