Cancer, the second leading cause of death in America, is perhaps medicine’s greatest remaining mystery. Medical research has revealed the underlying causes of most of the world’s diseases from micro-organisms causing infections to atherosclerosis causing heart disease and strokes to genetic diseases like sickle cell anemia and cystic fibrosis. But for such a common disease, we simply don’t know the answer to the all-important question — what is cancer? Why does it develop? Our understanding has undertaken many radical shifts, most recently in the past decade.
The ancient Greek physician Hippocrates, often called the father of modern medicine named our ageless foe using the word karkinos, meaning crab. This surprisingly astute description underscores the difficulty of cancer treatment, as well as its propensity to scuttle around the body, or metastasize. The ancient Greeks believed that all diseases were resulted from an imbalance of the four humors — blood, phlegm, yellow bile and black bile. Inflammatory diseases were caused by too much blood. Jaundice was caused by too much yellow bile, and cancer was caused by too much black bile. Treatments aimed to remove the excess black bile, including those oldies but goodies — bloodletting, purging and laxatives. But try as they might, nobody could actually find any black bile.
By the 1700s, humoral theory gave way to lymph theory, which attributed cancer to a fermentation and degeneration of stagnant lymph fluid. This theory correctly focused on the fact that cancer is derived originally from our own tissues that had somehow become perverted. By the mid 1800s, the microscope allowed another major leap forward in understanding cancer by focusing on the cells that make up our tissue, which were observed to grow exuberantly and out of control. This formed the basis of the first modern paradigm of understanding cancer — as a disease of excessive cellular growth.
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A normal adult organ, such as the lung, does not keep growing over time until it is the size of a small boulder. Normal lung cells also don’t move around, heading downtown to chat with the liver. Yet in lung cancer, a small group of rogue cells proliferates and does not stop growing or moving around, until either you kill the cancer or it kills you.
This paradigm of cancer as a disease of excessive cell growth suggested a logical solution to those pesky cancer cells. Kill them. From this paradigm, we developed weapons of mass cellular destruction — cutting (surgery), burning (radiation) and poison (chemotherapy). Doctors calibrate and combine these indiscriminate methods of killing cells to kill the cancer slightly before they killed the patient. If they were lucky. This was an impressive advance in cancer therapeutics and still forms the basis of many of today’s treatments. However, these modalities of this first paradigm ultimately reached their limits by the mid 1970s because it did not answer the deeper question of why those cancer cells were growing excessively.
The transformation of normal cells into cancerous ones is not an entirely random process. Things that increase the risk of cancer are called carcinogens. The earliest identified substance was soot (causing scrotal cancer), but since then, tobacco smoke, ionizing radiation, asbestos and certain viruses and bacteria have all been identified as carcinogens. Finding the link between all these disparate carcinogens could suggest the solution to what was causing cancer.
The genetic revolution of the late 20th century provided an answer, leading to a new understanding of cancer. Genes contain the necessary instructions for cells to either grow or stop growing and a mutation of those genes could command cells to grow excessively. All carcinogens cause genetic injury, and by chance, damage to a critical growth gene could lead to cancer. By the 1990s, the first new treatments targeting the underlying specific genetic defect succeeded beyond our wildest imaginations. It seemed simple to find the specific genetic defect of each different type of cancer and develop a drug or antibody to correct it. Multi-national research efforts with multi-billion-dollar budgets like the Human Genome Project and The Cancer Genome Atlas searched diligently for those genetic mutations. Did they find some? Yes, you could say that. By 2018, almost six million different mutations in various types of cancer have been identified
The variation was bewildering. Some cancers had hundreds of mutations and others had none at all. Different patients with similar cancers had distinct mutations. Even within the same patient, cancers taken from different sites had distinct mutations. Finding drugs to counter all these mutations was clearly impossible. As the enormity of the task dawned, progress in cancer therapeutics slowed. The new genetic paradigm of cancer started with great promise that has been largely unfulfilled. Once again, this hypothesis failed to answer the question of why. Genetic mutations were causing cells to grow too much. But why were these cells mutating?
Recently, a new and fascinating concept of cancer has emerged. Cancer develops through genetic mutations, but those mutations are not random. There is only one power in the biological universe strong enough to coordinate the hundreds of gene mutations into a coherent behavior that defines cancer.
Cancer is an evolutionary disease. But cancer does not evolve in a ‘forward’ manner but ‘backwards’. Cancer cells are more primitive than normal cells. Cancer cells are less specialized. Cancer cells are less differentiated. Indeed, these are the very terms used by pathologists to describe the appearance of cancer cells. The medical term anaplaisia, often used to describe cancer cells, is derived from the Greek roots ana “backwards” and plasis “formation”. Cancer is not some random genetic mutation but a targeted reversion to an evolutionarily earlier state. Cancerous behavior already exists buried deep within all cells and cancer is following this guided path back towards its evolutionary origins as single celled organisms. Why?
Some researchers hypothesize that this cellular reversion is a survival response against chronic damage. Persistent, sub-lethal toxins, such as tobacco smoke or ionizing radiation place a natural selection pressure that favors the simpler, hardier earlier cell that contain more survivalist traits, but also manifests those traits that make cancer unique — its excessive growth, its propensity to move around (metastasize) and its immortality.
This explains how the seed of cancerous behavior exists in all cells of multicellular organisms — from humans to dogs to rats to simple life forms like the microscopic hydra. By pursuing the mystery of cancer’s genesis past the beginnings of humanity and right to the edge of multicellular life, this paradigm of cancer as an evolutionary disease has many profound implications and answers many of the paradoxes of cancer. How can cancer develop from any cell in the body? How can cancer affect virtually every multicellular life form on Earth? Why is cancer so common?
But even the hardiest seed cannot flourish without the proper soil. In conditions of excessive nutrition and growth (obesity and type 2 diabetes, for example) cancer is an enthusiastic passenger. Reshaping our view of cancer as an evolutionary disease means we can apply the entire field of evolutionary biology to ‘the cancer problem’ and begin taking back control of those factors that affect its growth. The seed of cancer may exist in all our cells, but that does not mean we have a predetermined date with the Emperor of all Maladies. We have the power to change the soil in which this seed is planted, and therefore, our oncologic destiny. Read more in my book, The Cancer Code.
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