In 1931 German physician, physiologist and biochemist Otto Heinrich Warburg won the Nobel Prize for his discovery that cancerous cells—unlike most healthy human cells, which produce energy using oxygen via respiration—favor the anaerobic process of fermentation, or the conversion of sugar into acids, gases or alcohol, even in the presence of oxygen. This has perplexed scientists ever since because fermentation is a far less efficient means of generating energy than aerobic metabolism, hence its pejorative tag as a “wasteful metabolism.”
But a team of scientists from the University of California, San Diego, has discovered that although oxygen-based metabolism is a more efficient means of energy production, the costs required to produce the molecular machinery that drives respiration are twice those needed to ferment the sugar glucose. Their work could have implications in identifying potential targets in treating cancer.
The team measured what is called proteome allocation—or the fraction of all cellular proteins devoted to various tasks—to determine the metabolic costs of generating energy and cell growth in Escherichia coli bacteria. The enzymes that facilitate respiration—the raw machinery that normally supports human cellular life—are large and lumbering and need to be produced prolifically to keep us, and our steadily growing cells, going. Put another way, a higher percentage of a fast-growing cell’s proteome is dedicated to growth whereas a smaller fraction is available for other cellular processes, including energy production.
University of California, San Diego, physics and biology professor Terry Hwa, who led the study, likens his findings, recently published in Nature, to coal versus nuclear energy. "Coal factories produce energy less efficiently than nuclear power plants on a per-carbon basis, but they are a lot cheaper to build,” he said in a statement. So the decision of which route to generate energy depends on the availability of coal and the available budget for building power plants.” Fast-growing cells find fermentation the cheaper path. In this sense it is coal energy for cells. (Scientific American is part of Nature Publishing Group.)
The idea that cellular metabolism and growth might be based on the cost-benefit balance of producing the proteins necessary to generate energy and grow was first proposed by a team of Dutch theoretical biologists in 2009. Hwa’s findings confirm those findings. And although prevailing dogma views cancer as a genetic disorder—or really a complex of disorders caused by countless possible mutations—some researchers are coming around to the idea that the ultimate pathologic insult might be impaired or altered energy production.
Thomas Seyfried, a biologist at Boston College who was not part of this study, feels that cancer is a metabolic disorder, citing the large body of evidence implicating mitochondrial dysfunction in cancer. Mitochondria—or the “powerhouses” of our cells—are where cellular energy production takes place. “There is now substantial evidence from a broad range of disciplines showing some degree of defect in the number, structure or function of mitochondria in all types of tumor cells. These mitochondrial defects cause the enhanced glucose uptake and the fermentation seen in tumor cells,” Seyfried explains.
In a 2014 paper by Seyfried and colleagues published in Carcinogenesis he cites ample evidence to support his claim, including showing that a cell’s tumor potential is suppressed if it is transplanted with normal mitochondria; and conversely that transferring mitochondria from tumor cells into the cytoplasm of normal cells increases the chances that those once normal cells will become cancerous. He also points out the large body of work connecting the etiological dots: Many of the mutated genes associated with cancer seem to exert their effects by impairing cellular respiration. It is also possible, Seyfried strongly feels, that transitioning from respiration to fermentation produces free radicals that cause genetic mutations associated with cancer.
Seyfried also suggests a possible evolutionary explanation for fermentation in cancer cells, citing work by Carlos Sonnenschein and Ana Soto at Tufts University showing that the default state for cells is to proliferate, like cancer cells do, and that aerobic respiration in the mitochondria normally helps keep this growth in check. “Unbridled proliferation driven by fermentation metabolism was the state of existence for most cells before oxygen entered the atmosphere some two billion years ago,” he explains. “A gradual loss of respiratory control together with a compensatory fermentation underlies the origin of cancer.”
The association between energy production and cancer is likely far from being completely understood, and although Hwa cautions that he is not a cancer biologist, he feels there is definite promise in pursuing treatments that tinker with metabolism. “I can see that interfering with fermentation could be an effective strategy to slow down tumor growth,” he explains, “since slow-growing cells rely more on respiration to generate energy—then, in principle, this treatment strategy is naturally more disruptive to fast-growing cancer cells than normal cells.”
Current cancer treatment emphasizes interfering with cell signaling pathways that could lead to runaway cellular growth. “But from this study,” Hwa says, “[we found] that maybe we don't need to be so concerned with signaling and could instead work to slow down the efficiency of fermentative processes. We can then count on cancer cells’ growth to slow down as they shift to respiration.”
As more and more mutations associated with varying cancers are uncovered, developing oncology therapies could seem a Sisyphean undertaking. But a single pathology—one that perhaps results in the mutations associated with cancer—could make developing effective cancer therapies a whole lot easier.
As Otto Warburg’s work alluded to nearly a century ago, perhaps this entails simply encouraging cancer to take a breath of fresh air.