CHAPTER 12 - Epigenetics
Are identical twins really identical?
Most people would say, “Well, they have the same DNA don’t they? Of course they’re identical.”
It’s true that identical twins have the same DNA. As embryos, they start off as one cell, but at the time of the first cell division from one cell into two, the eggs fully separate. They start to divide again as two individual cells, forming two individual embryos from a single fertilized egg.
But on the long road from a single cell to the trillions that make up a human being, subtle changes emerge that give rise to differences in the physical characteristics (the “phenotype”) of each twin.
Scientists wanted to know why. They had the same genes, so why didn’t all the genes turn on in the same sequence and give rise to twins that should be almost carbon copies of each other? Were there switches that helped to turn the genes on or off, that differed between each twin? Eventually, the study of these genetic switches (in twins, plants, insects and human disease) would form the science of epigenetics.
Epigenetics is often misunderstood. The multiple definitions that have been used by different researchers over the last few decades hasn’t helped the confusion [272-275]. But to think of it more simply, epigenetics is the study of mechanisms that change the action of DNA, without change to the DNA code itself, some of which may be passed onto the next generation of cells.
Epigenetics is important to biology. It’s through epigenetics that individual genes are turned on and off at the right time, making each cell what it is - a skin cell in the skin, liver cell in the liver, nerve cell in the brain etc. It also controls what enzymes or other proteins the cells need, and when. It’s involved in the timing of our development - for example, there is evidence that epigenetics has a key role in the timing of puberty in girls [276].
The epigenetics involved in the function and replication of adult cells has been fairly well studied. But when it comes to the epigenetics that is involved in the passing of characteristics from generation to generation, there isn’t much data from animal studies, and even less from human studies. Because this side of epigenetics is poorly understood, a lot of myth gets easily passed off as fact in the lay scientific media. When it comes to the passing of epigenetic ‘marks’ from generation to generation, the vacuum of knowledge is filled with speculation that seems to fit our preconceived ideas.
Bird sums it up: “Despite the paucity of data from animal studies, this type of epigenetics has caught the general imagination because, in principle, it is stable but potentially affected by the environment. The possibility that acquired ‘marks’ can be passed from parents to children has a deliciously Lamarckian flavour that has proved difficult to resist as a potential antidote to genetic determinism.” [277]
This theme, that we are not the sum of our genes but that we can make our own choices and rewire our thoughts, is one of Dr Leaf’s key themes. She often claims that epigenetics is science “finally catching up with the Bible”. She also teaches that toxic thoughts create epigenetic marks which are then passed on to your children, as if epigenetics was the biological vehicle for the “Sins of the Fathers” affecting their children, grandchildren, “unto the third and to the fourth generation.” (Exodus 34:7) So it’s important to establish what the current scientific understanding of epigenetics is, and then see if Dr Leaf’s assertions about epigenetics and thoughts fit.
In order to do that, I need to briefly take you through some basic cell biology to establish some fundamentals, and then we will look properly at the science of epigenetics.
Biology of cell division
Our body is made up of cells. Cells are arranged in groups, which are called tissues. Tissues of different types cluster together to form organs, and multiple organs working together make up the body.
Cells in our body are constantly dying and are replaced by new cells. Each tissue has a number of cells whose job it is to divide to form new cells. In babies and children, cells are produced in a controlled way and more cells are produced than die, which provides growth. In an adult, the number of cells made roughly equals the number of cells that die, maintaining our function. In disease states and in normal aging, the number of cells produced can’t keep up with the increased loss of cells, and so our organs atrophy (shrink and shrivel).
The type of cell division required in this process of growth and maintenance is a form of copying, which is called “mitosis” (pronounced “my-toe-sis”). In mitosis, the DNA is preserved. Every new cell gets all 46 chromosomes, a full complement of DNA.
There is a different form of cell division that takes place when sperm cells and egg cells are made. Sperm and eggs are designed to meet together, so to ensure the new embryo only has 46 chromosomes, the sperm and the eggs go through a process of division called “meiosis” (pronounced ‘my-oh-sis’). In meiosis, each sperm or egg cell only gets 23 chromosomes, one of each pair of chromosomes, allocated at random.
The process of sperm production occurs all the way through the life of a man, from puberty until old age. Up to 120 million sperm are produced daily. It takes about 74 days for a sperm to reach maturity. Sperm that aren’t utilised are broken down after about 30 days [5: p975-6].
The process of forming eggs is completely different. A woman’s entire set of eggs is formed when she is still a foetus. At the time of birth, there are 2 million ova, but half of these are “atretic” (meaning: “deteriorated”). The degeneration of the eggs continues during development, and the number of viable eggs across both ovaries at the time of puberty is less than 300,000. Only one of these eggs reaches maturity per menstrual cycle (or about 500 in the course of a normal reproductive life); the remainder degenerate [278].
Cell biology of gene regulation
All of our cells have the same DNA, but our bodies contain many different types of cells: nerve cells, liver cells, blood cells, skin cells, and many others. Different cells are made because different parts of the DNA code are utilised. Imagine an Easter Egg factory. There are different varieties of Easter Eggs, but the basic recipe and shape are much the same for all of them. The same basic set of instructions for shape and recipe will be used for all the eggs, but then there will be other instructions, one set of instructions for a different size of one variety, and another set of instructions for a different flavour of another variety.
In a similar way, cells share a similar basic structure and function, and will require the same basic DNA code for all cells. But the variety of cells, tissues, and organs require extra instructions that differ between the different types. Each different type of cell has certain sets of genes that are "turned on" or expressed, as well as other sets that are "turned off" or inhibited. They come about because these cells have distinct sets of transcription regulators. Some of these regulators work to increase transcription while others put the brakes on.
Normally, transcription begins when an RNA polymerase binds to a so-called promoter sequence on the DNA molecule. In recent years, researchers have discovered that other DNA sequences, known as enhancer sequences, also play an important part in transcription by providing binding sites for regulatory proteins that affect RNA polymerase activity. Regulatory proteins cause a shift in chromatin structure that promotes the reading of the DNA code. A more open chromatin structure is associated with active gene transcription.
Some regulatory proteins control multiple genes. This occurs because multiple copies of the regulatory protein binding sites exist within the genome. Consequently, regulatory proteins can have different roles for different genes, and this is one mechanism by which cells can coordinate the regulation of many genes at once.
Epigenetics in the normal cell
Epigenetics comes in to help with this process of regulation. Each of the three main epigenetic mechanisms changes the way the DNA interacts with the regulatory proteins, which help control the genes that are active or inactive.
DNA methylation is a chemical process that adds a methyl group to a specific DNA code sequence known as a CpG site. DNA methyltransferases (DNMTs) are enzymes that add the methyl tag. DNA methylation is used in some genes to differentiate which gene copy is inherited from the father and which gene copy is inherited from the mother, a phenomenon known as imprinting [279].
Histones are proteins that help DNA to wind into a tight bundle. Without histones, DNA would take up a lot of room. “Unraveled, the DNA contained in each cell would stretch nearly 2 metres, yet the DNA must fit inside the cell nucleus, a structure about 6 microns (six thousandths of a millimeter) in diameter. This is equivalent to stuffing 10,000 miles of spaghetti into a regulation-sized basketball.” [280] Histones are modified in two ways, either by the addition of an acetyl tag or a methyl tag, to an amino acid called lysine. Methylation of a particular lysine (K9) on a specific histone (H3) is a common marker of gene silencing. In contrast, methylation of a different lysine (K4) on the same histone (H3) is a marker for active genes [279]. RNA antisense transcripts, noncoding RNAs, or RNA interference can also turn off genes.
What controls the methyl and acetyl tagging of the DNA strand and the histone complex? The answer is the activity of specific enzymes that catalyse the process. These proteins are themselves made by the machinery of the cell following the instructions of the DNA code.
Epigenetics according to Dr Leaf
Dr Leaf refers to epigenetics a number of times, in the same style that she promotes all the science that she discusses. She writes that epigenetics is a new scientific breakthrough which shows that science is finally catching up with the Bible. The first evidence of DNA methylation was proposed in 1969, so it’s a bit of an exaggeration to call it a new scientific breakthrough. That aside, Dr Leaf writes in her prologue,
“What you are thinking every moment of everyday becomes a physical reality in your brain and body ... These thoughts collectively form your attitude, which is your state of mind, and it’s your attitude not your DNA that determines much of the quality of your life. This state of mind is a real, physical, electromagnetic, quantum and chemical flow in the brain that switches groups of genes on and off in a positive or negative direction based on your choices and subsequent reactions. Scientifically, this is called epigenetics” (original emphasis) [2: p13-4].
So according to Dr Leaf, thoughts form attitudes, attitudes then become your state of mind, and thoughts effect the flow of every known substance or force, which switches genes on and off at will. She takes her fundamental assumption, “mind controls matter” and extrapolates: Thoughts control everything including epigenetic tagging, and since we also control our thoughts, we therefore control our own epigenetic code.
She follows on from this in the Introduction chapter, “How we think not only affects our own spirit, soul and body but also people around us. Science and Scripture both show how the results of our decisions pass through the sperm and ova to the next four generations, profoundly affecting their choices and lifestyles. The science of epigenetics (the signals, including our thoughts, that affect the activity of our genes) explains how this plays out.” [2: p24]
Again, the assumption that “mind controls matter” is key to her tangential logic: Epigenetic marks can be passed onto subsequent generations. And thoughts can control epigenetic marks. And the Bible says that God punishes the sins of the fathers to the third and fourth generation. Therefore our thoughts can be passed on to our great great grandchildren through epigenetics.
In chapter 3, Dr Leaf expands her theory via a full chapter on epigenetics. Her opening paragraph contains her fundamental assumption, “Our choices - the natural consequences of our thoughts and imagination - get ‘under the skin’ of our DNA and can turn certain genes on and off, changing the structure of our neurons in our brains. So our thoughts, imagination, and choices can change the structure and function of our brains on every level: molecular, genetic, epigenetic, cellular, structural, neurochemical, electromagnetic, and even subatomic.” [2: p55-6] That’s quite an expansive list. Dr Leaf doesn’t offer any evidence here about the validity of her all-encompassing statement; she just states it as truth.
She goes on, “... the science of epigenetics, which is tangible, scientific proof of how important our choices are ... This is because choices become signals that change our brain and body, so these changes are not dictated by our genes. Our thinking and subsequent choices become the signal switches for our genes.” [2: p56]
That’s a very brave statement to make. If thoughts really are the primary driver that switches our genes on and off, then perhaps Dr Leaf can explain what’s driving the signal switches for the genes of embryos, who don’t have any thoughts or make any choices. Plants don’t think at all, yet their genetic machinery and epigenetic tagging works just fine. Dr Leaf’s statement about the influence of thoughts on our genetic function is nonsensical.
In the next section, Dr Leaf attempts to clarify further, “The decisions you make today become part of the thought networks in your brain.” [2: p57] She then discusses the genetic code that we have in matched pairs of chromosomes, the assumption being that the decisions become part of the thought networks of our brain through genetic and epigenetic means. The data from our working memory that we sometimes perceive as our thoughts can also become part of our neural network, but only by the formation of memory. Memory is not dependent on genes or epigenetics any more than any other cellular process is, except for the more permanent forms of memory, which involve gene expression to make a protein needed to keep the neuron in an excitable state [281].
She summarizes with an overly simplistic model of epigenetics, “So methyl markers switch off genetic expression and acetyl markers switch on genetic expression. The ‘switching on or off’ is based on the signal, and we can choose to switch.” [2: p61] While it’s true that methyl markers of CpG islands of DNA are mostly associated with repression of gene activity (“switching off”), the DNA of some actively transcribed genes have been found heavily methylated, so methyl tags may do nothing at all [282], while methyl marking of histone proteins can switch genes off or on [272].
Even if we could influence the methyl tagging of our DNA and histones by our thinking, how do we have any control over which of the 30,000 genes we would be switching on or off, and in which of our trillion cells? Specifically tagging a specific gene sequence within a specific cell would be like tagging a single grain of sand in a sand box. So Dr Leaf’s statement about our epigenetic markers is overly simplistic, and there is no evidence that our thoughts control epigenetic markers.
The generational curse
Perhaps the most audacious suggestion that Dr Leaf makes is that epigenetics is the vehicle by which thoughts can pass down from generation to generation. She opens the next section of the chapter with, “Science has demonstrated how the thought networks pass through the sperm and ova via DNA to the next four generations.” [2: p57] Although when she says that “Science has demonstrated”, she actually meant, “Because Time Magazine said so”.
In the Time Magazine article “Why Your DNA Isn't Your Destiny” [283], several examples of trans-generational passage of traits are given. Most notable are those in roundworms or fruit flies. The agouti mouse described by the article, and tendered by Dr Leaf as evidence of epigenetic inheritance, were pregnant when fed the diet high in methyl group donor vitamins. The vitamin caused the gene to change its expression, but only for one generation, which is not an example of epigenetic inheritance, just a change in prenatal nutrition. This isn’t a new discovery, but is well documented and is a standard medical practice. Pregnant women have been using prenatal supplements for decades, like folate to reduce the risk of spina bifida, for example.
The article also discusses a study of generations of Nordic families and the association of their nutrition to the longevity of their offspring. Interesting for sure, and possibly evidence for imprinting, but we already know that correlation does not equal causation, so it remains to be proven if the Time magazine claims are robust.
Scientific mysteries?
Dr Leaf suggests that no one really understands why identical twins are not always identical, although she would have us believe that it’s their individual perception of the world that causes the difference [2: p58].
In truth, there really is no mystery. Those who hold that epigenetics is the key to genetic expression don’t tell you that the effect of genes on a person’s development is up to nine times stronger than epigenetics and environmental factors, depending on the trait in question. For example, Autism has a correlation between identical twins of up to 90% [284]. Of the remainder, epigenetics will account for some and so will other environmental effects.
Epigenetics is a complex pattern of markers that change rapidly without the same precision as DNA. Unlike DNA, which has one copying error in about 100 million base pairs, epigenetic tags have an error rate of one in twenty five [277]. The epigenetic tags undergo a process known as “epigenetic drift” which is the natural loss of the epigenetic tags at random parts of the DNA.
Epigenetic markers also affect different cells differently, and different tissues differently, depending on the timing of the environmental stimulus. For example, an epigenetic change of an embryonic stem cell will change the development of the embryo into a baby, and possibly an adult. An epigenetic tag of the DNA of a mature adult cell will only affect that cell [285]. How that plays out is going to differ wildly between individuals, even with the same genome. Most epigenetic marks don’t make any difference at all [277, 285].
Scientists refer to the epigenetic system as being stochastic in nature [72]. “Stochastic” means “having a random probability distribution or pattern that may be analysed statistically but may not be predicted precisely.” [3] Epigenetics is not particularly precise.
Nor is there solid evidence that epigenetics is intergenerational in humans. DNA is stripped of epigenetic tags as the sperm and ova are formed. So any epigenetic tag that’s formed is unlikely to make it through to the second generation, let alone the fourth. Kota and Feil confirm, “In the early germ cells, called primordial germ cells, the genomes are wiped clean of most of their DNA methylation and of other covalent chromatin modifications that are associated with somatic gene regulation, so that germ cells can acquire the capacity to support post fertilization development.” [286]
Coming back to the facts about the life-cycles of sperm and eggs that I discussed earlier, it’s clear that only epigenetic marks made after the development of the sperm would be passed on to the children. This limits the effects on generations of most epigenetic changes to the last 104 days. When eggs develop, most of them die, and the ones that do survive discard three quarters of their original DNA, which has already been stripped of its epigenetic markers anyway [286].
There is currently no evidence that how we think changes the function of the DNMT enzymes that write the epigenetic tags onto the DNA, nor the effects of the stress system. It’s a brave call to suggest that the mind is the epigenetic factor that switches genes on and off [2: p58-9].
Choices and predispositions
Dr Leaf further extrapolates by suggesting that the bad choices of parents go on to become the children's predispositions because of epigenetics [2: p58-9]. But as I discussed before, if that were true, only bad choices made in the previous 74-104 days by the father could be passed down to curse the next generation, as that is the life cycle of a sperm.
In women, any specific epigenetic marker that could be passed on to her children would have to be made to the specific egg that was ovulated at the time of conception. Since there are about one million potentially viable eggs in the ovaries of a woman when she is born, the chances of a specific choice getting passed on literally becomes one in a million. But epigenetic markers don’t specifically target egg cells, so a single choice could affect any cell in amongst all the cells in a woman’s body, which blows out the probability to more than 100 trillion to one.
Based on probability alone, the change of a single choice being passed onto the offspring is so small that it is approaching zero.
What’s more, only some of the bad choices could ever be passed on, because of epigenetic drift, the high error rate in copying epigenetic marks, and the stripping of the epigenetic code when gametes are formed. The random, unpredictable nature of the epigenome doesn’t sound like a tool that would be used by a just, loving and eternally unchanging God.
Therefore, despite Dr Leaf’s bold claims, the suggestion that our bad choices or sins are passed onto our children through epigenetics is both bad theology and bad science.
In the section “Scientific Evidence of God’s Grace”, Dr Leaf writes, “Scientists have found that in a loving and nurturing environment, acetyl epigenetic markers increase on the genes in the hippocampus that keep us calm and peaceful. The more acetyl markers, the more these peace genes in the hippocampus express and dampen the stress response. A toxic choice produces the opposite effect: The acetyl markers reduce and the methyl markers increase, causing us to have less peace.” [2: p61]
Modern scientific findings show that Dr Leaf’s conclusions are overly simplistic. Wu et al [120] reviewed a number of studies which showed that stress in mice and rats actually increased histone acetylation, not decreased it, the opposite of what Dr Leaf claims. It should also be noted that the studies done on imprinting from maternal care, which Dr Leaf alludes to, showed changed to the epigenome from maternal care in mice and rats. The data does not relate to personal choices in humans. Dr Leaf’s conclusion is tenuous at best, and is not scientific evidence of God’s grace, unless she’s referring to the grace of God in rodents.
The ultimate ironic twist is that most epigenetic markers are dependent on genetic factors for their formation or the level of their expression [285]. So despite Dr Leaf claiming that epigenetics means we are not the product of our genes, the truth is that epigenetics is just as much dependent on our genetic expression as the rest of our biology.
Conclusion
Epigenetics is fundamental to life, changing the way in which the genes in our DNA are recruited or silenced. Even though it was first written about nearly 70 years ago, it’s still a relatively young field of research. There is lots of excitement about it, the “cutting edge craze” if you will. Epigenetics will be the key to a number of mysteries that current science still finds locked tight.
Dr Leaf assumes that all epigenetic markers influence generations to come, when in fact there are only a few examples in plants and insects, one or two in animals and none in humans. She makes a number of other broad and very bold claims about epigenetics to attempt to support her theories, which are not backed up by the current understanding of the science of epigenetics.