The approval of the first CRISPR-based therapy is just the beginning of more wasted money in our pathetic healthcare system. Although CRISPR makes unintended genetic modifications and deletions, potentially cancer-causing, there’s a bigger problem. Treating patients with CRISPR, a genetic modification procedure, is hype given that >90% of disease is environmental, not genetic. Example, most people with the genetic sickle cell trait do not have sickle cell disease (SCD). What triggers SCD – it’s the environment.
The multi-million dollar CRISPR-mediated somatic genome editing procedure of those with sickle cell disease has been approved. However, most people with the sickle cell genetic trait do not have sickle cell disease. That is, the genetic sickle cell trait is not causative for sickle cell disease. Please understand, the vast majority of people with the genetic alteration do not have sickle cell disease. So, is it a genetic disease – no. Are genetics involved, yes. Environment, our exposome, is the trigger for sickle cell disease. It’s a mismatch between ancient genetics, what we evolved in our bodies long ago to match the ancient environment, and today’s modern environment, including pollution and foods that we didn’t evolve to eat (more about this later).
So what is sickle cell disease and why did sickled blood cells evolve? First, red blood cells are typically round and flexible, so they move easily through small areas in blood vessels. In sickle cell anemia, some red blood cells are “sickled,” that is, they are shaped like sickles or crescent moons. The sickled cells also become rigid and sticky, which can slow or block blood flow. Resistance to severe malaria afforded by the sickle-cell trait has led to high frequencies of the sickle-cell mutation. Sickle cell is estimated to have originated more than 7000 years ago in tropical climates where mosquitos are transmitting malaria at high rates. Malaria is a severe disease and often life threatening. The sickle cell mutation is relevant to malaria because infection of a red blood cell with the malaria parasite (a type of plasmodium carried by mosquitos) leads to hypoxia (loss of oxygen). In individuals of the AS genotype such blood cells sickle and are then eliminated by macrophage cells of the body’s immune system, lessening the burden of infection (see Luzzatto, 2012). Considering the Sickle Cell Trait, sometimes a person will inherit a gene for normal Hemoglobin A from one parent and a gene for Hemoglobin S from the other parent. This is Hemoglobin AS, also known as sickle cell trait. Sickle cell trait occurs in one out of every 10-12 black Americans and usually causes no health problems. SS is a severe form, affecting 65% of people who have SCD. People with this form inherited one gene encoded with hemoglobin S from each parent. In the SS form, much of the hemoglobin is SS in the person, which can be triggered to cause chronic anemia.
An important method for distinguishing genetic from environmental influences is the study of identical twins. Identical (monozygotic) twins occur in about 0.4% of births. To be useful for studies of hematology and clinical features, both twins must survive long enough to provide adequate data. These conditions are not frequently met and the largest available study contained six pairs of identical twins in Jamaica (Weatherall et al. 2005). A comparison of twin pairs finds that genetic factors influenced growth and hematological indices but that clinical events in the twin pairs were frequently discordant, once again suggesting the importance of nongenetic influences.
While the role of genetic factors in sickle cell disease (SCD) has been extensively investigated, genetics only explains a small amount of the observed phenotypic variability in sickle cell trait individuals. The two best-characterized genetic modifiers are determinants of hemoglobin F (HbF) levels, and the co-inheritance of alpha-thalassemia. In the new CRISPR therapy, physicians remove a portions of the person’s own bone marrow stem cells, then scientists/technicians edit the cells with CRISPR, physicians destroy the rest of the person’s untreated bone marrow with potentially cancer-causing irradiation and/or chemotherapy, and then reinfuse the edited cells back to the bone marrow. To be clear, the CRISPR procedure for SCD involves a conditioning regimen of chemotherapy and/or irradiation, increasing one’s odds of cancer, to eliminate the patient’s stem cells to prepare the patient for the new edited cells.
In the clinical trial used for approval, patients had a history of at least two severe VOCs (clogged blood vessels) during each of the two years prior to screening. The primary efficacy outcome in the trial was freedom from severe (moderate and mild wasn’t considered) VOC episodes for at least 12 consecutive months during the 24-month follow-up period. A total of 44 patients were treated with CRISPR. Of the 44 patients treated with CRISPR, 29 (66%) achieved this positive outcome. In other words, 66% of sickle cell patients treated with CRISPR were able to be free of severely clogged blood vessels for 12 months. We always must ask the questions, “compared to what?” For example, was the treatment compared to something other than doing nothing? Nutrition is a factor, and CRISPR should be compared to diet strategies. Considering SCD is associated with intestinal barrier dysfunction, CRISPR treatment should be compared with those SCD people using a diet that remediates intestinal barrier dysfunction. But there’s no money incentive to test dietary treatments for SCD because physicians don’t make money by advising good diets and biotech doesn’t either. So the clinical trials for CRISPR treatment were compared to doing nothing, not compared to changing one’s diet to reduce the severe blood clotting. Would changing diet work better than the $3 million dollar CRISPR procedure? We don’t know because our privatized, deregulated, capitalistic health care system won’t make that comparison.
If we study a significant number of people in the SCD population, not just 44 people, how many will really benefit? How long will the positive benefits of the therapy last? What are the long term risks, and how many will later have cancer because of the treatment?. The science of CRISPR is truly remarkable, and deserving of a Nobel Prize. Prof. Dr. Jennifer Doudna, Ph.D., and Prof. Dr. Jill Banfield, Ph.D. who first described CRISPR to Dr. Doudna while the two were talking at Berkeley, are both pioneering scientists of the first rank. The medicine of CRISPR for gene editing is not so great, at least so far. CRISPR treatment is unproven, expensive, and potentially dangerous. It’s great for hype and for profits though.
Now for a twist in the story. I love using CRISPR for treatment. I invented and sell a product that’s been on the market since 2015. The way I use it is within a natural form – using CRISPR-containing bacteria to treat conditions where there is bacteriophage overgrowth, such as in acne. CRISPR in bacteria is an adaptive immune system that inactivates viruses, including the bacteriophage form of viruses. Bacteriophage populate bacteria in the skin in the acneic state because in this condition, the bacteria lose their CRISPR system and can’t inactivate the bacteriophage. The bacteria in the acneic skin are infected with inflammation-causing bacteriophage. Our MB-1 product provides CRISPR-containing bacteria to the skin to kill the bacteriophage, simply by spraying it on the skin.. It works well, is easy to use, and the procedure doesn’t involve huge amounts of money and adverse side effects. I learned about bacteriophage from Prof. Dr. Gunter Stent, Ph.D. when I was a student at Berkeley. He wrote a seminal book, “Molecular Biology of Bacterial Viruses,” (I still have my copy!) and was a great teacher. I was lucky to have learned from him, and would never have made this leap to using natural CRISPR as a therapeutic for bacteriophage had it not been for his influence.
Back to using CRISPR for gene editing of somatic cells in people. There’s a huge amount of money flowing into developing this treatment, and if the treatment really doesn’t work well and increases the odds of cancer, it’s a waste of money – especially because all of that time and money could be used to develop strategies that do prevent the triggers of the disease and do so without causing cancer. CRISPR diverts capital that could be used to develop much better strategies. Alas, genetics is in vogue and the hysterical mass media is largely unaware of the pitfalls – why? Because they bobble their heads when they see a physician in a white coat, someone mistakenly called “doctor,” who is either clueless about the etiology and epidemiology of disease, and/or just loves money and will do any procedure to make it, regardless of whether it works or causes illness. The guys in the white coats in the clinics also haven’t a clue about what CRISPR really is and what it does. Basically they’re little more than technical sales people for the biotech company. Whatever the FDA approves, they’ll sell – that’s how they make money. And what the FDA approves, usually doesn’t work, but only causes harm. I’m not making this up, they approve almost everything, and the drugs cause harm – even Glaxco scientists will tell you this.
As the CDC reports, “Most people with SCT [sickle cell trait] do not have any symptoms of SCD, although — in rare cases — people with SCT might experience complications of SCD, such as pain crises and, in extreme circumstances, sudden death. More research is needed to find out why some people with SCT have complications and others do not.” The CDC is saying that more research is needed to find the environmental causes of SCD, yet the money flows to genetic research and multi-million dollar CRISPR treatments that have limited value, and increase the probability of cancer in the treated patients. In a capitalistic healthcare system, this is big bucks for physicians, biotech companies, hospitals, and other adjunctive entities that have been medicalized.
So if most people with the genetic trait (SCT) don’t have SCD, what triggers the disease? The prevalence rates, i.e. proportion of people in the populations, who have the SCD is not known. We know more and more people have the disease, but we don’t know the prevalence rate. If that rate were increasing, we would have evidence that the environment is triggering more and more SCD. Is the increasing amount of pollution in the world triggering more SCD? We don’t know because we spend our money on genetic research and genetic therapies that have very limited value to mankind. Understanding and cleaning up our environment is not a big money maker for physicians and corporations – in fact, they would lose much money given that the environment is responsible for at least 90% of our diseases, and medical prescriptions for environmental changes are neither reimbursable nor understood to medics.
CRISPR for Heterozygous Familial Hypercholesterolemia
CRISPR is being used in clinical trials to treat another indication called Heterozygous Familial Hypercholesterolemia, where people who eat a poor diet have too much LDL (a form of cholesterol) in their blood. Again, we have a mismatch of ancient genetics with modern day diet. So the strategy here is to genetically modify the person instead of changing the diet. Here’s the trick in this study. The original CRISPR toolset acts like scissors that cut both strands of DNA, making the DNA edit, and then bringing the cut ends of the DNA back together. The process is complicated and often editing mistakes are made. For example, unintended rearranging of sequences can turn on cancer genes, what some scientists call “genetic vandalism.” In contrast, base editing is more precise, where only one DNA strand is edited. The base technique is less likely to injure non-targeted parts of the genome. Sounds pretty cool, right?
Ten people have been edited in this manner. One patient dropped out before completing the trial, so we’re down to 9 who received the gene-editing drug candidate. Only 3 people received the gene editor at therapeutic levels, i.e. a high dose. Of the 3 receiving the high dose, it temporarily taxed the liver, increasing markers for liver stress that gradually subsided. One patient dosed at the therapeutic level experienced a myocardial infarction (Grade 3) the day after treatment, where Grade 3 ischemia is a predictor of serious complications after acute myocardial infarction. And one of the 9 people studied receiving a low dose died from cardiac arrest about five weeks after the treatment.
How many of these people would have died or had a heart attack if they had instead of being gene edited, received a low-fat, low-saturated fat, low salt, low-processed carbohydrate, whole food plant-based diet loaded with fiber and micronutrients? We don’t know because these studies are not done. The dietary inclusion of flaxseeds, almonds, avocados, tomatoes, turmeric, and green tea, for example, have been found to lower LDL levels. As Salehin et al (2023) report, “An unhealthy diet is the most significant potential behavioral and modifiable risk factor for ischemic heart disease. Despite these established facts, dietary interventions are far less frequent than pharmaceutical and procedural interventions in the management of cardiovascular disease.” Again, diet prescriptions don’t make money for physicians, clinics, or biotech companies. Million dollar CRISPR procedures do.
All hail CRISPR gene editing medicine! Please bobble.
Stem Cells, Health, Technology 