The Warburg effect is present in every disease!
Otto Warburg worked on cancer cells. From the beginning of the twentieth century, researchers knew how to grow cells in Petri dishes. The precursor was Robert Koch (1843-1910). He was the great German scientific rival of the French Louis Pasteur. To isolate the bacillus responsible for tuberculosis, he had the idea to grow it on agar-agar. Agar-agar was a sugar used by his wife for making Jello. Its utilization to grow and isolate pure cultures, stems from its ability of remaining transparent and “solid” at 37 °C. Moreover, most bacteria do not degrade it, meaning that colonies of germs can be seen and isolated.
The necessity for growing cancer cells was responsible for the improvement of such a culture medium. These cells are grown in a medium rich in fetal calf serum at 37 °C with 5% CO2 and 20% Oxygen. The very reason of the use of fetal calf serum and very high concentration of CO2 is not explained and appears to result more of a tradition dating from the early times of cell culture;
Warburg had invented a device with which he could measure cell respiration. The only cells available, at his time, were cancer cells. As he could not study human cells extracted from inflammation of Alzheimer, Otto Warburg did not study, if fermentation was present in other diseases than cancer.
Even today, normal cells barely grow in Petri dishes. What most researchers call normal cells, are not really normal. They have been modified to grow in the laboratories by the admonition of genes or transformed by a long chemical process. There are no inflammatory cells or cells from Alzheimer or autistic patient to study the Warburg effect in the laboratory.
Inflammation is a common feature
Galen described it in the Roman times as the association of tumor, pain, and increased temperature.
Multiple chemical molecules, trauma, heat or freezing, infection, pollution or allergy or even mosquito bite can cause inflammation. Inflammation has many names. Crohn’s disease is inflammation of the colon, while ulcerative colitis is inflammation of the rectum. Pneumonitis corresponds to inflammation of the lungs.
When a foreign body, such as a splinter, is inserted into the superficial epidermis, there is no inflammation. When the splinter reaches the underlying dermis where the capillaries lie, there is inflammation. The splinter has damaged the blood vessels.
Vascular leakage is a constant feature of inflammation. It is caused by direct damage, resulting from a foreign body, burn or necrosis. The leakage results in the extrusion of proteins from the blood to the surrounding tissues. There is no protein outside the blood vessels in the normal extracellular space. In inflammation, because of the vascular damage, these proteins flowing from the damaged vessel will reach the extracellular space to be broken down into smaller peptides. This increased concentration of proteins is a signature of inflammation. In the pleural effusion when the cause is inflammation, there is an increased concentration of proteins or in the feces of a patient suffering from ulcerative colitis.
When there is suspicion of meningitis, caused either by bacteria or viruses, the physician does a spinal puncture. Insertion of a needle into the spinal canal, allows collecting cerebrospinal fluid for diagnostic testing. Normally, there is little spinal fluid that extrudes and no protein in the liquid. If there is inflammation such as meningitis, there is increased pressure and proteins are present in the spinal liquid. Similarly, after a long exercise, the walker has blisters. The liquid is yellow because it is rich in proteins.
In every kind of inflammation, an extracellular liquid that is rich in proteins surrounds the cell. Such proteins will impact the diet of the surrounding cells. Some cells will die while others will proliferate. In the words of the physicists, the increased concentration of proteins increases the osmotic pressure. The Dead Sea contains water saturated with salts. Here, the osmotic pressure is high because of the high concentration of salts. If you take a bath in the Dead Sea, you can be hurt because of this increased pressure : if you have even a small blister or wound, you will get out of the salty water quickly.
Inflammation is a clinical feature. Increased osmotic pressure is a physical notion. They are synonymous. In every inflammation, you have increased concentration of proteins. The osmotic pressure normally at 300 mOsm jumps at 500 to 600 mOsm. If a high osmotic solution is injected under skin of the mice, there will be inflammation.
Here is a clinical demonstration concerning the treatment of constipation. The patient takes an enema rich in Sorbitol, a chemically inert molecule. Sorbitol is a solution having high osmolarity. The osmotic pressure results in increased pressure inside the rectum with water flowing in to decrease the osmotic pressure created by the Sorbitol. Diarrhea follows relieving the constipation of the patient.
Clinicians had suspected for a long time, the role of the Warburg effect in the inflammation. Here again, the evidence comes from the PET scan. When the physician looks for a deep-seated inflammation, he injects the same radioactive labeled glucose in the vein of the patient. The increased uptake of glucose is less than the one in a malignant tumor but it is enough to localize the inflammation.
Increased blood concentrations of glucose such as seen in untreated diabetes or obesity are a well-known risk factor of inflammation. To prevent death of the diabetic patients, because of torpid inflammation such as ulcers of the legs, the physicians had to amputate them. In animals a regime rich in sugar increase the risk of inflammation. Conversely, a regime low in sugar (low-carb or ketogenic) decreases the risks of inflammation.
Inflammation may resolve by itself and most bronchitis, burns, or hepatitis do not result in long term consequences.
Chronic inflammation is secondary to the persistence of the inflammatory agent and leads to fibrosis. For example, hepatitis resulting from persistent alcohol consumption, or unrelenting autoimmune disease will result into fibrosis of the liver. It is most commonly called cirrhosis, which means in Greek that the liver has become hard and fibrotic. Persistent bronchitis caused by excessive smoking may result in change in the lung architecture with lung fibrosis and emphysema.
Another consequence of chronic inflammation is the occurrence of cancer and neurodegenerative diseases, which needs to be further researched. In cancer, the release of entropy is in the form of biomass, cell proliferation and tumor growth. In neurodegenerative diseases the production of entropy (in the form of disordered biomass) increases. The secretion of the proteins outside the neuron results in the formation amyloid plaques in Alzheimer’s disease. In Parkinson’s disease, the proteins stay inside the cells as intracellular deposits (Lewy’s bodies).
The increased osmotic pressure in the extracellular space will divert the metabolic fluxes and cause the Warburg effect. M. Hamraz has grown cells in a Petri dish. Addition of mannitol in the culture medium increases the osmotic pressure around the exposed cells. Mannitol, like Sorbitol is chemically inert, but it increases the osmolarity. Within seconds, the cell opens its gates to glucose, shuts down its mitochondria and secretes lactic acid even in the presence of oxygen. This is the Warburg effect.
The cells under physical pressure from Mannitol express the Warburg effect.
Hamraz, M., Abolhassani, R., Andriamihaja, M., Ransy, C., Lenoir, V., Schwartz, L., Bouillaud, F. (2020). Hypertonic external medium represses cellular respiration and promotes Warburg/Crabtree effect. The FASEB Journal, 34(1), 222-236.
The role of inflammation is central to a wide variety of diseases. At the beginning of the twentieth century researchers wanted to induce cancer in the animals. They did not know that chemical or virus could induce cancer. They thus resorted to chronic inflammation. Their idea was to burn repeatedly the skin of the animals to finally cause cancer. The other option was to use what was called, the long forgotten, physical carcinogenesis. These researchers would thus implant silicone under the skin of the animal. If the implant was smooth, there was neither inflammation nor cancer. However, using harsh implant, the rat suffered from inflammation and later of cancer.
James, S. J., Pogribna, M., Miller, B. J., Bolon, B., Muskhelishvili, L. (1997). Characterization of cellular response to silicone implants in rats: implications for foreign-body carcinogenesis. Biomaterials, 18(9), 667-675.
What the clinician knows is that chronic inflammation paves the way for cancer. Lung cancer is a consequence of chronic bronchitis; liver cancer of cirrhosis and hepatitis. Chronic inflammation like Crohn’s disease or ulcerative colitis is a risk factors for colorectal cancer. Whatever the organ at stake, chronic inflammation always increases the risk for cancer.