IN THE BEGINNING THERE WAS DNA, AND THEN THERE WAS THE EPIGENOME
Books on epigenetics are flying off the shelves. These days, I’m often asked “whether a certain trait or phenomenon is genetic or epigenetic.” Back in the 1960s and 1970s, as more and more became known about DNA and its role in heredity, the debate was still about “nature or nurture?”: Are certain diseases and traits determined by genes or by the environment? Other concepts in this debate were “innate or acquired?” It became increasingly clear that one could not speak of traits that are purely genetically determined and others that are purely environmentally determined. It was always about both, but the ratio can vary enormously. But is “genetic or epigenetic” really the same as “nature or nurture”? Is the epigenome also heredity? Just as the genome is seen as the substrate of heredity and inheritance?
I’m from the era before DNA. During my medical training in the 1960s, DNA had only just been discovered as the vehicle through which genetic information was transmitted from one organism to another. DNA was responsible for the inheritance of traits—that was it. It was called an “information carrier.” The DNA codes became known. More and more was learned about the nature of the codes (base triplets) in the DNA that were thought to determine the sequence of amino acids, which in turn determined the properties of the protein “for which that DNA encoded” (quotation marks by the author JvdW). After all, the properties of a protein were determined by the sequence of amino acids from which it was composed. But there’s a catch in the phrase “the protein for which DNA codes.” “Coding” can be—and is often interpreted here as—an activity. Take it a step further, and you’re doing what many neurophysiologists do today: you’re giving the description a causal slant—in other words, the description becomes the (causal) explanation. A well-known expression in this kind of scientific euphemism is, for example: “This or that gene is responsible for / plays an important role in trait X.” And the unsuspecting layperson takes this even further, saying: “Trait X is in my genes. Can I help it that I’m this way? It’s because of my genes.” A geneticist wouldn’t put it quite so bluntly, but it was during those years that the so-called Central Dogma of molecular biology emerged. This was formulated in 1958 by Francis Crick (one of the “discoverers” of the structure of DNA) and held that the fundamental flow of (genetic) information within a cell goes in one direction: from DNA to RNA and from RNA subsequently to the proteins. The differentiation of cells and tissues in the embryo, for example, was reduced to “coding” and thus an “activity” from “inside” (the genetic code) to “outside” (the cell, and further on the organ, and even further on the organism). Related to this, the common jargon emerged that “genes are expressed” in the organism—yet another “activity” from “inside” to “outside.”
Everyone accepted the terminology without question. The concept of “DNA thinking” was born. This phrase was coined, among others, by me in a report published by a group of Dutch biologists and submitted to the Dutch government under the title *Is There a Future in Our DNA?* (1993). The embryologist Ernst Blechschmidt (1904–1992) also protested, loud and clear. He argued that DNA could never be an active principle. He also described the phenomenon of DNA being able to replicate itself as impossible. We now know that this is not the case. DNA cannot replicate itself, but it can be broken down by enzymes within the cell and then replicated again by other enzymes. Why did Blechschmidt reject the central dogma? According to the dogma of molecular biologists, differentiation in the embryo proceeds “from the inside out,” and it is the genes that determine which traits appear in the embryo. Of course, genes are determinative in a certain sense, but they certainly cannot be seen as the explanation or cause of differentiation.
At that time, embryologists had already been working with the concept for decades that zones develop within an embryo (later referred to as morphogenetic fields) in which cells differentiate into various types of tissues and cells. It was a matter of location and orientation. Morphogenetic fields are tissue zones in which, for example, the metabolic conditions of the cells differ from those of the surrounding environment, causing the cells to begin exhibiting different behavior. A good example of this is the morula stage in humans. These 8–64 cells are considered to be genetically identical, but morphologically they are no longer so, because—quite logically, I would almost say quite MORPHOLOGICALLY—a center and a periphery emerge within such a cluster of cells. (That said, this does not mean that a few-days-old embryo is nothing more than a “clump of cells”; it is a multicellular individual or organism, which is distinct from a mere clump of cells.) The metabolic conditions in the center differ from those in the outer zone. The cells in the center begin to behave differently, and eventually, other characteristics emerge there as well: the embryoblast forms. The cells in the periphery of the morula differentiate into a trophoblast. This can also be confirmed experimentally: it has been demonstrated that you can move an embryoblast cell into the trophoblast, after which it adapts to the new conditions and becomes a trophoblast cell. The reverse is also conceivable and demonstrable. However, after some time (one or more days), this is no longer possible, and the transplanted cell retains its original properties. Why? A common answer is: “by then, the properties have become fixed in the genes,” in other words: the cell has definitively differentiated. So neither the genes nor the DNA cause the differentiations but are differentiated within the context of the organism. The differentiation proceeds from “outside to inside.”
To embryologists and morphologists, it was clear: the organism is constantly differentiating into different fields, and these fields in turn differentiate into subfields, and in this way the whole organism differentiates into its parts and cells. Blechschmidt identified a pattern of eight distinct “metabolic fields” that can occur in the embryo. In fields where cells cluster together (densification), cartilage forms. In fields where cells are “stretched” (dilatation)—that is, organized in a linear fashion—muscle tissue forms. It is important to note that this does not concern biomechanical processes but rather physiological processes and the (growth) behavior of the cells. Blechschmidt’s “Stoffwechselfelder” are what others, such as the biologist Paul Weiss (1920) and Rupert Sheldrake (1980), have referred to as morphogenetic fields.
But geneticists and molecular biologists—and by extension, everyone and their mother—continued to think in terms of genes that “code for certain traits.” That something is a code is one thing, but that doesn’t necessarily mean it encodes. The article lying before you contains information, and you can read that text, but of course you can’t regard the letters and words in the book as the cause of the words and letters you read and the thoughts that arise in your mind. Information is a process. If the genetic information in the genome isn’t read in some way, nothing happens. That’s what Blechschmidt meant. But the geneticists seemed to think differently: the central dogma.
It was not until 2000 that the Human Genome Project (HUGO) was declared provisionally complete with great fanfare, and a rough map (90%) of the human genome was presented to the world in the presence of, among others, Bill Clinton, then President of the United States. The project took more than 10 years, involved thousands of geneticists, and cost billions. Today, with a modern DNA sequencer in a biological laboratory, one can “analyze” the genome of a human or an animal in just a few hours. But HUGO was also something of a disappointment. It had been thought that the project would take an enormous amount of time and yield a particularly complex genome because humans were believed to have far more coding genes than the simple organisms that had been studied up to that point. However, this turned out not to be the case. The current understanding is that a human has at most 20,000 to 25,000 protein-coding genes (exons). That is not particularly many. There are plants that have 50,000. And the difference from other so-called higher animals was also relatively small. The difference from a chimpanzee is at most 1 to 2%. A mouse has about 30,000 genes, and only a small number of genes are unique to the mouse compared to humans. It had already dawned on geneticists that it could not be the case that there was a gene for every trait. And those 20,000–25,000 protein-coding genes in humans accounted for only 1.5% of the total human genome. So what about the rest? At the beginning of this century, that 98% of DNA was still called junk DNA, because it was thought to have no function—since a gene was (at that time) defined as a segment of DNA that encoded a protein.
A quick aside on that last point. It has always surprised me that, back then in genetics, 98% of our genome was interpreted as “junk DNA.” It was thought to have no function—that is, it didn’t encode a specific protein. How can a biologist (since I assume most modern biologists are Darwinists or think in neo-Darwinian terms) possibly assume that, through evolution, a creature would develop with 98% “useless” DNA? I have always understood that useless things do not survive the thresholds of natural selection and survival of the fittest. In my interpretation of Darwin’s theory of evolution, useless organs or bodily structures naturally do not occur: everything in the body must have a meaning or at least a function. If a particular body part cannot be assigned a physiological function, it often does have a function morphologically and in the body’s morphogenesis. Later, the term “junk DNA” was relativized by the idea that it would partly involve evolutionary debris, e.g., viral DNA that had been incorporated into the human genome for a time and had more or less “stuck” there. But junk DNA is now at the center of genetic research because it is increasingly being recognized that so-called “non-coding” DNA plays a very important role in the regulation of genes and the structure of chromosomes (see below). It will likely take several more decades before junk DNA is also “decoded.”
Gene regulation? Yes, these days “orchestration” is the buzzword in genetic biology. You could say that a single set of genes can “account for” different organisms because, during an animal’s development, genes are turned on and off within a specific time frame (sequence and timeframe). It is also conceivable that genes are switched on and off in multiple phases of development. Clusters of genes that are activated together have also been discovered. The best-known example of this are the so-called Hox genes. These are genes that function as architects or blueprints of the body during embryonic development. They are thought to determine the placement of body parts, for example, along the anterior-posterior axis of the body. (Incidentally, the word “determine” reappears here as an activity!) And so the idea became increasingly accepted that genes—or the genome—are regulated, orchestrated. That there are molecular substances that can indeed activate a gene, inhibit it, or even multiply it, resulting in an enormous repetition of base codes. So, contrary to Crick’s central dogma, this involves information flows from “outside to inside.” These regulatory molecular substances were called epigenetic factors and are now even referred to as the epigenome. This would then be a kind of control system with which parts of the human genome can be turned on and off. This sparked a surge of interest in epigenetics within genetic biology. There are even biologists who, following the example of the HUGO project for the human genome, are attempting to map the human epigenome.
As a result, epigenetics—a branch of genetics—is currently the focus of much attention. A particular trait is linked to a specific genetic structure, but it is epigenetic factors that orchestrate the gene in question (including turning it on or off, or inactivating it under certain conditions and in specific regions of the developing embryo). And all of this is, in a sense, viewed causally: a particular trait may be epigenetically or more genetically determined. This is also how some genetic manipulations work: within the organism, genes are manipulated, activated, or silenced using epigenetic tools. This is a more subtle form of manipulation than the still-common method of manipulating DNA, which involves altering or blurring the code structure of a gene. I am referring here to the modern, common “cut-and-paste” approach in the genome, such as with the famous CRISPR-Cas method. In this way, knockout mice can also be created in which certain genes can be turned off using DNA methylation (a well-known epigenetic factor), for example, and then serve as a model for a disease caused by a specific genetic defect. Nowadays, for example, the aging of organisms is interpreted as a malfunction of the control system, the epigenome, and even something like biological age is determined by this epigenome and its activity.
But the morphologists and embryologists saw the outcome of the Hugo Project (once again) differently. Based on these new findings, they concluded: “See, those are our morphogenetic fields; it is not the genes that differentiate us, but rather the organism that orchestrates its genes and thereby differentiates itself.” One of the instruments or media for this within the organism are these epigenetic factors produced by cells, for example depending on the metabolic environment. And that brings us to Blechschmidt: Genes are not active principles that differentiate the body; the embryo is a whole, an organism, and it is the organism that plays with, registers, and differentiates its genes. The central dogma turns out to be a massive fallacy: differentiation proceeds rather from ‘outside to inside’.
To understand what’s going on here, you might compare a gene to a neuron. A nerve cell isn’t simply a cell that turns on and off and then, for example, triggers a muscle to contract; rather, a neuron constantly maintains a complex state of activity. The frequencies of the continuous depolarization and repolarization of such a neuron can change rapidly and create patterns. And depending on its state of activity, that neuron then has a certain effect on, for example, another neuron or a muscle cell. I think that with a gene, too, you shouldn’t think of it as an activity but rather as a (rapidly variable) state of activity. A gene is not simply a piece of DNA; a gene is a DNA strand that is packaged in a highly complex manner and embedded in a complex environment of enzymes and epigenetic factors. It is that “packaging” that determines the activity state of the genome. The genes in the cells of your fingertip are the same genes as those in your liver cells; the difference lies in the “activity state”: which parts of the genome are open (can be “read”), and which parts are “covered” or turned off? It is also important to realize that these variations in activity state are reversible and do not concern the genetic code itself.
I’ll draw an example from the human musculoskeletal system. In a limb, the bones are “enclosed” within a complex network of ligaments and muscles. It is the contraction and relaxation of these muscles that determine the position of the limb and its skeletal components relative to one another, and that allow them to adapt at lightning speed to the required posture or movement. In fact, our locomotion is not movement but a rapid change in the state of activity of our musculoskeletal system. The German language would speak of Gestaltung: a change in form and shape. With a little good will, muscles and skeletons can be regarded as a duality that works together. Together they determine the posture and movement, the state of activity of the limb. Neither is the cause of that state of activity: where would muscles be if they did not have the resistance of the skeletal elements? Both are necessary but not sufficient conditions for the state of activity of our musculoskeletal system. Think of the muscles as the epigenetic factors and the skeleton as the genome. If you alter the gene structure (code) through manipulation, that naturally leads to a different characteristic of the organism. If you saw off a piece of my thigh bone, I would have to move differently. But that does not prove that, in the normal, uninjured state, it is my skeleton that causes my posture and movement? The fact that genetic manipulation of a gene has consequences for the characteristics of the organism in question does not prove that that gene is the cause of the characteristic or encodes for that characteristic. “Determining” is not synonymous with causing; rather, the genome specifies the constraints and limitations. There are, so to speak, only two places in the world where (the change in) the genome causes (i.e., alters) a trait, and that is in the mutations that occurred during evolutionary development and… in the experiments of geneticists. Just like neurophysiologists, they manipulate a substrate, and that leads to a change: the intervention is then indeed the cause of the changes. But that does not prove that the normal, unaltered situation is also a relationship of cause and effect. No, genes are, a genome is, just like the brain, a necessary but not sufficient condition for traits or consciousness.
And so we’re back to square one. Back to square one? Yes, it is the organism that differentiates itself and orchestrates the genes to do so. DNA is not an active (coding) principle. DNA, the genetic code, is a necessary but not sufficient condition for traits. There are no diseased genes; organisms can be diseased, and this can be “caused” by an abnormal gene structure but just as easily by improper orchestration. In short: genes have no traits; an organism has traits, and a necessary but not sufficient condition for those traits is often a gene. But… The damage is done. The idea that genes are causal (differentiating principles) has remained firmly and massively entrenched in people’s minds. Even the fanatical and neo-Darwinist professor Richard Dawkins regards humans and all living beings as nothing more than vehicles for genomes and asserts that it is the genomes that evolve in evolution. I must strongly protest this. The mechanisms of selection, adaptation, and survival of the fittest have taken place and operated at the level of organisms and primary reality, not at the level of genomes. Moreover, I do not wish to be a vehicle for a genome. I am a being of mind and body, and humanity has evolved both thanks to and in spite of its genes. This also applies to the individual human being.
“It’s in my, our DNA”—it’s so easy to say. But is it true? Or is it perhaps only half-true? For an AIDS patient, you need both the HIV virus and a human being. For a trait, you need both a DNA code and an organism. Evolution did not take place at the level of genes. It was at the level of living organisms that it was determined whether a genetic mutation was functional and beneficial, and whether it was passed on to offspring. DNA was discovered in the quest to understand how heredity works as a process. Heredity had been known for a long time (almost since ancient times), but it was believed that the substrate of heredity was found in the chromosomes, the genes, and later DNA. That is indeed the case. It is about the transfer of information. But just as a virus can never become an AIDS patient, information on a genome can never become an organism. Of course, all sorts of things—such as predisposition and constitution—are “encoded” in our genes, but we are not our genes. In the past, we still had a constitution and ways of being; now we have only genes. People tend to view genes as something external to themselves more so than a constitution: “I can’t help being a criminal; it’s in my genes.” We are human thanks to and in spite of our DNA. Genes are the necessary but not sufficient foundation upon which we can develop as organisms. I believe, however, that I can calmly continue to present my phenomenological and spiritual embryology, which adheres to the adage that we do not begin as cells but that we are organisms from the very start. The zygote is not a cell but a single-celled human organism. And it is that whole that differentiates itself. Life did not begin with DNA; life began with single-celled organisms. And yes, indeed, on the border between life and death there are the viruses, conceivable as a packaged strand of DNA equipped with tools. But can they multiply on their own? No way; for that they still need the enzymatic machinery of living cells.
Finally, I’d like to say a few words in favor of epigenetics. Biologists such as Bruce Lipton and others have suggested that it may well be possible for us to alter the activity of our genes from external sources—and here we’re really talking about our environment (“nature”). That is conceivable and has already been demonstrated in some cases. For example, scientists studying the elderly are attempting to demonstrate that administering the body’s own substances can influence an individual’s biological age. But whether we can also alter the structure of our genetic codes and thereby pass on acquired traits to our offspring is still not widely accepted or proven. When it comes to explaining the mechanisms of development and evolution, we still have to rely on Darwinian models, but there are also increasing indications that Lamarck’s idea—that “nurture” can determine “nature”—might well have merit. Nature or nurture? remains the question. Both are half-truths and necessary but not sufficient conditions. Sometimes the ratio is 90 to 10, other times it is 10 to 90. DNA cannot possibly be the molecule of life. Roughly speaking, DNA is the most lifeless and highly structured molecule that living beings can produce; it is almost pure formula. As a substance, DNA is almost “formless” (“snot”) and devoid of properties. Life did not begin with DNA. This is becoming increasingly clear. Pure DNA is incapable of anything. DNA, in the context of an organism, can play a role, including in differentiation and in evolution.
What sometimes bothers me about scientific developments is that “the scientific community” isn’t very eager to admit that a particular concept, once considered dogma, has turned out to be a misconception. It’s sometimes said that medical treatments “last” no more than 20 or 30 years before they have to be replaced by another evidence-based treatment method. Fine, that may be the case, and it actually is part of the practice of science; constantly re-evaluating, and revising and adapting as necessary, is almost standard practice in science. But admitting and acknowledging mistakes—that is not so common in the scientific realm. Nowadays, societies, governments, and nations are expected to offer apologies and acknowledge that they have committed serious errors in the past, such as colonizing peoples and practicing slavery. But from the scientific community, you will never hear that “science” officially apologizes for such a terrible error in thinking as the central dogma. Why might that be important? Then those kinds of terrible memes like “it’s in my DNA” would not have taken root in people’s minds and exerted a significant corrupting influence on our society.
The final paragraph of the report *Is There a Future in Our DNA?* (1993) reads as follows: The prevailing paradigm (I would add: the neurogenetic paradigm) excludes the mind, and thus also the notion that there is more at work in the living reality around us than mere matter. The Dutch philosopher JH van den Berg (1984) summarizes it as follows. What is banished is ‘the idea that the world, both the living and the non-living, is not first and foremost governed by matter and by the laws of this matter. Also this idea that in living beings, life is the most important thing, and that after that comes the living matter that serves that life. The idea that life as such changes, evolves, and mutates, and that life, striving of its own accord, invites or compels molecular programming to change along with it […] As soon as the political obligation to think exactly the opposite lapses, the conviction returns that this well-ordered and well-adorned world around us is governed by spirit.”
Jaap van der Wal MD PhD, anatomist-embryologist and phenomenologist
Address: jaap.vanderwal45@kpnmail.nl. Sibemaweg 33D, 6224 DA Maastricht, Netherlands. Independent researcher – retired associate professor of medical anatomy and embryology.