Analyses of tumors sometimes reveal a gene rearrangement or mutation, but no DNA mutations are found in many cancers, suggesting that mechanisms for cancer initiation are broader than is typically thought. Thinking outside the cancer mutation box.
In the nineteen-seventies, Dr. Mina Bissell, Ph.D., a professor at UC Berkeley and the Berkeley Lab, was establishing the importance of the microenvironment in the development and spread of cancer. Meanwhile, at the same time, Dr. Bruce Ames, Ph.D., a professor of biochemistry at Berkeley, devised a ground-breaking way to test whether a chemical might cause cancer by assaying for mutagenesis. Various other concepts of cancer biology at the time were promulgated beyond what Dr. Bissell had found. Biology at the time was controlled by genetic fashionistas – the structure of DNA had been discovered and conceptualized, and biological reductionism was at its height. Some thought DNA was responsible for nearly everything. Dr. Ames’ studies of DNA mutagenesis were embraced therefore, while Dr. Bissell’s would only be embraced much later. Dr. Ames, like Dr. Bissell, knew very well that mutagenesis of DNA was not the whole story of cancer. But if we listen to physicians, such as Francis Collins, M.D. and Leroy Hood, M.D., proponents of genomic-based precision medicine, we are led astray. They predicted people would carry a card with their genome sequence on it, and physicians would use the genetic information to treat your disease. I remember when I was a professor at UCSD and a group of us heard Collins say this – we all laughed. This was so stupid. Knowing one’s DNA sequence has not been predictive of health. Within the framework of the DNA hype was one concept of cancer that was simple and easy to grasp – that cancer resulted from genetic mutations—changes in a cell’s DNA sequence that were related to cells dividing uncontrollably. These mutations were sometimes inherited, induced by viruses, or generated by random copying errors in dividing cells. They could also be produced by physical or chemical agents, such as radiation treatment, ultraviolet radiation, and benzene.
Drs. Ames and Bissell knew better than to believe the genetic hype. To the contrary, Dr. Bissell had published a paper finding that a cancerous cell full of mutations could be returned to a normal phenotype, a non-cancerous cell, by returning the cancerous, mutated cell back to a normal microenvironment. Key here is the root word – environment. In other words, the environment is controlling cancer formation. Dr. Ames, knew his test wasn’t a comprehensive method for predicting carcinogens. Epidemiologists were learning, for example, that exposure to estrogen-like chemicals, such as diethylstilbestrol (DES), increases the risk of vaginal, cervical, and breast cancer, and toxicologists found similar results in experimental mice and rats models. Further support for the non-mutagenesis model of cancer was that DES wasn’t found to be mutagenic in cell cultures. Instead, DES has been found to alter proteins and genetic expression. Additional classes of carcinogens were added to the list. One feature of cancer cells is that they avoid detection by the immune system. We now understand that chemicals that suppress the immune system, such as prescription cyclosporine, are cancer-promoting, even though they don’t cause mutations in DNA. Other drugs for the eye also increase the risk of cancer, such as the topical drugs used for glaucoma. Sadly, these drugs that lower intraocular pressure don’t work well (about 40% of people with glaucoma don’t have elevated IOP) and induce many eye and other health problems.
Our exposome, what we’ve been exposed to throughout our lives, determines about 90% of your health status (Rapapport et al, 2010), not genetics. Even so-called “genetic diseases” such as sickle cell anemia are characterized by, as the CDC says, “People with [sickle cell trait] usually do not have any of the symptoms of sickle cell disease and live a normal life.” So why is it that most people with the genetic trait said to cause sickle cell, don’t have the disease? We don’t know the environmental determinants of sickle cell because we don’t study them. Instead, because it’s easy to do so and is in fashion, we study the genetics and create unaffordable genetic treatments for the disease that are so cumbersome that it requires the patient to be in the hospital for months and potentially for a year while spending millions of dollars for one treatment. Not often discussed in the media is that the sickle cell treatment requires chemotherapy to eliminate bone marrow cells. Chemotherapy has side-effects, including an increased risk of different types of cancer. In this case, while the treatment paradigm can lead to diminished healthspan, focusing on the environmental causes of sickle cell can increase healthspan. A stated by Roberts et al (2012) in the prestigious journal, Science, state: “The general public does not appear to be aware that, despite their very similar height and appearance, monozygotic twins [twins with the same inherited genetics] in general do not always develop or die from the same maladies.” Again, it’s the environment, not genetics.
Treatment’s a money-maker though, something that will benefit a few – a few millionaires and billionaires, and possibly a few patients. To make even more money, the billionaires will have the drugs made in India, where it’s cheap to manufacture, yielding higher profits, record profits, for the wealthy drug companies. These bad drugs are a part of your exposome. Who cares if these drugs manufactured in India are killing and maiming people, the pharma companies make gobs of money and that’s what counts in deregulated capitalism. When I say the drug may benefit a few patients, we have to ask the question, “compared to what?” Will the treatment benefit patients who do nothing other than the treatment? Possibly it is better than doing nothing. Is treatment better than altering one’s exposome? Probably not. Most clinical trials for a treatment use “doing nothing” as the comparator. The trial will not be the treatment versus a beneficial alteration of the patient’s exposome. Such as clinical trial would likely lead to failure for the CRISPR clinical trial. If that happens, money is lost and we can’t have that because the treatment system is about making money.
Although FDA has approved this treatment, will it be commercially viable, and will it really work and be safe? Or will it be like most FDA approved treatments that don’t work, and the many that are later pulled from the market for severe safety issues? We live in a country that is dominated by the treatment paradigm, and largely ignores the most important determinant of our health – our environment. Calling sickle cell anemia a genetic disease, when the environment is key and most people with the sickle cell genetic trait don’t have symptoms, is but one example.
Looking at the greatest determinants of healthspan, exposure to environmental toxicants has been shown to associate with molecular hallmarks of aging (Pandics et al, 2023). Advances in geroscience have led to a paradigm shift in our understanding of the pathogenesis of chronic age-related non-communicable diseases (NCDs). It is now recognized that all age-associated diseases share common underlying cellular and molecular mechanisms of aging. These mechanisms include increased oxidative stress, matrix breakdown, cellular mitochondrial and energetic dysfunction, impaired cellular stress resilience, genetic instability and DNA damage, induction of cell senescence, heightened state of inflammation, epigenetic dysregulation, altered proteostasis, disruption of intercellular communication (including endocrine changes), stem cell dysfunction, and dysregulation of energy sensing pathways. Proteins are particularly labile, including to the many nanoparticles in the environment, leading to aging processes throughout the body. Aging is a great predictor of cancer.
A recent paper demonstrates how air pollution induces cancer. The mutation numbers in the control mice were not significantly different from those in the treated mice. Whatever had caused the tenfold increase in the number of tumors in these mice wasn’t producing new mutations inside the cancer cells. Using air pollution in a liquified form that can easily be applied, Hill and his colleagues suspected that the effects of the liquefied air pollution were found outside the cancer cell, in the cell’s microenvironment that Dr. Mina Bissell, Ph.D. had taught us decades ago. So they went back to the tissue, dissecting out the tumors, cutting slices, and looking under the microscope. The lungs of the mice that had been exposed to the air pollution, they found, were full of inflammatory cells, not an abnormal amount of mutations.
A key factor in the tumor development therefore were inflammatory cells, especially a particular type of macrophage which was releasing a potent inflammatory signal, interleukin-1 beta. When the interleukin-1 beta was blocked with an antibody, the effect of air-pollution exposure was reduced. When Hill, Lim, and Weeden performed their experiment with immune-deficient mice (no macrophages), the effect of air pollution disappeared. Evidence that the macrophages, and their chemical signals, were promoting tumor development.
Once again, the environment was causing the cancer, not mutations in the DNA. We need to spend more time and money on the environmental determinants of diseases, including cancer. Alas, this isn’t a money-maker for pharma and physicians.
Stem Cells, Health, Technology 