Warburg and cancer as a metabolic disease due to mitochondrial dysfunction
I have decided to post information on the exciting research that has consumed us the past seven years. This research was stimulated by the wonderful work of Otto Warburg. He is one of my research heroes. He stated that cancer was caused by a defect in cellular respiration due to mitochondrial dysfunction. In the 1920’s he showed cells produced their energy by fermenting glucose in the cytoplasm producing large amounts of lactic acid. Normal cells produced energy in the mitochondria by oxidative phosphorylation. This involves the inner membrane (electron transport chain) of the mitochondrion. Cancer cells crave large amounts of glucose and this craving is the rationale of using the PET scan to diagnose and stage disease in cancer patients. Cancer cells use glycolytic metabolism even in the presence of adequate oxygen. This is known as aerobic glycolysis and the “Warburg Effect”. Warburg made his own equipment to perform these experiments and won the Nobel Prize in 1931. He later won another but Hitler would not let him go to receive the award. Although Warburg was of Jewish decent, Hitler left Warburg alone knowing he worked on cancer and Hitler had a tremendous fear of cancer.
What about the origin of mitochondria? Well, most know it as the powerhouse of the cell. The cellular organelle involved in cellular respiration and energy production. Few laymen know its evolution of origin. It is postulated and there is strong genetic evidence that mitochondria are evolutionary bacteria that were engulfed by eukaryotic cells 3-4 billion years ago. This created a symbiotic relationship and thus we and many forms of life developed.
We have worked on cancer iron metabolism and cancer immunology for many years, but Warburg’s and recent work of Thomas Seyfried, Ph.D., inspired me to look at mitochondria in our breast cancer patients. We had studied the ultrastructure of breast cancer specimens in in many patients by electron microscopy. Therefore, I decided to review these electron micrographs. I found that mitochondrial appearance in these micrographs could be divided into 3 groups:
- mitochondrial plentiful and normal
- mitochondria sparse and abnormal
- mitochondria essentially absent
After defining these 3 groups, the patient’s charts were reviewed. The patients in group one (mitochondria plentiful and normal) were found to have low grade tumors and good overall survival. The patients in group two (mitochondria sparse and abnormal) had more aggressive tumors, poor outcome and survival. The patients in group three (mitochondria absent), had very aggressive tumors with much poorer outcome and survival. This observation impressed me that Warburg was correct about cancer cell metabolism being caused by defective mitochondrial leading to aerobic glycolysis.
One night as I thought and prayed about this problem and how to approach it; I soon realized if mitochondria are evolutionary bacteria, then they may act like bacteria. I thought why can’t we isolate normal mitochondria from normal cells and see if they can enter cancer cells and reverse the “Warburg Effect”? This led to our work on mitochondria organelle transplantation in breast cancer cells. These results will be presented in the next posting.
We welcome comments and questions!
Robert L. Elliott, M.D., Ph.D., Dsc