Stem Cells, Health, Technology

Many biological systems exhibit remarkably high phenotype robustness, despite mutations. Mutations matter not. It’s the environment, stupid. And the environment is increasingly toxic. Diseases, including cancer, result.

The headline reads, “Cancer rates in people younger than 50 are rising, new study finds. Doctors don’t yet know why.” In 1977, four scientists, Higginso, Muir, Doll, Peto explained the evidences that 80% of all cancers were caused by environmental factors (our exposome). Whether we think about cancer or heart disease, environmental factors, not genetics, are causative. For example, infections are estimated to contribute to 20% of all human tumors, and fat in the diet increases colorectal cancer, prostate cancer, and breast cancer, to name a few. Exposure to a high fat diet will alter lipids (e.g., lipid derived hormones) and proteins (e.g., hormone receptors) in the body. What has happened is a mismatch between what the body evolved to eat and what the modern diet is providing many people. So there is a mismatch between evolutionary factors and diet. The genetic reductionists would erroneously call this a mismatch between genetics and diet. If we consider a mismatch between diet (exposome) and evolutionary factors, then a healthy intervention would be to modify one’s diet. Such an intervention would be efficacious, and importantly, without negative side effects. Instead, in our reductionist medical world that is focused on treatments for profit, the physicians want to change your genetics (the FDA, run by physicians, is one organization that sells this view). Yes, physicians want you to become a GMO (genetically modified organism).

Now there are some cool and expensive means by which they can modify your genetics. One technique is called CRISPR. Venture capitalists and private equity love this stuff. It’s a new way to make boodles of cash. These are some of the Neoliberal people funding our politicians and regulators in an ongoing effort to protect capitalism from democracy. The money making strategy is to do interventions on the person instead of preventative interventions on the person’s exposome through regulatory capture of the FDA and politicians overseeing the FDA. This group of people are so caught up in their little world, existing in an echo chamber that espouses the technological marvels that they fund are changing the world for the better. Their thoughts, they believe, are the objective truth. Money does this to people. Books, in this example, about CRISPR, will be written to falsely engender this VC-derived status quo in the greater populace. What we have here is status quo fundamentalism dressed up as objective truth. The more money they make, the more they believe they are the arbiters of objective truth. This is true throughout the money-making scheme of the US medical-industrial complex. The more money a physician makes, the higher they are on the pecking order. Surgeons think they’re the shit, because they make the most money. They don’t know anything about diet and health, but they’ll tell you not to eat healthy things like beans because they probably read something in Reader’s Digest about lectins. Because their minds have been captured by money, and money is derived by medical interventions not by preventative exposome strategies, CRISPR it is. People will be begging for it once the TV runs this story line over and over.

But it’s the exposome that mostly causes cancer, and the environmental influences act at many proteins pathways in the human body, leading to many types of cancer. The over reliance on highly reductionist genetic assays does not consider the complex and permutable pathogenesis of tumorigenesis.  One can have mutations galore, yet not have cancer. Dr. Mina Bissell, Ph.D., an eminent professor at Berkeley, showed us that decades ago. She has won a number of prestigious awards for her work. Cancer won’t express in cells riddled with mutations unless those cells are in an abnormal environment; i.e. a microenvironment/extracellular matrix (ECM) that is abnormal. This abnormal matrix is caused by abnormal proteins, such as damaged collagen or HAPLN-1. Further, if you take cancerous cells and put them into a normal microenvironment/extracellular matrix, the cancer reverts back to a normal phenotype – no more cancer, meaning no more abnormally high growth. Stress is one factor that disturbs the ECM and drives cancer. Stress activates cortisol, something that breaks down the ECM and can also inactivate the egress of stem cells. So stress breaks down the ECM through cortisol and hinders the rebuilding of the ECM through inhibition of stem cell egress. Stress is an important factor in our exposome. Such simplistic genetic mapping of disease would benefit, for example, by mapping of a given epigenome and proteome onto a set of phenotypes as a function of the environment. 

I’ve argued, and indeed there is much evidence for, an abnormal microenvironment/extracellular matrix being an underlying cause for many diseases, including neurodegenerative disorders. And what is the abnormal microenvironment/extracellular matrix? It’s mainly abnormal proteins – damaged proteins, or proteins in the wrong place. So an abnormal proteome is the underlying cause of disease, including cancer, not genetics. Just remember, biological systems exhibit remarkably high phenotype robustness, despite mutations. But, change the proteome, then the phenotype changes. And what changes the proteome? It’s the exposome. As an example, toxic air elicits toxic, inflammatory immune proteins in the human body. And inflammation has long been recognized as a major cause of disease, which then damages other proteins. It’s a cascade of damaged proteins damaging other proteins. Many proteins can act as epigenetic elements, including prions. They change the expression patterns of our DNA, and these expression patterns can be inherited. Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. Again, we’re not talking about genetic changes. Rather, we’re talking about proteins that alter DNA function without a change in the DNA sequence. Many of the proteins affecting DNA expression, epigenetic elements, are intrinsically disordered. That is, these proteins that affect DNA expression do not adopt a single structure in the cellular milieu (reviewed in Wu and Fuxreiter, 2016). Despite their prevalence in eukaryotic proteomes (e.g. ~30–40% of human proteins; reviewed in Vincent and Schnell, 2016), intrinsically disordered sequences have typically been omitted from biochemical studies for convenience (reviewed in Oldfield and Dunker, 2014). It is now clear that these disordered protein sequences, long thought to be unimportant, can drive diverse biological functions, including inherited functions. This includes protein inheritance and protein regulation of gene expression.

Yes, protein inheritance. Proteins themselves can be inherited (protein inheritance), without any interaction with DNA. This can be part of cytoplasmic inheritance where proteins are carried from the egg and the sperm. And proteins have another trick. Some can self-template and multiply themselves. Again, this occurs without the influence of DNA. Prion and prion-like proteins are known to self replicate. So proteins that are affected by the environment can themselves be self replicating or control other mechanisms of replication. Thus, the environment can control all mechanisms of replication through modifications of proteins.

We live in times where the EPA was gutted by Ronald Reagan, who was a shill for the rich and their corporations, and where current politicians such as Ron DeSantis in Florida have curtailed public health. While DeSantis was chiding people not to wear masks, the rate of Covid-19 infection and deaths skyrocketed. DeSantis would channel Reagan in the worst way, and without the swaying finesse that Reagan possessed. Grinding his teeth as he bullied small school children, DeSantis would be found out easily except for the easily fooled in state full of age-addled seniors. The early Reagan administration (1981–1983) launched an overt attack on the EPA, combining deregulation with budget and staff cuts, whereas the George W. Bush administration (2001–2008) adopted a subtler approach, undermining science-based policy. DeSantis has decided to follow their lead. As such, Florida has become a haven for biblical diseases, such as leprosy, malaria, West Nile virus disease, Eastern equine encephalitis, and St. Louis encephalitis. Other mosquito-borne diseases in Florida include chikungunya, dengue fever, malaria, yellow fever, West Nile virus, and Rift Valley fever. Dengue fever is particularly bad. The virus affects hundreds of protein types in your body. Parkinson’s Disease is one complication from a Dengue infection. Another is, you guessed it, cancer. Dengue virus infection has been found to be significantly associated with a higher risk of leukemia. Five people have died recently in Tampa from flesh-eating bacteria. Go to the beach in Florida, and die, or possibly deal with colorectal cancer as a result of the infection. A striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. Your exposome matters, including your exposure to bacteria and viruses, and good public health matters. DeSantis is clueless and reckless, and the people of his state, especially the children, suffer as a consequence. Meanwhile in Texas, the most polluted state in the US, controls on pollution are headed in the wrong direction. For example, Texas’ environmental agency enables companies to increase oilfield wastewater disposal in rivers throughout the state. Over 168 billion gallons of cancer-causing waste water is produced every year by oilfields in Texas.

If proteins being bombarded by a toxic environment is the main culprit in diseases, how did this mumbo jumbo about hereditary genetic diseases arise? Let’s look at how the simplified notion of hereditary genetics that many physicians believe came about. And remember, it is this simplified view of hereditary genetics, “baby science,” that has been foisted on the medical world by physicians such as Francis Collins, where even fraud is used to drive their preconceived ideas. Unless you’ve lived under a rock for the past 25 years you’ve heard the idea that once your genome has been sequenced your health status and disease susceptibility will be understood. Francis Collins said that everyone would be carrying a card with their genome sequence on it, and physicians would use the genetic information on the card to diagnose your ills. Silly stuff. It never happened, and never will. But Collins actually believed it. And much of the hysterical mass media were led to believe it too. No questions asked. A physician in a white coat has spoken, and you shall believe. Collins also believed that the scientists working for him had fully sequenced the human genome back at the turn of the century. They hadn’t. Leroy Hood, another physician, was also promulgating this genetic nonsense. Hood would make much money by creating companies that fooled people into believing his nonsense and investing big bucks. Arivale in Seattle was one of his failures. If what Hood was espousing were true, the company would be booming. But what the many people working on the human genome project had done was a partial, error riddled sequence of the human genome. Something that has little to do with disease.  As Dr. Alfonso Martinez Arias Ph.D. explains in his new book, “The Master Builder.” “It’s not our genes that define who we are, but our cells. And cells are composed mostly of proteins. Despite this, and because of his ignorance with only a baby’s grasp of the intricate science, Collins would claim in 2003,  ”If you are looking for a disease gene you can be confident that it exists in one continuous stretch of highly accurate sequence.” Simple solutions for complex problems are nice if they work. Twenty-five years hence, this one hasn’t.

Remember, if the physician driven idea that your health status is determined by genetics, then there is nothing you can do to change your health status. Only a physician with a drug or procedure is able to ameliorate the disease. The idea is simple, insidious, and is driving a generation of people with a highly increased incidence of disease. Looking for diseases in all the wrong places, in the genome, means missing where the diseases originates, the exposome.

When the genetics-driven medical revolution failed to materialize, the next mantra would become; diseases are complex and involve many genes, not just one gene. And the many genes are dispersed throughout the genome, making them hard to find and correlate to a particular disease. This would lead to years more of work, and millions of dollars in funding, to find the complex set of genes underlying diseases. It hasn’t worked, and never will. Why? Because most disease is driven by one’s exposome. Over 90%. This includes the ever rising number of people with cancer. From Bessonneau and Rudel (2020), “Increasing evidence suggests that environmental factors, rather that inherited genetic factors, are the major causes of chronic diseases, including breast cancer.” 

How did this medical genomics nonsense come about? Let’s look at the science, and then look at how medics “babyfied” the genetic science. In the mid-1800s, an Austrian monk named Gregor Mendel performed a series of pioneering experiments on heredity by breeding plants. Using garden peas (Pisum sativum), he demonstrated that traits such as seed color and plant height are passed down to the next generation in, as one example, a 3:1 ratio — three plants with yellow peas for every one with green peas. Mendel proposed that unknown particles, called “factors,” what we now call genes, were the source of this pattern of heredity. The type of factors inherited from the parents by each offspring determined whether the offspring would have the ‘dominant’ majority or ‘recessive’ minority trait. The work was beautiful, and initiated a framework within which to understand hereditary genetics. But it was only a part of the story. It was too simple. The Mendelian way of thinking left no place for the influence of the environment, natural selection, epigenetics and other considerations in heritability. Surprisingly, the hereditary genetics view also leaves out proteins, part of cytoplasmic inheritance, as important hereditary signals.

In the late 1800s, English zoologists William Bateson at the University of Cambridge and Raphael Weldon at the University of Oxford were formative in the hereditary genetics debate. The two opposed one another. Bateson was reductionistic – genetics, and only genetics, was what mattered. Weldon viewed variation in traits as a spectrum — influenced by genes, yes, but also by development, the environment and the ancestral history of each species. When Bateson was elected to a committee of the Royal Society of London, he used his influence to change the rules to prevent research by Weldon, and other committee members, being published in its journals. Weldon, incensed at what he saw as a deliberate attempt to silence scientific progress, established an independent publication, Biometrika, with his supporters — the eugenicist Francis Galton and his protégé Karl Pearson. Bateson, in turn, dedicated almost half of his 1902 book, Mendel’s Principles of Heredity, to attacking Weldon’s research directly. Bateson’s cancel culture would lead to a hundred years of overly simplistic genetic nonsense. The genetics cult had been born, and a simple story told over and over again by the cult’s devotees would create a massive following.

But some have learned to question authority. Scientists cannot be conservatives. We must always question what we know. Otherwise science stops, and conservatism rules. At that point you have a cult. You believe in something regardless of the evidence against it. And hereditary genetics became a cult where believing that heredity only came about through mutations in the genome. Many would believe in something regardless of the evidence against it and whether or not it’s harmful. Conrad Waddington was a scientist. He questioned authority and proposed in 1942 that traits can change before genes do. This occurs, for instance, when fruit flies (Drosophila melanogaster) exposed to ether develop a second thorax, complete with wings, where a wingless abdominal segment should be (C. H. Waddington Evolution 10, 1–13; 1956). Selective breeding of these flies results in offspring that develop a body with two winged segments without further ether exposure. Waddington named this phenomenon ‘epigenetic inheritance’ — epigenetic meaning ‘above the gene’. That this idea was rejected for decades is a testament to the tenacious hold of Mendelian inheritance pushed upon by Bateson. Jean-Baptiste Lamarck thought that changes developed during life that were a functional advantage to an organism could be inherited precisely because they were a functional advantage. The way to test that idea was pioneered by Conrad Waddington over 50 years ago (Waddington 1957, 2014), as recently argued Dennis Noble (2016, pp. 216–219). Physiologists have also found a number of inherited health problems that are not genetic (Gluckman and Hanson 2011). We’ve known this for many years. The effects of long periods of starvation can be detected through several generations in humans (Heijmans et al. 2008) and in animals (Rechavi et al. 2014).

In the popular literature, some people cite the cutting the tail off of a rat that is not epigenetically inherited as evidence against epigenetic inheritance. This is the so-called Weismann Barrier. But even Weismann didn’t believe this nonsense. More silly stuff. Cutting the tail off of a rat is not a phenotypic change, it just a wound and loss of tissue. Epigenetic inheritance occurs, including protein and cytoplasmic inheritance. Global changes in the epigenetic landscape are a hallmark of cancer, and proteins controlling the epigenetics are key to methylation and histone modifications. To summarize, proteins are subjected to environmental regulation, and proteins, having been affected by the environment, are responsible for most diseases. And epigenetic inheritance occurring though protein mechanisms is responsible for most inherited diseases. Cancer is not about genetics, it’s about proteins and epigenetics and how they are being perturbed by a toxic, infectious environment.