Introduction
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"[7].
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.[1] 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.[2] 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 Överkalix'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. [3]
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. [4]
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[5]. These disorders
include obesity, hypertension, hyperlipidemia, and type 2 diabetes[6].
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 diabetes—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 timing—the ages at which grandmothers
and grandfathers experienced a food surplus—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.
The studies by Pembrey and other epigenetics researchers suggest
that our diet, behavior, and environmental surroundings
today could have a far greater impact than imagined on the health
of our distant descendants.
The Epilogue
So far in this paper I have only discussed epigenetics, a science
that is not directly related to homeopathy or miasms. But the whole
purpose of collecting all this research information in one place
is to create a framework for understanding the possibilities of
a relationship that might exist between epigenetics and miasms.
The theory of epigenetics and the research that has been done so
far makes one thing very clear – our diet, environment, toxins,
our social environment and family bonds – all have the ability
to modify our genetic code and its expression. This is not just
a new understanding into our evolution and adaptation but it is
very fascinating too! The big question that I will probe in the
next part of this article is ‘Can long-term chronic
infectious disease like Scabies, Gonorrhea and Syphilis induce epigenetic
changes in our genetic code?’ If we are able to find
a link then the theory of miasms will stand on a scientific footing!
References
1. Lumey LH: "Decreased birthweights in infants
after maternal in utero exposure to the Dutch famine of 1944–1945".
Paediatr Perinat Ep 1992, 6:240-53.
2. Kaati G, et al.: "Cardiovascular
and diabetes mortality determined by nutrition during parents' and
grandparents' slow growth period". Eur J Hum Genet
2002, 10:682-8.
3. Anway MD, Cupp AS, Uzumcu M, Skinner MK 2005
"Epigenetic transgenerational actions of endocrine disruptors
and male fertility". Science 308:1466–1469
4. Anway MD, Leathers C, Skinner MK 2006 "Endocrine
disruptor vinclozolin induced epigenetic transgenerational adult-onset
disease". Endocrinology 147:5515–5523
5. Morley R 2006 "Fetal origins of adult disease".
Semin Fetal Neonatal Med 11:73–78
6. Hales CN, Barker DJ 2001 "The thrifty phenotype
hypothesis". Br Med Bull 60:5–20
7. R.A. Waterland, R.A. Jirtle, "Transposable
elements: targets for early nutritional effects on epigenetic gene
regulation". Mol Cell Biol, 23:5293-300, 2003.
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