Medical progress is invariably thought of as being based on looking ahead into the fu-ture, but the current buzz in the world of cancer research surrounds a man who did most of his work in the 1930s. His name is Otto Warburg, and he was a German biochemist who, although awarded two Nobel Prizes for Medicine, died in 1970 with his ground-breaking cancer theory discredited and all but forgotten.
Today, however, scientists are actively looking back at his work and acknowledging it as an important insight into the cancer process. So, could a simple pre-Nazi hypothesis be the answer to a problem that has eluded thousands of cancer experts and their billions of research dollars?
Nowadays, cancer is a huge medical industry, but when Otto Warburg first proposed his theory about cancer in 1924, the condition was relatively rare, and cancer research was virgin territory. Trained in both physics and chemistry, while in his late 30s, Warburg carried out some detailed studies of the assimilation of carbon dioxide and oxygen into plant and animal cells, and noticed something strange about cancer cells. They didn't use oxygen in the same way as did normal cells; in fact, he observed that cancer cells used hardly any oxygen at all.
Normal cells take in oxygen through their mitochondria. These parts of the cell are the descendants of bacteria that took up residence in the original single-celled ancestors of animals and plants (see box, right). These tiny tubular organelles use oxygen to break down carbo-hydrates (glucose), thereby releasing energy. However, Warburg discovered that cancer cells appear to bypass mitochondria. Instead, they obtain energy through a process he called 'fermentation' (now termed 'glyco-lysis'), in which energy is extracted from glucose without the use of oxygen whatsoever.
To most of his contemporaries, this observation was merely a curiosity but, to Warburg, it was fundamental-a view he maintained staunchly to the end of his life.
"The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar," he told fellow scientists a few years before his death. "From the standpoint of the physics and chemistry of life, this difference between normal and cancer cells is so great that one can scarcely imagine a greater difference. Oxygen gas, the donor of energy in plants and animals, is dethroned in cancer cells, and replaced by an energy-yielding reaction of the lowest living forms, namely, a fermentation of glucose," he said, in a lecture at a meeting of Nobel laureates in Lindau (30 June 1966).
Warburg proved his theory by "the simplest conceivable experimental procedure". He cultured animal cells in a test-tube, growing them under reduced oxygen pressure; after 48 hours, the cells had become can-cerous. Then, even after the oxygen pressure had been restored to normal, the artificially created cancer cells carried on dividing into yet more cancer cells. It appeared that once the fermentation process had been established in each cell, said Warburg, the process was "irreversible".
At the time, the Warburg hypoth-esis was fiercely debated. Some argued that it was paradoxical. For example, why would cancer cells, known to multiply rapidly and, therefore, inevitably having huge energy requirements, come to depend on glycolysis, which is relatively inefficient, over the more efficient oxygen respiration?
The answer boils down to how cancer takes root in the body, he said. It's known that cancer survives by deliberately cutting itself offfrom the normal bodily processes (which, incidentally, is one reason why conventional chemotherapy so often fails with solid tumours). This is because the tumour needs to protect itself against the mito-chondria in healthy cells, the primary job of which is to kill rogue cells-such as cancerous ones-in a process called 'apoptosis' (programmed cell death). This means that, in order to proliferate, cancer has to find an energy-production system that doesn't use oxygen.
Even in the 1930s, this was an heretical theory, and it was no doubt his Nobel Prizes (awarded for his work in another branch of medicine) that saved Warburg from falling into ignominy. As it was, he was gradually sidelined, ignored and ultimately forgotten. Cancer research movedon to the study of genetics, which gradually became the dominant theory.
Looking with new eyes
It wasn't until 2002 that scientists at the Department of Molecular Biology laboratories at the University of Madrid carried out a detailed investigation into the metabolic processes involved in liver, kidney and colon cancers. Among their findings, they found two separate mechanisms that could spur the growth of these cancers, both based on the same principle-the inhibi-tion of mitochondria in normal cells.
Although Warburg had lacked access to the technology that could clarify the precise mechanisms, it was the first vindication of his theory; indeed, the Spanish research-ers were quick to acknowledge that their findings offered "strong support for the Warburg hypothesis" (Cancer Res, 2002; 62: 6674-81). Since then, the same Madrid-based team has discovered similar mechanisms for lung and breast cancers.
Other researchers soon took up the baton. Two radiologists at the University of Arizona pointed out that the entire radiological com-munity had been using the 'Warburg effect' for years-in body-scanning machines. Hospital PET (positron emission tomography) scans rou-tinely use measurements of glycolysis in tumours to 'stage' the cancer: the more glycolysis, the more malignant the tumour. An increased breakdown of glucose, they reminded the world, is "a near universal property" of cancer (Nat Rev Cancer, 2004; 4: 891-9).
Swiftly following on from this observation, a team of molecular biologists at the University of Texas confirmed that cancer cells thrive in an oxygen-depleted environment and increase glycolysis. More important, their laboratory experiments also showed, for the first time, that if glycolysis is inhibited in cancer cells, it "effectively kills cancer cells", resulting in "massive cell death" (Cancer Res, 2005; 65: 613-21).
The supreme accolade to Warburg's hypothesis has now come from two of the world's most prestigious institutions, Harvard and MIT. A team comprising scientists from both these universities, led by professor Stuart Schreiber, took a detailed look at every stage of how normal cells change into cancer cells. Particularly focusing on the cells' metabolism, the team re-discovered exactly what Warburg had proposed 70 years earlier: as cells become more cancerous, they progressively abandon obtaining energy from their mitochondria and shift over to glycolysis, gradually becoming anaerobic and hypoxic (oxygen-depleted).
What's more, this process appears to have a genetic component, too, thereby establishing a place for Warburg's theory in mainstream science.
"We have gained insight into the relationship between two models of carcinogenesis, one (the Warburg hypothesis) based on increased energy production by glycolysis in cancer cells . . . and one based
on cancer-causing genes," says the report. So, instead of being contra-dictory models, the two are evidently interlinked (Proc Natl Acad Sci USA,
2005; 102: 5992-7).
Warburg's hypothesis also ties in with the less mainstream theory that makes a connection between cancer and acidity. For years, alternative cancer therapists have recommended an alkaline diet to fight cancer. The Warburg effect now offers a possible scientific explanation, as the major byproduct of glycolysis is lactic acid. Indeed, the most recent speculation is that the production of lactic acid is the main way in which cancer spreads, with the acid giving cancer cells "a competitive advantage for invasion" (J Bioenerg Biomembr, 2007 Jul 12; Epub ahead of print).
Treatments based on the Warburg effect
Today, the world of oncology is abuzz with talk of the 'Warburg effect'. At its simplest, it helps to explain why cancer patients lose so much weight. It's not just that their immune systems are compromised, but also because glycolysis is so energy-inefficient that cancer cells need to consume lots of glucose to thrive and multiply, thus using up the body's stores of carbohydrates.
This hunger for glucose was once thought to be a mere byproduct of tumour growth, but the recent research has rediscovered that it's fundamental to the whole disease process. The hunt is now on to find compounds that can block or even reverse it. Experts are now specula-ting that cancer's Achilles heel may be its 'sweet tooth'.
Behind closed doors, we can be certain that the drug companies are already well down the sugar road. The reward is immense: what the Warburg effect offers is a unique way of attacking cancer cells that will leave healthy cells totally intact. This is not some obscure genetic difference, but a fundamentally basic contrast between two ways of powering up cells: cancer cells use glycolysis; normal cells use oxygen respiration. As Warburg pointed out, the two methods couldn't be more different.
Are there any existing treatments that exploit the Warburg effect? Hydrogen peroxide and ozone therapy have already shown some promise (see box, page 7). However, for diet, nutrition and supplements, there appears to be no research trying to connect the new discoveries with existing therapies such as vitamin C.
The most active nutritional research is taking place in Warburg's native country at the University of Jena. There, a team headed by Dr Michael Ristow is going back to first principles, and checking whether Warburg was right-in particular, his pessimistic claim that, once trig-gered, cancer is irreversible. Ristow's group has shown that the Nobel laureate might have been mistaken. They have been testing a naturally occurring human protein called 'frataxin' that is known to stimulate mitochondria, and have shown that cancer cells can be "forced into mitochondrial metabolism". This "efficiently suppresses cancer growth", says Ristow (Curr Opin Clin Nutr Metab Care, 2006; 9: 339-45). His ultimate wish is to find wholly nutritional cancer treatments.
Last month, however, an American nutritionist announced that he had discovered a nutritional break-through based on the Warburg effect using essential fatty acids (EFAs) (Med Hypoth, 2007 24 July; Epub ahead of print). His name is Brian S. Peskin, CEO of Swing Aerobics Licensing of Houston, Texas, and his new book, co-authored with Amid Habib, The Hidden Story of Cancer (Houston, TX: Pinnacle Press, 2006), is creating quite a stir in alternative-medicine circles. However, it's still early days, and to be accepted more widely, Peskin will need to bolster the evidence for his claims (see box, page 8).
Currently, much more notice is being taken of discoveries made in Edmonton, Canada. Early this year, researchers there at the Universityof Alberta reported the results of the first trial of a drug that specifically exploits the Warburg effect (Cancer Cell, 2007; 11: 37-51). They tested the compound dichloroacetate (DCA), used for decades to treat both lactic-acid buildup and rare childhood disorders affecting cell mitochon-dria. What DCA does is it stimulates mitochondria, encouraging them to increase their oxygen intake to break down glucose.
The Canadian researchers decided to try it for the first time on cancer cells in the laboratory. Human breast, brain and lung cancer cells were cultured, and then exposed to DCA. Within five minutes, the cancer cells began to behave more like normal cells, increasing their oxygen respiration and decreasing lactic-acid production. While acknowledg-ing their immense debt to Warburg, the researchers believe he was wrong on only one count: cancer is not irreversible.
They then went on to test DCA in rats. The animals were injected with virulent cancer cells to produce tumours. Then, some of the cancer-injected rats were given DCA in their drinking water.
Within a few weeks, there was a striking difference. The DCA-treated rats had developed much smaller tumours (on average, about 40-per-cent smaller), and there was even evidence of cancer cells being killed by normal, healthy immune-system cells.
"DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," says the Alberta team leader, Dr Evangelos Michelakis. "One of the really exciting things about this compound is that it might be able to treat many different forms of cancer."
However, dichloroacetate is a byproduct of chlorine and, hence, potentially toxic. In fact, tests have shown that relatively high doses of DCA can cause cancer, at least in rats, but it may not apply to humans (Toxicology, 1996; 114: 207-21).
The good news is that, at the dosages already being used for childhood cellular diseases, no major side-effects have been reported (Arch Dis Child, 1997; 77: 535-41). What's more, as it's an old drug and not patentable, it's very inexpensive.
But there's the paradox. Drugs need costly clinical trials to bring them to market. That research is almost always funded by drug com-panies-but not if there's no prospect of a lucrative patent.
Michelakis is now appealing for donations to fund clinical trials, which partly explains the current hoopla surrounding DCA. By all means, dip your hands into your pockets, but be aware that the findings in people are unpredictable at this time. The Alberta group's published evidence to date is based on trials involving fewer than 50 rats, and Warburg's legacy deserves better than that.
Warburg on evolution
Warburg believed that cancer is a throwback to our earliest moments in our evolutionary past. His theory was that cancer cells are like the first primitive cells that appeared on the planet, and that it was oxygen that kickstarted these early simple cells into differentiation, thus leading to the development of plants and animals.
"The early history of life on our planet indicates that life existed on Earth before the atmosphere contained free oxygen gas," said Warburg, in a lecture given to Nobel laureates in Lindau, Germany, in 1966. "The living cells must therefore have been fermenting cells and, as fossils show, they were undifferentiated single cells. Only when free oxygen appeared in the atmosphere-some two billion years ago-did the higher development of life set in to produce the plant and animal kingdoms from the fermenting, undifferentiated single cells.
"The reverse process, the de-differentiation of life, takes place in cancer development. The highly differentiated cells are transformed into non-oxygen-breathing fermenting cells, which have lost all their body functions and retain only the now useless property of growth . . . What remains are growing machines that destroy the body in which they grow."
Promising oxygen therapies
- Ozone therapy claims to exploit the Warburg effect by super-oxygenating the body (ozone is normal oxygen plus an extra oxygen molecule). The treatment is widely used by German naturopaths, and is also available from some alternative practitioners in the UK and US. However, there is little convincing evidence for its benefits in cancer, in part due to the lack of proper clinical trials.
Clearly, though, ozone can have significant anti-cancer effects. In the lab when cancer cells are cultured in an ozone environment, their growth rates have been reduced by up to 90 per cent (Science, 1980; 209: 931-3).
A recent medical audit of the Hufeland Clinic in Bad Mergentheim, Germany, where ozone is used along with other complementary therapies, showed remarkable anti-cancer benefits even for people with advanced disease (Integr Cancer Ther, 2005; 4: 156-67).
Ozone is generally delivered to the body either via the blood, or via the appropriate body cavities.
- Hydrogen peroxide is water with an extra oxygen molecule used by some alternative cancer therapists against cancer-often successfully. Because it is fairly toxic by mouth, it is injected into the bloodstream. However, there have been no clinical trials to test its use because, like DCA and ozone, it is not patentable. Although considered safe in the right hands, one death has recently been attributed to the treatment.