In the 1920s, a Nobel Prize-winning cell biologist named Dr. Otto Warburg made a discovery–that cancer cells produce energy differently than other, healthy cells. Instead of using aerobic respiration like the rest of our cells do, cancer cells use the process of fermentation to produce energy. You’ve probably heard statements like “cancer thrives in an acidic environment” and “cancer can’t survive in an oxygen-rich environment.” Dr. Otto Warburg’s research is the basis for these statements and many alternative cancer therapies have aimed to cure cancer through these concepts. But for nearly a century, scientists haven’t known why cancer cells use the process of fermentation for energy. Aerobic respiration produces more energy per unit of carbon, so why do cancer cells choose a metabolic pathway that’s so inefficient? Researchers think they may have the answer.
A team of physicists and biologists from UC San Diego published a study in the December 2015 edition of Nature, examining the metabolic costs of synthesizing the enzymes and other biological apparatus required for both fermentation and aerobic respiration within the bacterium E. coli. They also studied the metabolic savings of generating energy through aerobic respiration. They found that the cost of protein synthesis overrules the metabolic savings for fast growing cells.
“What we discovered could be compared to the difference between generating energy by a coal factory versus a nuclear power plant,” said Terry Hwa, a professor of physics and biology at UC San Diego who headed the study. “Coal factories produce energy less efficiently than nuclear power plants on a per-carbon basis, but they are a lot cheaper to build. So the decision of which route to generate energy depends on the availability of coal and the available budget for building power plants.”
“For cells, it turns out that there are also two costs to consider,” he added. “One is the cost of raw material. Aerobic respiration generates more energy per carbon atom than fermentation. The other is the opportunity cost of synthesizing enzymes. This cost refers to the number of the protein-making machinery, or ribosomes, that need to be recruited to synthesize the relevant enzymes. We showed that the enzymes for respiration are bulky and slow compared to those for fermentation, so a lot of such enzymes need to be synthesized, tying up a lot of ribosomes, in order for respiration to happen at substantial rates. This is an important cost because the number of ribosomes is the growth limiting factor.”
In other words, cancer cells are trying to grow at such a rapid rate, that they can’t spend time building ribosomes and proteins needed for aerobic respiration, so, they turn to fermentation instead. It may produce less energy per carbon unit, but it doesn’t require all of the “equipment.”
“For fast growing cells with plenty of nutrients, if a lot of ribosomes are used to make respiratory enzymes, then few of them are available to make other growth proteins, including the ribosomes themselves. This would slow down growth and is disadvantageous to cells. The higher carbon efficiency of respiration is not an important consideration here since nutrients are plentiful. On the other hand, when nutrients are scarce and cells cannot grow fast, then the demand for ribosomes by other cellular functions is reduced, and the cost of tying up ribosomes is less important. In the meantime, using respiration to generate energy conserves the precious carbon supplies, which is a much more important consideration in poor nutrient conditions.”
The idea of this opportunity cost to cell growth was first suggested several years ago by a team of theoretical biologists from the Netherlands. In the UC San Diego study, Hwa and his collaborators experimentally characterized the cost of synthesizing fermentation versus respiratory enzymes by using proteomic mass spectrometry and discovered that respiratory proteins are twice as expensive as fermentation proteins for the same rate of energy generation. Their study is the first time such a cost has been established for any living system. The researchers also developed a mathematical model that quantitatively predicted the pattern of metabolic waste excretion in response to perturbations they applied to affect the physiological state of growing cells.
While it is not clear whether the same rationale underlies the origin of “wasteful metabolism” in cancer, the researchers said, they believe their results provide another way to think about the process.
“Instead of something going wrong that should be fixed, this may be the universal strategy necessary for rapidly growing cells,” explained Hwa. “The results may also have implications in biotechnology: metabolic engineers are always trying to reduce metabolic waste in engineered organisms in order to reduce cost. Our findings suggest that reducing waste may be detrimental to the organisms and different strategies need to be devised to increase metabolic efficiency.”
More research needs to be done on the topic and how these concepts can be specifically applied to cancer treatments. One may theorize, however, that when cells are working optimally and efficiently because the body is being fully nourished with vitamins and antioxidants, the cost of building those ribosomes needed for aerobic respiration may be less, and the growth of healthy non-cancerous cells supported.