All the discussions centering around the mRNA Covid shots miss one fundamental point in their haste to point to either all the possible side effects and death and mayhem, or the life saving technology that delivered an mRNA brew miraculously concocted in weeks. That point is our current understanding of genomics, or rather, our lack thereof.
If you want to proffer an armchair opinion (and almost everybody does) on the efficacy and safety of the mRNA Covid shots, you cannot offer a considered opinion without understanding what we currently know about genomics. Consider this article to be a ready reference guide, Genomics 101, made simple and you need to read it in its entirety before you utter another word on mRNA.
I’d recommend most medical professionals do the same, as clearly, most do not understand what science understands about genomics, so, without further ado, a brief refresher course. Some of it may appear a little hairy to the uninitiated, but trust me, stay with it.
Technology Breeches the Genome Bottleneck
Nearly 100,000 highly diverse whole genome sequences are now available through the National Institutes of Health’s All of Us Research Program. In a decade, our sequencing bandwidth or capability has gone ballistic, enabling us to evaluate all RNA/DNA at a single cell level and in thousands of cells, all in parallel.
As we became more adept and effective at sequencing, the associated costs of investigating our individual genetic codes went from prohibitive to ridiculously cheap, illustrated very effectively by the graph below.
You can clearly see the first inflection point in 2007 with the first generation of NGS (454, SOLiD, Illumina). Next-generation sequencing (NGS) is a massively parallel sequencing technology that offers ultra-high throughput, scalability, and speed. The technology is used to determine the order of nucleotides in entire genomes or targeted regions of DNA or RNA.
Fast forward to the second inflection point in 2016, less dramatic, but of equal importance, with the maturation of the long read sequencers at PacBio and Oxford Nanopore Technology (ONT). These platforms are able phase genomes (untangle mother and father genomes when sequencing diploid cells) and treat every human genome like it’s a de novo (new) assembly problem. They can find novel content unrelated to the original reference sequence.
Let’s unpack some of the technical stuff here.
Diploid is a term that refers to the presence of two complete sets of chromosomes in an organism’s cells, with each parent contributing a chromosome to each pair. Humans are diploid, and most of the body’s cells contain 23 chromosomes pairs. Human gametes (egg and sperm cells), however, contain a single set of chromosomes and are said to be haploid.
Flip this graphic upside down, and that shows you what long read sequencers are capable of. They can take your diploid cell and unravel it into its original components, basically mum’s contribution and dad’s contribution. Unravel the diploid cells of your parents and grandparents, and you have all the required chromosomes to build your family line from scratch.
You can also identify all sorts of genetic issues you may have been gifted with, so its a really useful tool, both to identify existing and potential conditions and predict genetic outcomes.
The first generations of NGS sequencers were short read sequencers. They operate by looking for differences between your sample and a genome provided as reference. If your sample has novel genes that are not in the reference genome, then those are typically overlooked. How did we arrive at a reference genome?
The original human reference genome comprised a pool of 20 volunteers but resulted in 70% of the genome being derived from one African American donor. Those 100,000 genomes were sequenced on short read sequencers (50bp-500bp) and mapped back to this reference genome.
Newer longer read sequencers (10,000- 1Mb reads) do not need to rely on a reference genome, but can instead build a hypothesis-free genome from each individual. This allows the discovery of novel(new) content. If you have the time and the desire, this article in science chronicles the history of our genetic journey to this point. The quote below is taken from the same article, entitled “The complete sequence of a human genome”
Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.Science, DOI: 10.1126/science.abj6987
You’ll note the use of the terms predicted, functional studies, errors and other language confirming what we seemed to have glossed over in our haste to rebuild the human. While we now have a complete parts list (we think so) and we have a map to assemble the parts, we still don’t know how the different parts interact, which bits are dependent on others bits, and how, introducing novel laboratory synthesized parts will impact the whole.
To illustrate this more clearly, lets look to some of the most recent genetic discoveries (post mRNA Covid jabs) to understand just how clueless we actually are. You understand of course that by using the term discovery, we are indicating that we are still exploring and by it’s nature, that term indicates risk.
Microscopes and Genetics
In 1665 Micrographia was published by Robert Hooke. Microgaphia was filled with drawings of objects Hooke had observed with his compound microscope. He was the first person to use the word “cell” when describing living organisms.
Fast forward to 2008 and the debut of the TEAM 0.5. It is the world’s most powerful transmission electron microscope and is capable of producing images half a ten-billionth of a meter.
As our tools and technology improved, we were gradually able to peel back layer upon layer of interdependent worlds hidden within each human on a cellular level. With each new discovery, came the realization that we are actually far more complex than we had ever imagined. Then, in the last few decades, wonder was replaced with hubris, humility a blood soaked victim left to die on the battlefields of commercialized science.
No longer do we wonder at the complexities unravelling before our eyes, our thoughts now focused entirely on the field of genetics as they key to untold wealth. Master the human genome and you can combat aging, perhaps even arrest it completely. You can, at the cellular level, target any disease and, in theory, irradicate it. The potential to engineer children’s physical traits as they grow in the womb isn’t a reach, it is without doubt being explored by scientists.
We are not searching for the Holy Grail anymore. We have decided it is easier to simply build it ourselves, and it this hubris that led to mRNA treatments for Covid being released on the general public, but I digress. Back to proteins, novel human RNA ligase and other exciting discoveries.
In the last few days the National Human Genome Research Institute has announced the completion of a 47 human ‘pangenome’ project. This is 47 diverse genomes sequenced Telomere to Telomere and properly phased with the new longer read sequencers. These are sequenced to a far higher standard than the initial Human Genome project, which used Sanger and BAC end sequencing.
This amazing achievement represents phased perfect hypothesis free genomes, all cross compared to each other from diverse genetics around the world. A true and representative map of all humanity. Wonderful, I hear you say, inspiring. So where is the rub?
Even with the amazing sequencing developments, we are still discovering the functionality of some of the esoteric genes discovered 2 decades ago. Our process of reading DNA far outstrips our capacity to understand what it means and many genes in the human genome are homeless. In other words, we can guess at their roles, but we do not understand their function.
So, we have our map, we have all the working parts (that we can see given our current technology – remember the microscope) but we still don’t fully understand the workings of the functional machine.
Which, some people may feel, is sufficient to justify us tinkering with the bits and pieces, all the while adding in novel “laboratory engineered” extras. The problem is we’re dealing with life, and mistakes at a genetic level can potentially have species wide impact. Forget asteroids and solar flares, science has now acquired the ability to end us all on an macromolecular level.
As melodramatic as that may sound, it is a very real risk and the custodians of this technology have over the last three years proved themselves to be less than completely trustworthy.
Discovering a Human RNA Ligase
Meet C12orf29, a Human RNA Ligase. A what? Let’s explain first what an RNA Ligase is. Without getting to technical, RNA ligases participate in repair, splicing, and editing pathways that either reseal broken RNAs or alter their primary structure. They play an important role and can have dramatic impact on how RNA interacts in a cell. Scientists have just identified a new one, or rather figured out what one we discovered a while ago, actually does.
Remember all the genes we discovered, the purposes of which we are still investigating? Genomics use the acronym Open Reading Frame (ORF) in their name and a chromosome name (C12 = chromosome 12) to refer to these. This particular one, C12orf29 was discovered in 2003 in a large full length cDNA cataloging project in Japan. Two decades passed with this gene remaining in the realm of mystery. We had no idea as to its purpose, until now.
At first glance, C12orf29 looks like just another enzyme that modifies nucleic acids, but it turns out it is far more important than that. Enzymes like this had never been identified in vertebrates prior to this discovery. This paper, post mRNA global distribution, underscores how little we truly understand about RNA processing in the cell.
What does C12orf29 actually do then? Cells are able to survive without it, but once you raise ROS in the cell (Reactive Oxygen Species) as occurs with an immune response, your RNA breaks down more readily. C12orf29 comes in to repair some of that damage. So people with LoF mutations – gene loss that occurs through natural loss-of-function (LoF) – in this gene might be very susceptible to transcriptomic dysregulation during infection.
Immediately the questions begin to pile up. We just injected billions of people with modified RNA and only afterwards discovered a major human RNA ligase that we were blind to before injection. We don’t know how the RNA modification in the mRNA vaccines will interact with this newly discovered RNA Ligase. Will it concatenate (link together) them? Will the cell turn the modRNA into miRNAs and then RNA Ligases join miRNAs into longer pieces with different RNAi footprints?
To put this into proper context, Moderna and Pfizer developed a product that uses mRNA without being aware of many processes that unfold in the cell, the various genes that can and do interact on the RNA, and the potential consequences of the myriad unknowns in their model. It is the engineering equivalent of equipping a racing car with faulty brakes and releasing it at the top of a steep cliff with dodgy brakes.
The odds of it arriving unscathed at the base are so small as to be negligible. You and I are that car and we’re all headed hell for leather down the hill, with no brakes, to the painful conclusion of an experiment that may take generations to unravel.
What you need to takeaway from this
C12orf29 is not an outlier, it is one of many unknown quantities impacting interactions at a cellular level. Will we ever understand the full processes at work in our bodies and simply because we don’t yet have the full picture should we avoid intervening in these processes?
In answer to the first question, there can be no doubt that, given enough time, we will in fact completely demystify the human body and the interdependent processes that drive it. It isn’t going to be in the next decade though. Discoveries take time, scientific evaluation and proper investigation and even with the help of iterative AI, we may well be another 50 years away from fully grasping the complexities of our physiology.
The answer to the second part of the question may surprise you. It is also a resounding yes, but in the same breath, a very qualified yes. Where cutting edge medicine is able to utilize delivery vehicles like mRNA to attack diseases like serious, life-ending cancers, the risks are far outweighed by the potential benefits to the patient, namely life and the extension thereof.
Getting offered that car with the iffy brakes when you’re dying, as your only means to get to your family at the foot of the steep cliff, makes sense. Insisting to perfectly healthy patients who’ve already been down the hill on foot, that they must climb in or risk loosing their livelihoods, is ethically and morally reprehensible. Lying about the condition of the cars brakes, simply confounds the sin.
So are all those who’ve been injected with mRNA going to spawn a second head or watch their offspring grow tails? Have we actually damaged our reproductive capacity as a species? Questions abound with no answers, other than the painful reality of having to wait it out. That is the price we now pay as a society for toying with science we don’t as yet fully comprehend.
There is no debate, in my opinion, to be held on the widespread use of mRNA technology or the LNPs utilized to deliver the treatments. If it were a weapon, it would be outlawed by the Geneva Convention as having the potential to end our species. If, after reading this, you’re still comfortable climbing in the car, good luck on the way down. Just please understand that others have elected to walk until a model comes out with reliable brakes.