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Ram B. Singh (1), Fabien De Meester (1), Agnieszka Wilczynska (1), D.W. Wilson (2), A.P.S. Hungin (2)
(1)The Tsim Tsoum Institute, Krakow, Poland; (2) School of Medicine and Health, Durham University, UK.
World Heart J, 2011 (in press)
EVOLUTION: A MODIFIED SYNTHESIS IN RELATION TO INHERITANCE OF DISEASES.
Introduction.
These authors have discussed, for the last two decades, those environmental factors in general and nutrition in particular could be important in the pathobiology of epigenetic inheritance (1-4). This knowledge was unknown to Julian Huxley who published his landmark Monograph; ‘Evolution: The Modern Synthesis in 1942’. This monograph brought Darwin’s ideas into the 20th century and incorporated a knowledge of genes that was emerging in this century in the light of Gregor Mendel’s experiments on inheritance (‘ Monograph: Experiments with Plant Hybrids) at Hyncice (Vrazne) in the now Czech Republic. In the mid-century, Barbara McClintock discovered transposable elements where parts of the genome can jump around and cause mutations or alter the gene expression, skewing Mendelian ratios and inheritance patterns. This report disrupted the predictable Mendelian system that went into building the Modern Synthesis.
In The Origin of Species, Darwin wrote: “Natural selection can act only by taking advantage of slight successive variations; it can never take a leap, but must advance by the shortest and slowest steps”. It is possible, he believed that organisms gradually adapt to their environments via minute physical adjustments. Biologists have since found evidence that dramatic adaptations can also occur, for instance in the form of major morphological changes. These adaptations appear to be the cause of changes in structure from apes to man and various human races. It is not clear whether such adaptations may be responsible for the development of diseases or health or for development of man to humans.
The Modern Synthesis emphasizes that “ populations containing some level of genetic variations evolve via changes in gene frequency, induced mostly by natural selection and phenotypic changes are gradual with speciation and diversification into higher taxonomic levels come about over long periods of change. It seems that these ideas remained largely unchallenged for more than 50 years from now, although phenotypic changes have occurred rapidly in the last 100 years (1-6). Furthermore, evolutionary
biology, biochemistry, genomics, developmental biology, systems biology and the impact of the environment on genes concerning mechanism of evolution have grown significantly beyond the Modern Synthesis. It is possible that some lineages have greater ‘evolvability’ than others, independent of how much baseline genetic variation is present. In this connection, heritable phenotype variations may depend on the biology and biochemistry of the genes. Since some populations have more genetic variation than others and are expected to generate phenotypic variation more rapidly, the Modern Synthesis addresses ‘evolvability’ in a population which may not be a distinct trait, independent of genetic variation. The Modern synthesis also does not place emphasis on the influence of photosynthesis, flight, multicellu-larity which stands out against a backdrop of slow and steady evolution. It is therefore important that Modern Synthesis should be modified by the experts because Life Sciences are dynamic, and which continue to change.
The ability to evolve at a different speed than other species needs some particular characteristics. A prion that results from the mis-folding of the Sup35 protein in the yeast; Saccharomyces cerevisiae, may serve as a conduit for evolution of novel traits and as molecular vehicle for evolvability. The functional domain of Sup35 is highly conserved in a variety of organismal groups which serves as a translation termination factor. It may also help ribosomes to recognize stop codons on mRNA and thus mediates the normal translation of proteins. The yeast cells, which have aggregates of prions, read through about 5 to 10 % of stop codons in a given cell, so the mis-folded prions are not able to function correctly. The mRNA may stick around longer in cells enabling the expression of more proteins, so the cells with prions can express normally silent sequences beyond the termini of genes or express different levels of normal proteins. These cells are capable of expressing a wide variety of phenotypes (6). This study (6) found that nearly half of the conditions having the prion (PSI) led to significant phenotypic effects in some of the strains, which uncovered previously-hidden pheno-
typic variation in the yeast cells. This variation was advantageous in some of the conditions to which yeast cells were subjected. It is possible that prion (PSI) may act as capacitor and potentiator of ‘evolva-bility’, because switching into the PSI state sensitizes the yeast more efficiently to produce phenotypic diversity, with change in nutrition and other environmental conditions (6).
The low W-6/W-3 fatty acid ratio and coenzyme Q10 present in the cell membrane to which humans adapted during evolution, may have beneficial effects on this phenotypic diversity. The prion (PSI) can pass from mother to daughter yeast cells when they divide either mitotically or meiotically despite lineage where they revert back to non-prion state selection, resulting into beneficial adaptations (6). Depending on the strain, this occurs naturally at every 100,000-
1000,000 cell divisions or so depending on the strain. There are more extreme phenotypes, if the cell is stressed-out of an organism, compared to a benign environment which may possibly be independent of natural selection but this is not yet established. It is also possible that “natural selection” may not actually be “natural” but it is our ignorance about the environmental factors that are causing phenotypic variations, which would be clearer from the evidence on the facilitation of genetic variation.
Facilitated genetic variation.
A complex set of physical and chemical factors, coming into play during development , which can influence structures and functions that are beyond simple genome to phenotype translation, may be called facilitated variation. Several mechanisms have been proposed to explain facilitated variations including those related to oscillations of certain regulatory elements affecting segmentation in embryo and chemicals acting during development which can cause patterns of stripes or spots in the organism. In this connection, the role of nutrients causing birth defects and other biochemical phenotypes appear to be important. It seems that nutritional status of mothers and the psychological environment during the perinatal period could be important influencers in the facilitated variations. These variations may spark faster evolutionary alterations compared to random mutations, because developmental changes can create additional phenotypes upon which selection can act. However, many of these random mutations may be due to less known environmental factors and astrochronobiological factors like solar activity, geomagnetic forces and nutrients excess or deficiency, developing according to time structures.
The Modern Synthesis emphasizes that genotypes translate directly into phenotypes and evolutionary changes stemmed from the slow, gradual accumulation of the random genetic mutations. It seems that this simple explanation is quite complex in view of the developmental biology and biochemistry and astrochronobiology in the light of nutritional content of the cell. The Modern Synthesis ignores the complex gene interactions and sudden morphological reorganizations that occur during development, because in experiments and natural setups, there is discordance between genotype and phenotype. In one study, house finches which were natives to deserts began spreading throughout the United States in the 1940s through the pet trade (7). The birds were tracked for 19 generations over a span of 15 years at a study site in Montana which showed that the population of birds was developing unique beak morphologies as adaptations to the new environment related to availability of foods, at a surprisingly rapid rate (7) .This finding is also against the view expressed in the Modern Synthesis that it may be a random mutation. This evidence clearly shows the capability of the flinch to adapt rapidly to survive, against the environmental factors related to housing, the new habitats. The interacting embryonic processes resulted in an initial level of phenotypic variation greater than that predicted from underlying genotypic variation (7). The selection was essentially blind, during development of the egg, to the creation of the initial pool of phenotypic variation because it occurred only later when young birds began feeding on the foods available in their new habitat. The selection was able to determine which beaks were more or less suited to the environment which was related to the availability of foods, without looking into developmental process, by which this beak was produced, due to opportunity for diversification. It is not clear as to what extent the quality of the food or method of eating or nutrient content was responsible for phenotypic variation. From Environmental Cycles to the Non-Origin of the Universe(Fabien De Meester 2011 Personal Communication)
If one agrees that the East could not be wrong with the yin-yang conceptual representation of the Universe and everything it contains, and that the West must be right with the Theory of Evolution and everything it selects, then the notion of origin is irrelevant as "Everything" is about revolving "Nothing". Human can make the difference.
е»С«!>е
| Equivalence \
Nothing
АЯЛ L PARTICLE ,
| Energy, time, space |
Crystallization ^--------------
Melting
I Evolution I
Everything
The representation of nothing as yin-yang interaction between an elementary particle and its antiparticle counterpart. In a pure state of nothing, crystallization is spontaneous and exothermic. It leads to matter with release of energy, space and time. Natural selection does the rest, with matter and anti-matter submitted to a single rule, the fitter the better. Gravity is a manifestation of anti-matter and remains proportional to matter at all times. The system is entirely reversible with no time/space constraints.
Starting from that advanced though basic evidence-based scientific, philosophical and theological merged principle, one can analyze the world we live in with wisdom and rejuvenated curiosity as Human; body and mind are naturally selected advanced interacting components reminiscent of earlier more basic assemblages of matter and anti-matter, which evolved independently according to the same rule, ie Natural Selection. As Man shares a common ancestor with Stone that fills in the Universe, one perceives the true nature of matter, which naturally evolved to the complex human genome. Anti-matter is no more complicated to perceive; it started with gravity as its most basic anti-space manifestation in Stone and naturally evolved to mind in its most sophisticated anti-genome manifestation in Human.
The non-origin hypothesis of the Universe does require additional validation studies that keep ongoing at all levels, ie scientific, philosophical and theological. So far, it is an extrapolation of common knowledge. It helps though at taking today the right decision for the future of Humanity; (i) at scientific level, it appears that dark holes are of infinite low -not high - density, (ii) at philosophical level, it sounds like the aim of a human lifetime is to create Value, and (iii) at theological level, Human appears as a promising alternative concept to God.
In fact, Nature always keeps trace of its past and current man affairs follow the same cyclic, repeatable pattern of development as all phenomena in the entire Universe. By creating Value, Humans have the unique ability to counteract Nature and the today predictable future collapse of the Universe. The size of the challenge is to the height of Humanity as a Talent.
Multilevel epigenetic inheritance.
Passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA are described as multilevel inheritance. It is known that chromatin structure, remodeled histone proteins or methylated DNA, often mediated by environmental factors, can pass from parent to offspring without changing the actual sequence of the inherited genome. The Modern Synthesis proposed that genes were the primary units of inheritance and that evolution may be a change in the genetic composition of the population, although molecular mechanisms were unknown in 1942. If epigenetics play any role in evolutionary change, we must demonstrate that the changes last and are stable and cause heritable effects through several generations (8). Two groups of genetically identical Arabodopsis plants (Brassicaceae) were exposed to either hot or cold conditions for two; P and F1 generations in an experiment (9). The next generation; F2 from both groups was grown at normal temperatures, but the offspring (F3) from both groups were grown in either hot or cold conditions. The F3 plants grown in hot conditions and descended from P and F1 plants also grown in hot conditions produced five-fold more seeds compared to F3 plants grown in hot conditions but descended from cold treated ancestors ((9). It seems that epigenetic factors affecting flower productions and early stage seed survival, due to molecular adaptations, in these plants may have caused these mutations.
Can nutrient influence inheritance?
The poster child for epigenetic changes in mammals is the yellow agouti mouse, an epigenetic biosensor for nutritional and environmental changes. These fat and yellow mice owe their appearance to epigenetic modification that removes methyl groups from the normally methylated agouti gene (10). In a developing mouse fetus, if the above modification occurs shortly after fertilization, the baby mouse may exhibit the yellow fur and obese phenotype with greater risk of developing cancer and diabetes (10). However, the genetic code remains unchanged from normal mice. In one study, Waterland and Jirtle (10) altered the nutrient intake to serve as methyl group
donors in mouse mothers, to cause methylation or demethylation of the agouti gene. Increased supplementation of choline, betaine, folic acid and vitamin B12 in the diet of pregnant yellow agouti mice was able to decrease the incidence of deleterious phenotypes in offspring, by allowing for the remethylation of the agouti gene. If these mice be born with the agouti phenotype, they can pass that deleterious epigenetic trait in their offspring, regardless of their diet during pregnancy. This landmark study indicate that nutrients can cause phenotypic changes which can pass on through cell division and mating to the offspring due to their possible influence on (natural) selection (10). It is possible therefore to say; that we are what we eat and what our parents ate, and potentially what our grand parents ate which would be modification of the old Sanskrit saying ‘Aham Annam’ from the ancient Vedas (5000BCE). It may be also important to emphasize advances in Astrochronobi-ology particularly; time of eating, accordingly, therefore we are not only ‘what we eat’ but also ‘we are when we eat’ and when our father and grand father were eating (11). There is a need to study the effects of low W-6/W-3 ratio, arginine, taurine, cysteine, coenzyme Q10 on the remethylation of the agouti gene and their effects on phenotypic variations. However this mode of inheritance needs to penetrate more than a few generations before it earns a place in evolutionary concept. Epigenetic inheritance appears to be widespread but it does not mean that it lasts and causes ‘evolutionarily’ important effects. It is not clear until now, that if epigenetic changes are not stable for 20 to 30 generations, it would be relevant to evolution.
The biologists should be bold enough to revise the Modern Synthesis published in 1942, because several experiments related to epigenetics are underway to establish the role of environmental factors in inheritance. There is need for modifications of this landmark monograph which may be written by multiple authors including physicians
Observing inheritance in 3 to 4 or more generations among patients of diabetes, hypertension and coronary artery disease. The evolutionary theory appears to be quite flexible to incorporate well-substantiated new concepts, which continue to arise during the last few decades. In 1975, we (RBS) treated a patient of type 2 diabetes mellitus whose father also had a history of diabetes mellitus and died a sudden death. This 48 years old patient was, while under treatment (RBS) developed tightness in the chest and his electrocardiogram showed changes indicating myocardial ischaemia. He was treated and recovered
but after a few months died a sudden cardiac death in 1977. His son who was about 40 years, presented with type 2 diabetes mellitus, while under treatment, also died a sudden cardiac death next year. Diet and lifestyle history showed that they have /had a wholesale business of selling clarified butter (anhydrous milk fat) during the time of the 1st generation, clarified butter and hydrogenated fat, during the 2nd generation which continued during the 3rd generation. Thus, albeit a single family, all the three generations were sedentary and were consuming more than 40% of calories from clarified butter which may have caused inheritance of deleterious phenotypes in the offspring, resulting in to type 2 diabetes and sudden death.
The adverse effects of trans fat (unsaturated fats with trans-isomer fatty acids). and oxidized cholesterol present in the clarified butter consumed by the last three ‘degenerations’, on proinflammatory cytokines are well known and inflammation has been demonstrated to cause genetic damage. Sedentary behavior also enhances inflammation by its adverse effects on adiponectin, leptin and brain derived neu-rotrophic factor which are anti-inflammatory. Inflammation could be important in the pathobiology of epigthenetic inheritance. Now RBS is tracking the son (4t generation) who is about 30 years, to look for type 2 diabetes mellitus and coronary artery disease who may be a future candidate for sudden cardiac death in the 4th degeneration because he and his baby are consuming clarified butter and high W-6/W-3 ratio diet by using sun flower oil and they continue to be sedentary. We need to study genetic markers in this 4th generation to support this view. However, we need many more such observations and research because sufficient examples of transgenerational epigenetics are lacking. Most of the time, epigenetic characters are not inherited past one or two generations. The evolution of diet and the tsim tsoum concept:
A fundamental view of evolution in relation to human development from apes to man has been that the genetic makeup of contemporary humans which shows minor difference from that of the modern humans who appeared in Africa between 100,000 and
50,000 years ago (12, 13). The human evolution has been comparatively rapid during the past 50,000 years, as revealed by the molecular geneticists. There have been marked changes in the food supply with the development of agriculture about 10,000 years ago from now. However, only non-significant change in our genes occurred, during the past 10 centuries, due to presence of w-3 fatty acids, amino acids, vita-
mins and minerals in the diet and non-significant changes in the environment (12-15). There have been some structural modifications in individual DNA sequences, and altered gene regulation has been the dominant mechanism involved. Increased evolutionary rapidity in humans compared with rates for other primates, has resulted from unprecedented demographic expansion, which has provided a far larger pool of mutations, upon which natural selection can operate. The human Diaspora which has exposed humans to environmental changes appears to be quite different from those of their ancestral land in Africa and this rapid change may predispose deleterious epigenetic inheritance.
The spontaneous mutation rate for nuclear DNA is estimated at 0.5% per million years. Hence, over the past 10,000 years there has been time for very little change in our genes, possibly 0.005%. Our genes appear to be similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, the time when our genetic profile was established. Man appears to live in a nutritional environment which completely differs from that for which our genetic constitution was selected. However, it was only during the last 100-160 years that dietary intakes and environment have changed significantly, causing increased intake of saturated fatty acids (SFA) and lino-leic acid, and decrease in w-3 fatty acids, from grain fed cattle, tamed at farmhouses, rather than meat from running animals. There is marked decrease in the intake of vitamins and antioxidants. The food and nutrient intake among hunter-gatherers and during the Paleolithic period showed no remarkable differences. However, during the last 160 years, there is marked reduction in consumption of w-3 fatty acids, vitamins and minerals and proteins and significant increase in the intakes of carbohydrates, (mainly refined,), fat ( saturated, trans fat, linoleic acid) and salt compared to Paleolithic period (1-4,12-15). There are also marked changes in the environmental factors which may also have deleterious effects on epigenetic inheritance.
The Columbus concept of diet means that humans evolved on a diet that was low in saturated fat and the amount of w-3 and w-6 fatty acids was quite equal.(14) Nature recommends to ingest fatty acids in a balanced ratio (polyunsaturated:saturated: w-6:w-3=1:1) as part of dietary lipid pattern in which monounsaturated fatty acids is the major fat(P:M:S=1:6:1).These ratios represent the overall distribution of fats in a natural untamed environment. (www.columbus-concept.com). The Columbus foods include egg, milk, meat, oil , and bread, all rich in w-3
fatty acids, similar to wild foods, consumed about 160 years ago from now. Blood lipid composition does reflect one’s health status: (a) circulating serum lipoproteins and their ratio provide information on their atherogenicity to blood vessels and (b) circulating plasma fatty acids, such as W-6/W-3 fatty acid ratio, gives an indication of proinflammatory status of blood vessels. (a) and (b) are phenotype-related and depend on genetic, environmental and developmental factors. As such, they appear as universal markers for holistic health. Blood cholesterol is central to this approach. Its 3D-representation shows how circulating lipoproteins affect blood vessel integrity arising from their circulating throughout the body. Of major importance appear to be the essential dietary nutrients (essential amino acids, fatty acids, antioxidant vitamins and minerals) and the functional component of the regimen(diet, sport, spiritualism, etc) because these factors may be important in the epigenetic inheritance . An example is given of an essential dietary nutrient and of a functional component of man’s regimen that affect health in a predictive way derived from the 3D representation of blood cholesterol. Caption The Columbus Concept and its 3D representation of blood lipoprotein behaviours. "Bad" LDL-C, "good" HDLC, and "healthy" LDL-CC:HDL-CC ratios. CC= Columbus Concept. The Tsim Tsoum Concept is an extension of the Columbus concept. The word Tsim Tsoum is derived from Hebrew and it is similar to ‘ying yang’ in Chinese. (http://www.tsimtsoum.net/__________________editori-
als/tsimtsoum editorial 2ooo-Kosice-i4th-WCCN-and-5th-ICCD.pdf). It includes the simultaneous approach of controlling of Mind-brain- body connection and interactions of leptin, cholecystokinin, polyunsaturated fatty acid CoA, brain derived neu-rotrophic factor and neuropeptide Y secreted in the hypothalamus (16-18). The Tsim Tsoum Concept also presumes that if, and only if, diet and environmental factors are designed holistically, for individuals and populations or for any species, for several generations, they may be responsible for the alteration in biological functions causing epigenetic inheritance, resulting in the development of man to human and thence to superhuman.
In brief, it is possible that diet and other environmental changes, can modulate biological functions including genetic variations. If these environmental changes are subjected to species for several generations, they might predispose epigenetic inheritance.
However, more evidence is necessary to demonstrate the role of environment in the epigenetic in-
heritance. The Modern Synthesis needs modification in the light of above Advances.
Acknowledgements are due to Tsim Tsoum Institute, Krakow, Poland and International College of Nutrition for the support to produce this work.
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Correspondence. Dr Ram B Singh, The Tsim Tsoum Institute, Ul.Golebia 2, 31-007, Krakow, Poland
