Dhanvantari Ayurveda Center Michael Dick, Ayurvedic Practitioner, Leesburg, Florida e-mail:
Inside This Issue
Health and Science in the News
The Book Corner
Genetics and Ayurveda
Science and Health in the News
Some of you have heard about the use of bee sting therapy for treatment of pain associated with arthritis, MS, tendonitis, postherpetic neuralgia. Nut did you know that ancient Egypt and China used this therapy. Further, Hippocrates wrote about its use in connection with painful joints, too. (Source: Joe and Terry Graedon)
Food supplement, pycnogenol, has antiinflammatory and antioxidant actions. The Graedons report one reader got total remission from atopic dermatitis (eczema) after using it for 6 months.
Readers of People's Pharmacy submitted anecdotal accounts of successful use of Listerine for head lice. It's been reported that head lice have become immune to the insecticides used for their treatment. Speculations include alcohol accounts for this effect and possibly the thymol, eucalyptol, menthol, and methyl salicylate.
Know someone with Raynaud's disease (cold hands and feet, sometimes including numbness, pain, whiteness or bluishness) try taking a little cinnamon in your diet. Graedon's report reader popped cinnamon capsules and gained perfect relief after 6 weeks. Careful, cinnamon has a compound that is liver toxic when taken in excess--coumarin.
People's Pharmacy readers tips for relief from skin tags: New Skin Liquid Bandage when used for few weeks; Compound W; tying off at base with fine thread to starve blood supply leading to falling off.
Got a pesky case of nail fungus? Try equal parts of Listerine and white vinegar applied topically AM and PM--takes a long time. --Graedon's
The AP reported that testing with American ginseng might lessen cancer fatigue and the flaxseed might slow the growth of prostate tumors. Groups taking flaxseed, on post surgical histological examination, showed cancer cell growth 30-40% slower than control group.
The AP reported in June, 2007 that the FDA will begin phasing in a new rule that is designed to address concerns that existing regulations allowed supplements onto the market that were contaminated or didn't contain ingredients claimed on the label. This has been a long-standing problem and now dietary supplement manufacturers will be subject to more careful scrutiny of their products and their labeling.
THE BOOK CORNER
Recently, a book by the name of Plant Spirit Healing (Eliot Cowan, Swan-Raven & Co., and imprint of Blue Water Publishing, Inc, Newberg, Oregon, 1995), came to my attention and I purchased and read it. Cowan has been trained in shamanism and has practiced for about 30 years. He wrote the book to make known these extensive but arcane shamanistic practices and beliefs. This book is his story of how he came to know about and to become trained it native American shamanism; in the final chapter he presents 5 histories of shaman practitioners, having different teachers. Each story gives a slightly different picture of shamanism.
His truth is that plants possess healing power in two forms: a) the physical, chemical, and energetic nature of the plant and b) its spirit. We all know about the former but the latter is intriguing. I was made aware of this possibility some years ago when talking with others about how expert Ayurvedic doctors select and use plants for medicine. Two names comes to mind: Dr. Balraj Maharshi and Dr. Dvivedi. One or both communicated with plants psychically and learned their nature and uses directly from the plants. He writes of another way, by communing with the plant spirits, to enlist them to do the healing directly, rather than the herb itself. Dr. Dvivedi learned from the plant spirits what the plant body was useful for, whereas, Cowan writes of how one can enlist the plant spirit. Cowan made me aware that there are two ways of using intuition to be able to use plant-based therapies. Cowan writes (p. 24), additionally, there are four ways to build power of communing with the plants: special psycho-tropic drugs, dreaming, drumming, and pilgrimage. The first one is interesting because it evokes the memory of the Aryan use of the Soma Sacrifice. Some researchers feel soma was a psycho-tropic mushroom that opened the doors of perception to the higher Reality and hence would have infinitely expanded healing powers of the practitioner.
Cowan, describes interactions with spirits of plants that shamans supplicate to help heal humans. Cowan states that the spirits of the plants actually agree to do the healing on a spirit-to-spirit basis. The plant's constituents are not part of the healing, as no plant part is taken by the patient, but it's the spirit of a particular plant that has the power to help in the respective disease. Further the plant spirit works of the spirit of the sick body. This is purely energetic healing.
This book has implications for disease modeling; we have written on this topic in previous issues of The Ayurvedist. This model of American Indians includes the theme of spirit possession; and curse frequently is prominent among other cultures--notably, the African experience. Cowan also points to mental/emotional causes of disease. While he didn't state this directly one gets the impression from his writings that most diseases have this connection. From his writings ONLY we find a corroboration of our view of agents of disease: mental/emotional and spiritual. From what we know of the subject we can add toxicity and infection to their disease modeling. Treatment is generally different in each case, however, Cowan gives the impression that no matter what the agent of disease plant spirit healing may be invoked and applied successfully.
For these cultures the field of medicine / healing is consequentially quite esoteric and arcane. The diagnosis and treatment requires an expert—a shaman or similar tribal figure. “Purification” protocols usually have a very different theme, even at times are quite brutal and violent.
See the book inside cover for more readings on this topic.
Genetics and Ayurveda
In July of this year I viewed a "Nova Science Now" documentary. Its theme dealt with the human genome, specifically the epigenome. The genome is the term chosen to represent the DNA and surrounding/accompanying material. This statement means that there is DNA (comprised of 4 base sequences--ACGT) or gene material and non-gene matter. The latter is the object of our interest here as theorists have described its role in terms of the nature/nurture debate.
Ayurveda declares that one inherits tendencies and these tendencies display as vata, pitta, and kapha materially and functionally; Ayurveda also affirms that the control of vata, pitta, and kapha is effected through diet, lifestyle, and thoughts/feelings, etc.. We have mentioned in earlier Newsletters the identical-twin research that has confirmed this point--nurture accounts for 70% of the influence for health outcomes and genes only, on average, for about 30% of health outcomes.
What is interesting is how science is explaining the validity of the identical twin research findings--the epigenome. The epigenome has been shown to regulate gene expression and diet and lifestyle regulate the epigenome. (See detailed technical explanation of epigenetics below from Wikipedia.com .) Recently researchers are finding that obesity in adults manifests as increased tendency of childhood obesity in following generations. There are numerous other tendencies that follow from epigenetics but this is not our main point. The point is that DNA expression can be "conditioned" by diet and lifestyle and now we have scientific data that confirm and explain the how and why of it. As suggested below, we now have some basis for evaluating survivability and adaptation/evolution. We engage in those activities and diet which have the capacity to promote wellness or not and pass these traits along to our progeny. Remember that Caraka and Vagbhata, both, stated that the condition of the uterus at the time of conception is critical to determining constitution and now we have the scientific basis for this assertion. They stated that immunity and strength of the organism can be acquired and now we have support for this assertion, too. We also have a validation of the Ayurvedic perspective that food is medicine (or not) and that the lifestyle is also important.
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Epigenetics is a term in biology used today to refer to features such as and modifications that are stable over rounds of but do not involve changes in the underlying sequence of the organism. These epigenetic changes play a role in the process of , allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.
Specific epigenetic processes of interest include , , , , , , , , , the progress of , many effects of , regulation of modifications and , and technical limitations affecting and .
Etymology and Definitions
The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.
Originally, the word "epigenetics" (as in "") was coined by in 1942 as a of the words "" and "". Epigenesis is an older word used to describe the differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics" the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a . Because all cells within an organism inherit the same DNA sequences, processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."
Another usage of the word "epigenetics" was employed by the psychologist , who developed an "epigenetic theory of human development" which focuses on psycho-social crises.
The modern usage of the word "epigenetic" is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence. The Greek "epi-" prefix of the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.
The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "" and refers to the overall epigenetic state of a cell. The phrase "" has also been adapted—the "" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for; more typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the or patterns.
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:
DNA methylation and chromatin remodelling
DNA associates with histone proteins to form chromatin.
Because the of a cell or individual is affected by which of its genes are transcribed, heritable can give rise to epigenetic effects. There are several layers of regulation of , one of which is remodelling of chromatin, the complex of DNA and the proteins with which it associates. Chromatin remodelling is initiated by one of two things:
Whereas DNA is not completely stripped of during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.
Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include , and . Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because lysine normally has a positive charge on the nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge causing the DNA to repel itself. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like so transcription of the gene can occur.
In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.
Lysine acetylation may also act as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well). Indeed, the bromodomain—a protein segment (domain) that specifically binds acetyl-lysine—is found in many enzymes that help activate transcription including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive ). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein recruits HP1 to K9 methylated regions. One example that seems to refute the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.
It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the .
DNA methylation frequently occurs in repeated sequences, and may help to suppress '': Because is chemically very similar to , CpG sites are frequently mutated and become rare in the genome, except at where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent , DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice. DNMT1 is the most abundant methyltransferase in somatic cells, localizes to replication foci, has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA). By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after , and therefore is often referred to as the ‘maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.
Because DNA methylation and chromatin remodelling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.
RNA transcripts and their encoded proteins
Sometimes a gene, after being turned on, transcribes a product that (either directly or indirectly) maintains the activity of that gene. For example, and enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the activity of the they encode. Other epigenetic changes are mediated by the production of different of , or by formation of double-stranded RNA (). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by , although in some systems where or are important, RNA may spread directly to other cells or nuclei by . A large amount of RNA and protein is contributed to the by the mother during or via , resulting in phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.
For more details on this topic, see .
are infectious forms of . Proteins generally fold into discrete units which perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of , prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.
are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. and URE3, discovered in in 1965 and 1971, are the two most well studied of this type of prion. Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect which results in suppression of in other genes. The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by premature stop codon mutations.
Structural inheritance systems
For more details on this topic, see .
In such as and , genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.
Functions and consequences
Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodelling, it has been hypothesised that plant cells do not have "memories", resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.
Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of and . These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially because of , and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.
Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. These effects may require enhancements to the standard conceptual framework of .
Epigenetic features may play a role in short-term adaptation of species by allowing for reversible phenotype variability. The modification of epigenetic features associated with a region of DNA allows organisms, on a multigenerational time scale, to switch between phenotypes that express and repress that particular gene. Whereas the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.
Epigenetic changes have also been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the , which affects their fur color, weight, and propensity to develop cancer. Although this change isn't adaptive since the underlying mutation is agouti gene was developed artificially, the observation of epigenetic change occurring in response to environmental factors opens up the possibility of organismal adaptive inheritance—a sort of . Although this remains speculative, if this does occur some instances of evolution would indeed be separate from standard genetic inheritance.
Epigenetic effects in humans
Genomic imprinting and related disorders
Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells. The most well known case of imprinting in human disorders is that of and —both can be produced by the same genetic mutation, , and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father. This is due to the presence of in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells. is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
Transgenerational epigenetic observations
Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed to famine in the 19th Century were more likely to get diabetes, suggesting that this was a transgenerational epigenetic inheritance
Cancer and developmental abnormalities
A variety of compounds are considered as epigenetic —they result in an increased incidence of tumors, but they do not show activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include , , , and compounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. for Vidaza(tm), a formulation of (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.
The epigenetic code is hypothesized to be a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. It consists of histone modifications defined by the histone code and additional epigenetic modifications such as DNA methylation. The base for the epigenetic code is a system above the genetic code of a single cell, called epigenetics. While in one individual the genetic code in each cell is the same, the epigentic code is tissue and cell specific. "The genetic code is the piano, the epigenetic code the tune."
From Wikipedia, the free encyclopedia
The genotype-phenotype distinction must be drawn when trying to understand the inheritance of traits and their evolution. The genotype of an organism represents its exact genetic makeup, that is, the particular set of genes it possesses. Two organisms whose genes differ at even one locus (position in their genome) are said to have different genotypes. The transmission of genes from parents to offspring is under the control of precise molecular mechanisms. The discovery of these mechanisms and their manifestations began with Mendel and comprises the field of genetics. The term "genotype" refers, then, to the full hereditary information of an organism. The phenotype of an organism, on the other hand, represents its actual physical properties, such as height, weight, hair color, and so on. It is the organism's physical properties that directly determine its chances of survival and reproductive output. But the inheritance of physical properties occurs only as a secondary consequence of the inheritance of genes. Therefore, to properly understand evolution by natural selection, one must understand the genotype-phenotype distinction.
The mapping of a set of genotypes to a set of phenotypes is sometimes referred to as the genotype-phenotype map.
An organism's genotype is a major (the largest by far for morphology) influencing factor in the development of its phenotype, but it is not the only one. Even two organisms with identical genotypes normally differ in their phenotypes. One experiences this in everyday life with monozygous (i.e. identical) twins. Identical twins share the same genotype, since their genomes are identical; but they never have the same phenotype, although their phenotypes may be very similar. This is apparent in the fact that their mothers and close friends can always tell them apart, even though others might not be able to see the subtle differences. Further, identical twins can be distinguished by their fingerprints, which are never completely identical.
The concept of phenotypic plasticity describes the degree to which an organism's phenotype is determined by its genotype. A high level of plasticity means that environmental factors have a strong influence on the particular phenotype that develops. If there is little plasticity, the phenotype of an organism can be reliably predicted from knowledge of the genotype, regardless of environmental peculiarities during development. An example of high plasticity can be observed in larval newts1: when these larvae sense the presence of predators such as dragonflies, they develop larger heads and tails relative to their body size and display darker pigmentation. Larvae with these traits have a higher chance of survival when exposed to the predators, but grow more slowly than other phenotypes.
In contrast to phenotypic plasticity, the concept of genetic canalization addresses the extent to which an organism's phenotype allows conclusions about its genotype. A phenotype is said to be canalized if mutations (changes in the genome) do not noticeably affect the physical properties of the organism. This means that a canalized phenotype may form from a large variety of different genotypes, in which case it is not possible to exactly predict the genotype from knowledge of the phenotype (i.e. the genotype-phenotype map is not invertible). If canalization is not present, small changes in the genome have an immediate effect on the phenotype that develops.
The terms "genotype" and "phenotype" were created by Wilhelm Johannsen in 1911.
Notes and references
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