Ravenous: A Review By Professor Tim Noakes

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Truth in the nutrition sciences has been critically advanced by the writings of investigative journalists who often arrive at their chosen topic indirectly.

Two stellar recent examples are Gary Taubes and Nina Teicholz whose seminal works (1-4) have forever changed the scope and direction of the global debate about “healthy” nutrition. They have shown that the modern nutrition sciences are influenced, nay directed, by forces more likely to cause illness than to promote exuberant health. Their contributions pose the fundamental question: Why does it take investigative journalists mainly self-taught in the science of nutrition – but not in the rigors of science discourse as both Taubes and Teicholz are rigorously trained in dismembering scientific deceptions – to expose what the rest of the world, diet professionals especially, apparently cannot see?

To these seminal, highly influential works of Taubes and Teicholz, we must now add a third – Ravenous, the first book of a third investigative journalist, Sam Apple. Ravenous completes a Trilogy of revolutionary contributions from these gifted writers. I do not make this judgement of his work lightly. Here’s why.

Ravenous is seminal because it provides the missing modern context for a bewildering scientific discovery, first reported in the 1930s, but whose relevance was then progressively ignored, downplayed and ultimately dismissed as wholly irrelevant. Yet now almost a century later, a growing body of new evidence, particularly that collected in the past 2 decades, gives an unexpected modern relevance to that rejected finding.

And this is no small matter. Crucially, like the scientific topics investigated by Taubes and Teicholz, it is not one that can ever be popular, at least not now, since it refutes what is presently an unchallenged belief in the science and practice of medicine and nutrition. So, like those of Taubes and Teicholz, Apple’s new challenge to medical and scientific obedience could only have been presented by someone whose livelihood does not depend on a rigid adherence to conventional (paid-for) medical dogmas. 

The central story in Ravenous is the biography of one of the most influential biochemists of all time, the German Professor Otto Warburg. Warburg was a huge personality; as Apple describes, a colleague once said that on the scale of arrogance from 1-10, Warburg rated 20. Many of his colleagues considered Warburg to be godlike. Which poses a colossal challenge for any writer daring to attempt the biography of such a deity. But Apple proves he is up to the task by producing a flawlessly researched, exquisitely constructed and magnificently narrated book that builds progressively to a thrilling climax. 

Ravenous succeeds at every level – it is story telling at its very best. Apple uses the life of the powerful but highly complex central character, Warburg, to educate us about his science, including the extraordinary growth of the biological sciences in Western Europe, Germany, in particular, in the period before, during and after World War II (WWII).  Warburg believes his destiny has been to discover the singular reason why all cancers develop. And in the process of his narration Apple shows how Warburg’s ideas, first pioneered nearly 90 years ago, and then discounted, are once more gaining some real traction. 

The book also covers many years of dark days when the influence in Germany of Hitler and the Nazis is everywhere, not least affecting the career prospects of Warburg whose Jewish grandparentage put nothing less than his life at extreme risk.  

We learn that at age 20 in 1903, Otto Warburg starts his scientific career in Naples studying urchin eggs. He wishes to answer the question: When do urchin eggs show the first signs of life? Warburg realizes that this happens when an urchin egg begins to use oxygen; that is, when it begins to respire. With time Warburg progresses to study the use of oxygen in the process of respiration in different tissues. And so he discovers his area of specialization – the research to describe the intracellular biological processes by which creatures use oxygen to extract the energy from the foods they eat. 

Warburg is fortunate to begin his specialized research in Berlin at a time when German scientists, many like he, Jewish, and many living in that city, are leading the creation of his novel scientific discipline, biochemistry, as well as many other specialties. The quality of these scientists and the work they are doing is simply astonishing. Their influence will echo down the ages. Apple reminds us that in the 13 years before the start of WWII, German scientists win one-third of all Nobel Prizes offered in many different disciplines. Besides Warburg, other German scientists of this period who will become scientific legends include Max Planck, Werner Heisenberg, Otto Meyerhoff, Paul Erlich, Robert Koch, Adolf Windaus, Emil Fischer and Hans Krebs, amongst others. It is impossible to overstate the impact they will have on the science we practice today.

Warburg iconic moment happens when he develops techniques to measure the oxygen use of cancer cells. To his utter dismay he discovers that these rapidly-growing cancer cells are not using oxygen to fuel that growth as do normal cells. Instead they have switched to a more primitive process, known as fermentation, in which the cancer cells convert glucose to lactic acid extracting energy without any need for oxygen.  In time, Otto’s unexpected discovery becomes known as the Warburg Effect. 

It is this iconic discovery that is at the core of this book. 

Warburg concludes, perhaps too grandly, that he has discovered the essential biochemical hallmark of all forms of cancer. Thus: “Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar”. This switch also means that cancer cells must avidly extract glucose from wherever they can source it. An essential source of that glucose for humans is the carbohydrate in our diet. 

At the time Warburg is aware that another extraordinary scientist, Frenchman Louis Pasteur, has described a similar phenomenon – which Warburg himself later labels the Pasteur Effect. Pasteur finds that yeast cells have the capacity to switch between the use of oxygen – in the process of cellular respiration when oxygen is available – or fermentation, when oxygen is absent. 

Warburg also knows of the work of another Nobel Laureate, the iconic English muscle physiologist, Professor A.V. Hill. Hill had concluded that during high intensity exercise, lactic acid accumulates and ultimately causes exhaustion because of an inadequate respiratory capacity in the exercising muscles. Hill concludes, incorrectly it now turns out, that this too must be caused by an inadequate oxygen supply to the exercising muscles. 

So perhaps Warburg is bound to conclude, as had A.V. Hill, that the fermentation process he measures in his cancer cells is also an identical response to an inadequate oxygen supply and the resulting impaired or absent respiration, unable to remove the lactic acid as it accumulates.  He theorizes that normal cells became cancerous only when they are exposed to oxygen-free, anaerobic conditions for some time. As a result they are forced to produce their energy exclusively from fermentation, ultimately losing their capacity for respiration. Warburg considers this to be a regressive metabolic choice.

The way in which he interprets his iconic finding directs Warburg’s scientific career down two paths: First he wishes to uncover the cellular mechanisms of respiration in healthy cells. And second, how these healthy mechanisms become altered in cancer cells. He believes that if he understands both, he will be able to produce interventions – magic bullets – that will kill any and all cancer cells. This certainly seems to be an honorable life goal. 

His interest comes at precisely the most opportune moment. For the rates of cancer are rising around the world, not least in Germany.  Scientists from many different countries begin to theorize that cancer is a modern disease, a “disease of civilization”. Some present evidence that cancer is uncommon in those populations that continued to eat the diets to which they had adapted over eons. Could the cancer epidemic be due to quite recent but profound dietary changes around the globe, they ask? Already animal studies have found that eating either less – fewer calories – or of diets with a reduced carbohydrate content reduces rates of tumor growth in experimental animals. Conversely in 1913 two scientists Eleanor van Ness van Alslyne and S.P. Beebe from Cornell University, New York, report that “when the diet includes carbohydrates the tumors grow luxuriantly”. 

None of this evidence contradicts any potential role of the Warburg Effect in the development of cancer. But perhaps Warburg ignores the important clue – that the body in which the cancer develops provides the soil for that cancer’s growth. Perhaps is not just about oxygen and failed respiration.

If Warburg is in the right place, Berlin, at the right time in the early 1930s, surrounded as he is by a culture of unmatched scientific excellence and with access to all the equipment and financial support that he could possibly wish, he is also very definitely the wrong person to be in that right place. Nor will his time, nor the place be right for very much longer. 

For Warburg has two Jewish grandparents making him a non-Aryan. At a time when Adolph Hitler’s Nazis are about to begin the most evilly repugnant program of murderous ethnic cleansing of non-Aryans in recorded history. How possibly will the non-Aryan Warburg be spared if he remains in Germany? The answer to that question produces another of the book’s intriguing, developing themes.

Apple suggests that Warburg’s arrogant belief that of all the world’s scientists, he alone is destined to find the cure for all cancers, unquestionably saves his career. And perhaps his life. For without a high degree of official protection, the sole safe option for a Jewish scientist working in Germany under the Nazis in the 1930s, is to emigrate. Yet, as if he is above any risk, Warburg blithely refuses to do so. Instead he becomes the only Jewish scientist among more than 2000 who is allowed to continue his research in Germany before, during and to the end of World War II (WWII). 

His diligent research suggests to Apple that Warburg survives only because Adolph Hitler and the other leaders of the Third Reich are aware of precisely what he is doing. And Hitler, that most evil man of the 20th Century, has an abiding fear of cancer. He has witnessed his mother’s death from disseminated breast cancer. He has also a life-long sugar addiction (besides an addiction to mood-altering drugs that Apple wisely avoids since it has no relevance to his enquiry although that particular addiction saved the Allied Forces on more than one occasion in WWII).  Hitler, a vegetarian, also suffers from chronic gastrointestinal upsets which are perhaps not so uncommon in committed vegetarians. But his continual discomfort convinces Hitler that he too could be developing a terminal gastrointestinal cancer.

Apple implies that Hitler believed that Warburg would discover a cure for cancer and so save Hitler from himself dying from cancer. So instead of being imprisoned or perhaps much worse, Warburg is protected and continues his research in apparently idyllic surroundings even until the Russian forces approach Berlin from the East in April 1945.  

It is from the story of Hitler’s sugar addiction and fear of cancer that Apple fashions the final third of his book, bringing it to a thrilling climax. And in so doing completes his description of Warburg’s ultimate contribution.

For it is those final 100 pages of text that lift Apple’s book from brilliant to exceptional. It does this by revealing the connections that other writers would likely have missed. In particular, that the growing global cancer pandemic first noted in Warburg’s time, is almost certainly being driven by the foods that we are currently eating. Yet by linking his story to Hitler’s own battles with a specific food, Apple takes it a step further.  He proposes that we may have overlooked the single foodstuff that is the greatest driver of our ill-health; the one food, the increased consumption of which over the past century, best explains the modern cancer epidemic. And what he writes can no longer simply be ignored as if, like Warburg, it is irrelevant.

Apple’s thrilling discovery is, in turn, forced on him by the reality that Warburg’s brilliant career begins to wind down even as the Russians are closing from the East at the end of WWII. 

So even though Warburg wins the 1931 Nobel Prize in Medicine or Physiology for his discovery of the role of iron as the “oxygen-transferring ferment of respiration” – since re-named much to Warburg’s displeasure, cytochrome c oxidase – and he comes very close to a second Prize for his discovery of other key components of cellular respiration – the respiratory chain including the isolation of nicotinamide and the flavins – yet Warburg falls short of his ultimate goal. He does not ever prove the molecular mechanisms of cancer nor whether there are specific foods causing cancer. Nor does he discover the magic bullet that will either disrupt fermentation or preserve respiration in cancer cells and so cure all cancers (according to his theory). For all purposes, his brilliant career is in decline by 1945.

But there is even worse to come. In 1953, the American scientist Sidney Weinhouse provides convincing evidence that many cancer cells have a normal capacity for respiration. In a direct contradiction of Warburg’s hypothesis, he shows that cancer cells simply choose fermentation over respiration. In time this discovery will lead to a more correct definition of the Warburg Effect. 

Also in 1953, the discovery of the structure of DNA by American James Watson and Englishman Francis Crick ushers in a completely new era in biology. In time Watson will suggest that the future of cancer therapy lies in understanding the genetic changes that cause healthy human cells to turn cancerous. Ironically, he is correct.  But as Apple shows, certainly not in the way Watson imagined.

These two events signal that Warburg’s career is pretty much over. Despite his prodigious contributions to the understanding of cellular respiration, it appears that the irresistible march of biological science has made him and his Warburg Effect largely irrelevant. Now all his theories seem to belong to a bygone era. 

And that is where any book about Warburg might logically have ended. The once great hero, aging, in decline, increasingly disregarded, and only just surviving in a country crushed by defeat in WWII. 

But author Sam Apple did not spend his five years’ researching and writing this book to bring it to such a sorrowful, pessimistic finish. Somehow he must have sensed that there was more; much more. But to uncover this deeper dimension would require that he develop yet another intellectual skill. He would have to become more than (just) a journalist divining an enthralling story from the published historical record.  Instead he would need to study, understand, interpret and then explain to his readers, the emerging field of cancer cell metabolism. The very topic that Warburg had helped pioneered nearly 100 years ago.

In so doing he provides the evidence that Warburg is not just another historical irrelevance. Rather Warburg’s problem is that he was constrained by the incomplete scientific knowledge then available to him. Now is the time, Apple shows, that Warburg’s legacy should be properly acknowledged. For we now know that Warburg was far more correct than he was ever in error.

His error was simply to misinterpret the true biological meaning of his Warburg Effect.  Which, correctly stated, is that many cancer cells have the intrinsic capacity and so can make the choice to increase their production of lactic acid even in the presence of sufficient oxygen and with an unimpaired capability for respiration. They are not forced to ferment glucose to lactic acid because they have no other option, as Warburg erroneously proposed.

This subtle distinction fully reestablishes the appreciation of Warburg’s proper contribution to modern cancer biology.

And so, out of Warburg’s apparent failure, Apple fashions a more complete story suggesting a much greater success and a more long-lasting influence.

Apple begins with a simple analysis of what Warburg had actually found. He had established that the key characteristic of many cancer cells is that they “overeat” or gorge on glucose. 

Already in the 1800’s, it was appreciated that cancers occur more commonly in those who are obese and who therefore overconsume food (for whatever reason(s)). Thus “overabundant food consumption unquestionably is the underlying cause of the root condition of cancer in modern life” (5). Animal experiments published in 1947 also found that diets restricted in calories or in carbohydrates were associated with either less cancer or less cancer progression. The possible biological explanations for these relationships would come only more recently and from an unexpected source – the discovery of the oncogenes.  The oncogenes are those portions of our genetic makeup that encourage cancer cells to grow. Which is different from causing the cancers. 

In 1997 researchers from Johns Hopkins hospital in Baltimore discovered that one such oncogene codes for the enzyme lactate dehydrogenase (LDH), the key enzyme in the fermentation pathway producing lactic acid. But wait a second! Was it not Warburg himself who had discovered LDH in his studies seeking to explain the biological basis of the Warburg Effect? If oncogenes increase LDH activity in cancer cells, then there could be a direct link between the fermentation pathway and the growth of malignant cancer cells.

The next bit of intriguing evidence was provided by one of the world’s most respected modern cancer researchers, Dr Craig Thompson of the Memorial Sloan Kettering Cancer Center. Thompson was not studying why cells grow, but rather why they stop. He specifically wished to understand what causes cells to die, literally to commit suicide, the process known as apoptosis. Thompson discovered that apoptosis is driven by the very cellular structures, the mitochondria, in which cellular respiration occurs. When the mitochondria become dysfunctional and stop respiring properly, they direct the cells in which they are located to kill themselves.

But wait a moment! Was it not Warburg who spent his life researching the intra-mitochondrial pathway – the electron transport chain – that is the key to healthy cellular respiration?

Thompson and others discovered that messages coming from outside the cells and which instruct mitochondria to take up more fuel – that is, to eat – are the key defenders of mitochondrial health, directing attentive cell towards survival and away from apoptosis. These messages are provided by growth factors in contact with each cell.

What Thompson realized is that cancer cells no longer obey the commands of these growth factors. Instead they no longer require these factors to tell them to stay alive and not to dissolve into apoptosis. So Thompson’s goal has become to identify “those specific genes that allow a (cancer) cell to (over)eat without permission from growth factors”.

It did not take long for Thompson to begin discovering some of the genes directing the production of growth factors. Like AKT/protein kinase B (PKB) that specifically increasing the glucose uptake and metabolism of cancer cells, thereby activating the Warburg Effect. Coincidental? Perhaps not. Is it possible that the Warburg effect might simply be the result of errant genes coding for delinquent growth factors which, in Thompson’s words, allow cancers to continue “gorging” on glucose without a proper permission? 

But could the Warburg Effect point to yet other diet-cancer links? 

Apple think so. He next presents clear evidence that both obesity and type 2 diabetes mellitus (T2DM) substantially increase cancer risk in all those human populations that have been studied. Both these conditions are now firmly linked to the medical condition of insulin resistance in which blood insulin concentrations are perpetually elevated in affected (hyperinsulinemic) persons should they continuously eat high-carbohydrate diets.

So what of possible links between hyperinsulinemia, cancer and the Warburg Effect? Well it just so happens that certain specific cancers including those of the prostate, uterus, breast, colon and lung overexpress insulin receptors on their cell membranes. And since insulin drives cellular glucose uptake, what could those overabundant insulin receptors possibly be doing there, other than driving the Warburg Effect?

Yet there is still more. Apple relates how in the late 1980s, Lewis Cantley at Cornell University, discovered another oncogene coding for the production of phosphatidylinositol-3-kinase (PI3K). Crucially PI3K is itself activated by insulin, specifically to stimulate the Warburg effect.

The final two chapters of Ravenous complete the circle of Walburg’s contribution, although from a more circuitous route. Apple explains that Emil Fischer was Walburg’s first teacher and most revered inspiration. Fischer revolutionized the understanding of carbohydrate structure establishing, in particular, the differences between two common carbohydrate building blocks, glucose and fructose. When combined, fructose and glucose produce sucrose, or common table sugar. 

The popular belief is that sugar cannot be harmful health because it contains glucose found in all starchy cereals.  And since cereal-eaters like the Ancient Egyptians and many modern Asian populations are the picture of health, then glucose cannot be an unhealthy food.  

But fructose must be even more healthy since it does not cause blood glucose and insulin concentrations to rise and so does not produce the damaging hyperinsulinemic response. 

We now understand this rather differently. Glucose present in sugar or cereals will raise blood glucose and insulin concentrations and is therefore undesirable for those with insulin resistance. Whereas fructose is perhaps even worse.  Because it is metabolized directly to fat in the liver where it becomes a key driver of a novel global pandemic, non-alcoholic fatty liver disease (NAFLD), responsible for worsening insulin resistance in humans.

In these two concluding chapters, Apple advances the theory that sugar (including the specific harmful effects of fructose) is the key, but ignored, nutritional driver of obesity, T2DM and heart disease and also, relevant to this book, cancer. He is not the first to link the dramatic increase in sugar consumption over the past 150 years to rising rates of the first three of these diseases. But he is perhaps one of the first to make a more direct link to cancer – “If you want to make a cancer happy, feed it fructose” (Richard Johnson MD).

So where does this leave the Warburg effect and its potential role in the development of cancer. 

Craig Thompson, quoted earlier, argues that what the Warburg Effect really does is to provide the cancer cell with an excess of building materials to allow for unconstrainted reproduction. In his words, the Warburg Effect “makes the cell independent of the normal signal transduction that controls its biology…We believe that’s a fundamental shift in the way we should be thinking about cancer”.  Thompson proposes that the advantages of deregulated glycolysis (the Warburg Effect) to a cancer cell are obvious: “If you put more fuel in, things will work more efficiently. The deregulation of the Akt pathway [is] simply upregulating your ability to take up nutrients, to conserve amino acids and lipids … to fuel cell growth.”(6). 

If Thompson is correct, perhaps the final solutions to the cancer problem will be provided by understanding the Warburg Effect. 

Precisely as Warburg himself had suggested more than 90 years ago.

A condensed version will be published on A Sweet Life.

Timothy David Noakes 

OMS, MBChB, MD, DSc, PhD (hc), FACSM, (hc) FFSEM (UK), (hc) FFSEM (Ire).

References:

  1. Taubes G. Good Calories Bad Calories. New York, NY: Anchor, 2008.
  2. Taubes G. The Case against Sugar. New York, NY: Knopf, 2016.
  3. Taubes G. The Case for Keto: The Truth About Low-Carb, High-Fat Eating. New York, NY: Knopf, 2020.
  4. Teicholz N. The Big Fat Surprise. Why Butter, Meat and Cheese Belong in a Heathy Diet. New York, NY: Simon and Schuster, 2014. 
  5. Hoffman FL. Cancer and Diet. With Facts and Observations on Related Subjects. Baltimore, MD: Williams and Wilkins, 1937.
  6. Garber K. Energy Boost: The Warburg Effect Returns in a New Theory of Cancer. Journal of the National Cancer Institute 2004; 96 (24):1805-1806.
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