Nearly 200 years ago, the founder of Homeopathy, Dr. Samuel Hahnemann found out that the effect of many diseases like Scabies, Gonorrhea and Syphilis can be present even after the acute infection is treated. He found out that this effect can be present in future generations also without the actual infection being acquired. This trans-generational effect manifested in the form of ‘disease predispositions’. He called these effects ‘Miasms’. The effect in the same generation was called ‘acquired miasm’ and the effect that was present in future generations was called ‘inherited miasm’.
The idea of miasms has remained one of the most controversial propositions of Hahnemann. Some of his detractors even called it the biggest mistake of his life. But the hypothesis has persisted in homeopathic circles and homeopaths still use it clinically.
Epigenetics is a new stream of science which deals with the effect of environmental and other factors on our genetic phenotype. It basically studies the heritable effects of what we do and experience in this life time in our future generations and has strong parallels with Hahnemann’s theory of chronic miasms.
This paper tries to present an epigenetic explanation for the theory of chronic miasms. This is Part I of this 2 part series. The first part deals with the science of Epigenetics and the second part will deal with the theory of Chronic Miasms and the relationship between the two.
Epigenetics – A Primer
Epigenetics concerns the chemical groups that bind to DNA and its associated proteins. These help determine the selective use of genes and influence cell fate. Abnormal epigenetic modifications and control can cause disease, including cancer.
What is Epigenetics?
The conventional view is that DNA carries all our heritable information and that nothing an individual does in their lifetime will be biologically passed to their children. Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of ‘switches’ that turn genes on or off – and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans.
From the Greek prefix epi, which means “on” or “over”, epigenetic information modulates gene expression without modifying actual DNA sequence. DNA methylation patterns are the longest-studied and best-understood epigenetic markers, although ethyl, acetyl, phosphoryl, and other modifications of histones, the protein spools around which DNA winds, are another important source of epigenetic regulation. The latter presumably influence gene expression by changing chromatin structure, making it either easier or more difficult for genes to be activated.
Because a genome can pick up or shed a methyl group much more readily than it can change its DNA sequence, Jirtle says epigenetic inheritance provides a “rapid mechanism by which [an organism] can respond to the environment without having to change its hardware”. Epigenetic patterns are so sensitive to environmental change that, in the case of the agouti mice, they can dramatically and heritably alter a phenotype in a single generation.
The conventional wisdom on genes goes something like this: DNA is transcribed onto RNA, which form proteins, which are responsible for just about every process in the body, from eye color to ability to fight off illness. But even after the sequencing of the human genome (completed in April 2003), there were many unaccountable facts to deal with. Why identical twins aren’t exactly identical? Why some people are predisposed to mental illness while others are not? The science of epigenetics tries to explain these differences which cannot be accounted for by the conventional approach of genetics.
Only two percent of our DNA – via RNA – codes for proteins. Until very recently, the rest was considered “junk,” the byproduct of millions of years of evolution. Now scientists are discovering that some of this junk DNA switches on RNA that may do the work of proteins and interact with other genetic material. Epigenetics delves deeper into our genome, involving “information stored in the proteins and chemicals that surround and stick to DNA.”
The Three Main Types of Epigenetic Information are:
Cytosine DNA methylation is a covalent modification of DNA, in which a methyl group is transferred from S-adenosylmethionine to the C-5 position of cytosine by a family of cytosine (DNA-5)-methyltransferases. DNA methylation occurs almost exclusively at CpG nucleotides and has an important contributing role in the regulation of gene expression and the silencing of repeat elements in the genome.
Genomic imprinting is parent-of-origin-specific allele silencing, or relative silencing of one parental allele compared with the other parental allele. It is maintained, in part, by differentially methylated regions within or near imprinted genes, and it is normally reprogrammed in the germline.
Histone modifications – including acetylation, methylation and phosphorylation – important in transcriptional regulation and many are stably maintained during cell division, although the mechanism for this epigenetic inheritance is not yet well understood. Proteins that mediate these modifications are often associated within the same complexes as those that regulate DNA methylation.
How do epigenetic modifications affect genes?
Genes carry the blueprints to make proteins in the cell. The DNA sequence of a gene is transcribed into RNA, which is then translated into the sequence of a protein. Every cell in the body has the same genetic information; what makes cells, tissues and organs different is that different sets of genes are turned on or expressed.
Starting from a zygote, an organism should successively activate most available genes during development in order to live. Thus, at adult age, all genes should be active. However, the simultaneous activity of all genes would produce an uncontrollable chaos of gene expression patterns not allowing coordinated cell- and organ-differentiation. Therefore, many genes need to be more or less permanently inactivated after they have done their job. Such a status can be triggered and maintained by an epigenetic tag. Because they change how genes can interact with the cell’s transcribing machinery, epigenetic modifications, or “marks,” generally turn genes on or off, allowing or preventing the gene from being used to make a protein. On the other hand, mutations and bigger changes in the DNA sequence (like insertions or deletions) change not only the sequence of the DNA and RNA, but may affect the sequence of the protein as well.
There are different kinds of epigenetic “marks,” chemical additions to the genetic sequence. The addition of methyl groups to the DNA backbone is used on some genes to distinguish the gene copy inherited from the father and that inherited from the mother. In this situation, known as “imprinting“, the marks both distinguish the gene copies and tell the cell which copy to use to make proteins.
What role does imprinting play in disease?
Because of their growth-related aspects, imprinted genes likely play a major role in the development of cancer and other conditions in which cell and tissue growth is abnormal. Imprinted genes in which the copy from the mother is turned on (maternally expressed) usually suppress growth, while paternally expressed genes usually stimulate growth.
In cancer, some tumor suppressor genes are actually maternally expressed genes that are mistakenly turned off, preventing the growth-limiting protein from being made. Likewise, many oncogenes — growth-promoting genes — are paternally expressed genes for which a single dose of the protein is just right for normal cell proliferation. However, if the maternal copy of the oncogene loses its epigenetic marks and is turned on as well, uncontrolled cell growth can result.
In the collection of birth defects known as Beckwith-Wiedemann syndrome (BWS), abnormal epigenetics leads to abnormal growth of tissues, overgrowth of abdominal organs, and low blood sugar at birth and cancers. Similarly, in the imprinting disorder Prader-Willi syndrome, abnormal epigenetics causes short stature and mental retardation as well as other syndromic features.
There’s also evidence in mice that some imprinted genes may play a role in behavior, particularly in nurturing and social situations.
The Research That Has Been Done
Toward the end of World War II, a German-imposed food embargo in western Holland – a densely populated area already suffering from scarce food supplies, ruined agricultural lands, and the onset of an unusually harsh winter – led to the death by starvation of some 30,000 people. Detailed birth records collected during that so-called Dutch Hunger Winter have provided scientists with useful data for analyzing the long-term health effects of prenatal exposure to famine. Not only have researchers linked such exposure to a range of developmental and adult disorders, including low birth weight, diabetes, obesity, coronary heart disease, breast and other cancers, but at least one group has also associated exposure with the birth of smaller-than-normal grandchildren. The finding is remarkable because it suggests that a pregnant mother’s diet can affect her health in such a way that not only her children but her grandchildren (and possibly great-grandchildren, etc.) inherit the same health problems.
In another study, unrelated to the Hunger Winter, researchers correlated grandparents’ prepubertal access to food with diabetes and heart disease. In other words, you are what your grandmother ate. But, wait, wouldn’t that imply what every good biologist knows is practically scientific heresy: the Lamarckian inheritance of acquired characteristics?
In a remote town in northern Sweden there is evidence for this radical idea. Lying in Ã–verkalix’s parish registries of births and deaths and its detailed harvest records is a secret that confounds traditional scientific thinking. Marcus Pembrey, a Professor of Clinical Genetics at the Institute of Child Health in London, in collaboration with Swedish researcher Lars Olov Bygren, has found evidence in these records of an environmental effect being passed down the generations. They have shown that a famine at critical times in the lives of the grandparents can affect the life expectancy of the grandchildren. This is the first evidence that an environmental effect can be inherited in humans.
Professor Wolf Reik, at the Babraham Institute in Cambridge, has spent years studying this hidden world. He has found that merely manipulating mice embryos is enough to set off ‘switches’ that turn genes on or off.
It has been shown that babies conceived by IVF have a three- to four-fold increased chance of developing Beckwith-Wiedemann Syndrome.
And Reik’s work has gone further, showing that these switches themselves can be inherited. This means that a ‘memory’ of an event could be passed through generations. A simple environmental effect could switch genes on or off – and this change could be inherited.
Arturas Petronis MD, PhD, Head of the Krembil Family Epigenetics Laboratory at the University of Toronto, in an article in the Nov 2003 American Journal of Medical Genetics, fills in some of the blanks: We know that there is a high concordance of identical twins with bipolar disorder, but epigenetics, he explains, may account for the 30 to 70 percent of cases where only one twin has the illness. Identical twins share the same DNA, but their epigenetic material may be different. Moreover, whereas DNA variations are permanent, epigenetic changes are in a process of flux and generally accumulate over time. This may explain, Dr Petronis theorizes, why bipolar disorder tends to manifest at ages 20-30 and 45-50, which coincides with major hormonal changes, which may “substantially affect regulation of genes … via their epigenetic modifications.”
In a 2003 pilot study, Dr Petronis and his colleagues investigated the epigenetic gene modification in a section of the dopamine 2 receptor genes in two pairs of identical twins, one pair with both partners having schizophrenia and the other having only one partner with the illness. What they discovered was that the partner with schizophrenia from the mixed pair had more in common, epigenetically, with the other set of twins than his own unaffected twin.
Recent laboratory studies on inbred mice demonstrated how changes to their diet might influence their offspring. Their fur can be brown, yellow or mottled depending on how the agouti gene is methylated during embryonic growth. When pregnant mothers were fed methyl-rich supplements such as folic acid and vitamin B12, their young developed mainly brown fur. Most of the babies born to control mice (not given the supplements) had yellow fur. Just as the conductor of an orchestra controls the dynamics of a symphonic performance, epigenetic factors govern the interpretation of DNA within each living cell.
In another experiment, scientists exposed mid-gestation pregnant rats to an environmental toxin (endocrine disruptor) at the time of embryonic gonadal (testis) sex determination. The offspring, or first generation males, had lower sperm counts and abnormal spermatogenesis (sperm production) in the testis. Approximately 10% of the animals were completely infertile. 
When this first generation was mated, the males passed down the same male low fertility disease state to the second-generation males, and so on. We found this disease state passed on through the four generations examined. This transgenerational disease condition occurred in over 90% of all males in all the generations we examined.
The frequency of disease transmission cannot be explained with a genetic DNA sequence mutation that would occur at less that 1% of progeny. Analysis suggested an epigenetic mechanism involving abnormal methylation of specific genes.
In a repeat experiment, transient exposure of a gestating female rat during the period of sex determination to the endocrine disruptor vinclozolin (ie anti-androgenic endocrine disruptor used as a fungicide in the fruit industry) induced an adult phenotype in the first F1 generation of breast tumors, prostate disease, kidney disease, immune abnormalities and premature aging. These adult onset diseases were transferred through the male germ-line to 85% of all males of all subsequent generations examined (ie F1-F4). The frequencies of diseases are similar to those observed in the human population. The mechanism involved is an epigenetic one involving an alteration in DNA methylation of sperm and the induction of new imprinted-like genes that modify the epigenome. This reprogramming of the epigenome becomes permanent and allows the abnormal pathology to be transferred transgenerationally to all subsequent progeny. 
An important emerging literature in humans is based on the observation that birth weight is inversely associated with a cluster of metabolic disorders now identified as the metabolic syndrome. These disorders include obesity, hypertension, hyperlipidemia, and type 2 diabetes. Moreover, these maladies are transmitted transgenerationally. In humans, this explains patterns of disease, especially those for which risk is determined in part during development, such as type 2 diabetes, cardiovascular disease and the rising risks of childhood obesity.
Such effects are readily experimentally induced, against a constant genetic background, by manipulating maternal diet or endocrine status in a broad range of mammalian species, including sheep, guinea pig, rat and mouse. In many of these experiments, birth weight was unaffected. The underlying mechanisms differ depending on when the adaptive response was cued by such environmental factors in development. Factors acting in the peri-conceptional period affect genomic imprinting and other epigenetic processes, hormone receptor development and embryo/trophoblast cell allocation, whereas cues later in fetal development alter structural and/or functional differentiation of tissues. The range of environmental stimuli and the capacity to induce a similar postnatal phenotype from early or late gestation cues suggests multiple pathways to a common and evolutionarily protected phenotype. There is also evidence that the magnitude of the fetal adaptive response and its long-term outcome is influenced by specific genotypes.
Michael Meaney, a biologist at McGill University and a frequent collaborator with Szyf, has pursued an equally provocative notion: that some epigenetic changes can be induced after birth, through a mother’s physical behavior toward her newborn. For years, Meaney sought to explain some curious results he had observed involving the nurturing behavior of rats. Working with graduate student Ian Weaver, Meaney compared two types of mother rats: those that patiently licked their offspring after birth and those that neglected their newborns. The licked newborns grew up to be relatively brave and calm (for rats). The neglected newborns grew into the sort of rodents that nervously skitter into the darkest corner when placed in a new environment.
Traditionally, researchers might have offered an explanation on one side or the other of the nature-versus-nurture divide. Either the newborns inherited a genetic propensity to be skittish or brave (nature), or they were learning the behavior from their mothers (nurture). Meaney and Weaver’s results didn’t fall neatly into either camp. After analyzing the brain tissue of both licked and non-licked rats, the researchers found distinct differences in the DNA methylation patterns in the hippocampus cells of each group. Remarkably, the mother’s licking activity had the effect of removing dimmer switches on a gene that shapes stress receptors in the pup’s growing brain. The well-licked rats had better-developed hippocampi and released less of the stress hormone cortisol, making them calmer when startled. In contrast, the neglected pups released much more cortisol, had less-developed hippocampi, and reacted nervously when startled or in new surroundings. Through a simple maternal behavior, these mother rats were literally shaping the brains of their offspring.
In November 2005, Marcus Pembrey, a clinical geneticist at the Institute of Child Health in London, attended a conference at Duke University to present intriguing data drawn from two centuries of records on crop yields and food prices in an isolated town in northern Sweden. Pembrey and Swedish researcher Lars Olov Bygren noted that fluctuations in the towns’ food supply may have health effects spanning at least two generations. Grandfathers who lived their preteen years during times of plenty were more likely to have grandsons with diabetesâ€”an ailment that doubled the grandsons’ risk of early death. Equally notable was that the effects were sex specific. A grandfather’s access to a plentiful food supply affected the mortality rates of his grandsons only, not those of his granddaughters, and a paternal grandmother’s experience of feast affected the mortality rates of her granddaughters, not her grandsons.
This led Pembrey to suspect that genes on the sex-specific X and Y chromosomes were being affected by epigenetic signals. Further analysis supported his hunch and offered insight into the signaling process. It turned out that timingâ€”the ages at which grandmothers and grandfathers experienced a food surplusâ€”was critical to the intergenerational impact. The granddaughters most affected were those whose grandmothers experienced times of plenty while in utero or as infants, precisely the time when the grandmothers’ eggs were forming. The grandsons most affected were those whose grandfathers experienced plenitude during the so-called slow growth period, just before adolescence, which is a key stage for the development of sperm.