Epigenetics

agouti mice methylated offspring
(image: agouti mouse offspring)

Epigenetics
Here’s an excerpt from Bruce Lipton’s 2005 book Biology of Belief:

page67, “Epigenetics: The New Science of Self-Empowerment”
…”While the Human Genome Project was making headlines, a group of scientists were inaugurating a new, revolutionary field in biology called epigenetics. The science of epigenetics, which literally means ‘control above genetics,’ profoundly changes our understanding of how life is controlled. [Pray 2004; Silverman 2004]. In the last decade, epigenetic research has established that DNA blueprints passed down through genes are not set in concrete at birth. Genes are not destiny! Environmental influences, including nutrition, stress and emotions, can modify those genes, without changing their basic blueprint. And those modifications, epigeneticists have discovered, can be passed on to future generations as surely as DNA blueprints are passed on via the Double Helix. [Reik and Walter 2001; Surani 2001]
“There is no doubt that epigenetic discoveries have lagged behind genetic discoveries. Since the late 1940s, biologists have been isolating DNA from the cell’s nucleus in order to study genetic mechanisms. In the process they extract the nucleus from the cell, break open its enveloping membrane and remove the chromosomal contents, half of which is made up of DNA and half of which is made up of regulatory proteins. In their zeal to study DNA, most scientists threw away the proteins, which we now know is the equivalent of throwing the baby out with the bathwater. Epigeneticists are bringing back the baby, by studying the chromosome’s proteins, and those proteins are turning out to play as crucial a role in heredity as DNA.
“In the chromosome, the DNA forms the core, and the proteins cover the DNA like a sleeve. When the genes are covered, their information cannot be ‘read.’ Imagine your bare arm as a piece of DNA representing the gene that codes for blue eyes. In the nucleus, this stretch of DNA is covered by bound regulatory proteins, which cover your blue-eye gene like a shirtsleeve, making it impossible to read. [p67] How do you get that sleeve off? You need an environmental signal to spur the ‘sleeve’ protein to change shape, ie detach from the DNA’s double helix, allowing the gene to be read. Once the DNA is uncovered, the cell makes a copy of the exposed gene. As a result, the activity of the gene is ‘controlled’ by the presence or absence of the ensleeving proteins, which are in turn controlled by environmental signals. [p68]
“The story of epigenetic control is the story of how environmental signals control the activity of genes. It is now clear that the Primacy of DNA chart described earlier is outmoded. The revised scheme of information flow should now be called the ‘Primacy of the Environment.’ The new, more sophisticated flow of information in biology starts with an environmental signal, then goes to a regulatory protein and only then goes to DNA, RNA, and the end result, a protein.
“The science of epigenetics has also made it clear that there are two mechanisms by which organisms pass on hereditary information. Those two mechanisms provide a way for scientists to study both the contribution of nature (genes) and the contribution of nuture (epigenetic mechanisms) in human behavior. If you only focus on the blueprints, as scientists have been doing for decades, the influence of the environment is impossible to fathom. [Dennis 2003; Chakravarti and Little 2003]
“Let’s present an analogy, which hopefully will make the relationship between epigenetic and genetic mechanisms clearer. Are you old enough to remember the days when television programming stopped after midnight? After the normal programming signed off, a ‘test pattern’ would appear on the screen. Most test patterns looked like a dartboard with a bull’s-eye in the middle, similar to the one pictured on the following page.
“Think of the pattern of the test screen as the pattern encoded by a given gene, say the one for brown eyes. The dials and switches of the TV fine-tune the test screen by allowing you to turn it on and off and modulate a number of characteristics, including color, hue, contrast, brightness, vertical and horizontal holds. By adjusting the dials, you can alter the appearance of the pattern on the screen, while not actually changing the original broadcast pattern. This is precisely the role of regulatory proteins. Studies of protein synthesis reveal that epigenetic ‘dials’ can create 2,000 or more variations of proteins from the same gene blueprint. [Bray 2003; Schmuker, et.al. 2000] [p69]
[caption for ‘test pattern screen’ picture: “In this analogy, the test pattern on the screen represents the protein backbone pattern encoded by a gene. While the TV’s controls can change the appearance of the pattern, they do not change the original pattern of the broadcast (the gene). Epigenetic control modifies the read-out of a gene without changing the DNA code.]
Parental Life Experiences Shape Their Children’s Genetic Character
“We now know that environmentally influenced fine-tuning described above can be passed from generation to generation”… [p70]
[skip to page 72]
“The epigenetic evidence has become so compelling that some brave scientists are invoking the ‘L’ word for Jean Baptiste de Lamarck, the much-scorned evolutionist who believed that traits acquired as a result of environmental influence could be passed on. Philosopher Eva Jablonka and biologist Marion Lamb wrote in their 1995 book Epigenetic Inheritance and Evolution – The Lamarckian Dimension: ‘In recent years, molecular biology has shown that the genome is far more fluid and responsive to the environment than previously supposed. It has also shown that information can be transmitted to descendants in ways other than through the base sequence of DNA.’ [Jablonka and Lamb 1995]
“We’re back to where we started in this chapter, the environment. In my own work in the laboratory, I saw over and over the impact a changed environment had on the cells I was studying. But it was only at the end of my research career, at Stanford, that the message fully sank in. I saw that endothelial cells, which are the blood vessel-lining cells I was studying, changed their structure and function depending on their environment. When, for example, I added inflammatory chemicals to the tissue culture, the cells rapidly became the equivalent of macrophages, the scavengers of the immune system. What was also exciting to me was that the cells transformed even when I destroyed their DNA with gamma rays. These endothelial cells were ‘functionally enucleated’ [absent the property of a nucleus], yet they completely changed their biological behavior in response to inflammatory agents, just as they had when their nuclei were intact. These cells were clearly showing some ‘intelligent’ control in the absence of their genes. [Lipton 1991].
“Twenty years after my mentor Irv Konigsberg’s advice to first consider the environment when your cells are ailing, I finally got it. DNA does not control biology”…. [p72]

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Book excerpt: Lifespan, by David A. Sinclair PhD, pp20-22 (the Information Theory of Aging)

Sinclair is among those who equate aging and disease: “Aging, quite simply, is a loss of information.”

“You might recognize that loss of information was a big part of the ideas that Szilard and Medawar independently espoused, but it was wrong because it focused on a loss of genetic information. But there are two types of information in biology, and they are encoded entirely differently. The first type of information—the type my esteemed predecessors understood is digital. Digital information, as you likely know, is based on a finite set of possible values—in this instance, not in base 2 or binary, coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA.

“Because DNA is digital, it is a reliable way to store and copy information. Indeed, it can be copied again and again with tremendous accuracy, no different in principle from digital information stored in a computer memory or on a DVD. DNA is also robust. When I first worked in a lab, I was shocked by how this ‘molecule of life’ could survive for hours in boiling water and thrilled that it was recoverable from Neanderthal remains at least 40,000 years old. The advantage of digital storage explains why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years.

“The other type of information in the body is analog. We don’t hear as much about analog information in the body. That’s in part because it’s newer to science, and in part because it’s rarely described when geneticists noticed strange nongenetic effects in plants they were breeding.

“Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means. The term epigenetics was first coined in 1942 by Conrad H. Waddington, a British developmental biologist, while working at Cambridge University. In the past decade, the meaning of the word epigenetics has expanded into other areas of biology that have less to do with heredity—including embryonic development, gene switch networks, and chemical modifications of DNA-packing proteins—much to the chagrin of orthodox geneticists in my department at Harvard Medical School.

“In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones. These beads on a string self-assemble to form loops, as when you tidy your garden hose on your driveway by looping it into a pile. If you were to play tug-of-war using both ends of a chromosome, you’d end up with a six-foot-long string of DNA punctuated by thousands of histone proteins. If you could somehow plug one end of the DNA into a power socket and make the histones flash on and off, a few cells could do you for holiday lights.

“In simple species, like ancient M. superstes and fungi today, epigenetic information storage and transfer is important for survival. For complex life it is essential… Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities. If the genome were a computer, the epigenome would be the software.”

…”Unlike digital, analog information degrades over time—falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied. No one was more acutely disturbed by the problem of information loss than Claude Shannon, an electrical engineer from the Massachusetts Institute of Technology (MIT) in Boston. Having lived through World War II, Shannon knew firsthand how the introduction of ‘noise’ into analog transmissions could cost lives. After the war, he wrote a short but profound scientific paper called ‘The Mathematical Theory of Communication’ on how to preserve information, which many consider the foundation of Information Theory. If there is one paper that propelled us into the digital, wireless world in which we now live, that would be it.”


Conrad Hal Waddington CBE FRS FRSE (8 November 1905 – 26 September 1975) was a British developmental biologist, paleontologist, geneticist, embryologist and philosopher who laid the foundations for systems biology, epigenetics, and evolutionary developmental biology.

Although his theory of genetic assimilation had a Darwinian explanation, leading evolutionary biologists including Theodosius Dobzhansky and Ernst Mayr considered that Waddington was using genetic assimilation to support so-called Lamarckian inheritance, the acquisition of inherited characteristics through the effects of the environment during an organism’s lifetime.

Waddington had wide interests that included poetry and painting, as well as left-wing political leanings. In his book The Scientific Attitude (1941), he touched on political topics such as central planning, and praised Marxism as a “profound scientific philosophy”.

…His family moved to India and until nearly three years of age, Waddington lived in India, where his father worked on a tea estate in the Wayanad district of Kerala. In 1910, at the age of four, he was sent to live with family in England including his aunt, uncle, and Quaker grandmother. His parents remained in India until 1928. During his childhood, he was particularly attached to a local druggist and distant relation, Dr. Doeg. Doeg, whom Waddington called “Grandpa”, introduced Waddington to a wide range of sciences from chemistry to geology.[1] During the year following the completion of his entrance exams to university, Waddington received an intense course in chemistry from E. J. Holmyard. Aside from being “something of a genius of a [chemistry] teacher,” Holmyard introduced Waddington to the “Alexandrian Gnostics” and the “Arabic Alchemists.” From these lessons in metaphysics, Waddington first gained an appreciation for interconnected holistic systems. Waddington reflected that this early education prepared him for Alfred North Whitehead’s philosophy in the 1920s and 30s and the cybernetics of Norbert Wiener and others in the 1940s… C. H. Waddington - Wikipedia

chromatin-nucleosome

chromatin

Why is DNA packaging required?

The length of the DNA is around 3 meters which needs to be accommodated within the nucleus, which is only a few micrometres in diameter. In order to fit the DNA molecules into the nucleus, it needs to be packed into an extremely compressed and compact structure called chromatin.

During the initial stages of DNA packaging, the DNA is reduced to an 11 nm fibre that denotes approximately 5-6 folds of compaction. This is achieved through a nucleosome order of packaging.

There are three orders of DNA packaging

  1. The first order of DNA packaging – Nucleosome.
  2. The second order of DNA packaging – Solenoid fibre.
  3. The third order of DNA packaging – Scaffold loop Chromatids Chromosome.

Also Read: DNA Replication

One of the benefits of DNA packaging is that it can be separated into things we use a lot and the things we don’t use at all. There are certain parts of DNA that are required only at certain times. Regions that are essential for the synthesis of proteins are loosely packed and are known as euchromatin. This helps the DNA to easily get in and make RNA. The heterochromatin has tightly packed DNA, which is rarely required.

A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins[1] and resembles thread wrapped around a spool. The nucleosome is the fundamental subunit of chromatin. Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.

DNA must be compacted into nucleosomes to fit within the cell nucleus.[2] In addition to nucleosome wrapping, eukaryotic chromatin is further compacted by being folded into a series of more complex structures, eventually forming a chromosome. Each human cell contains about 30 million nucleosomes.[3]

Nucleosomes are thought to carry epigenetically inherited information in the form of covalent modifications of their core histones. Nucleosome positions in the genome are not random, and it is important to know where each nucleosome is located because this determines the accessibility of the DNA to regulatory proteins.[4]

Nucleosomes were first observed as particles in the electron microscope by Don and Ada Olins in 1974,[5] and their existence and structure (as histone octamers surrounded by approximately 200 base pairs of DNA) were proposed by Roger Kornberg.[6][7] The role of the nucleosome as a regulator of transcription was demonstrated by Lorch et al. in vitro[8] in 1987 and by Han and Grunstein[9] and Clark-Adams et al.[10] in vivo in 1988…

“Several epigenetic processes involve chemical compounds that attach, or bind, to DNA or to proteins that package the DNA within cells called histones. When a chemical compound binds to DNA, certain genes switch on or off, selecting which proteins are made.

For example, the epigenetic process of DNA methylation involves the binding of a chemical compound called a methyl group to certain locations on the DNA. This binding changes the structure of DNA, making genes more or less active in their role of making proteins.

Another process called histone modification involves chemical compounds that bind to histone proteins. Ribonucleic acids, or RNAs, are also present in cells and can participate in epigenetic processes that regulate the activity of genes.

DNA methylation and histone modification are normal processes within cells and play a role in development, by instructing stem cells, or cells capable of turning into more specialized cells, like brain or skin cells.

Epigenetic processes are particularly important in early life when cells are first receiving the instructions that will dictate their future development and specialization. These processes can also be initiated or disrupted by environmental factors, such as diet, stress, aging, and pollutants…

Investigating the effects of the environment on the epigenetic regulation of biological processes and disease susceptibility is a goal in the NIEHS 2012-2017 Strategic Plan. NIEHS is currently supporting epigenetics research that is accelerating the understanding of human biology and the role of the environment in disease… In 2003, NIEHS-supported researchers made an important discovery that demonstrated the role of environmental epigenetics in development and disease.2 They used the agouti mouse in their study. The mouse has an altered version of the agouti gene, which causes them to be yellow, obese, and highly susceptible to developing diseases, such as cancer and diabetes.

The researchers fed the mice a diet rich in methyl groups. Through epigenetic processes, the methyl groups attached to the mother’s DNA, and turned off the agouti gene. As a result, most of the offspring were born lean and brown, and no longer prone to disease. This study was the first to demonstrate that it is not just our genes that determine our health, but also our environment and what we eat.

…The epigenome refers to all of the chemical compounds added to the genetic material of an organism that regulate its function.

NIEHS and the National Institute on Drug Abuse (NIDA) co-led a national effort, through the NIH Roadmap Epigenomics Program, to create a series of epigenomic maps representing locations on the DNA where chemical compounds attached in more than 100 different tissue and cell types, including blood, lung, heart, gastrointestinal tract, brain, and stem cells. The groundbreaking work was featured in a 2015 article in the journal Nature.3

…The epigenomic maps are available to the entire scientific community through the Washington University Epigenome Browser

…NIEHS-supported researchers have found that early-life exposure to nutritional and dietary factors, maternal stress, and environmental chemicals can increase the likelihood of developing disease and poor health outcomes later in life. In addition, some of the effects of these exposures can be passed down for multiple generations, even after the original exposure has been removed, through a process known as transgenerational inheritance…

Early life exposures can jumble DNA’s epigenetic marks

“Because the human genome contains the blueprint of life, its spiraling sequence of four nucleotides — thymine, adenine, cytosine, and guanine — is designed to be stable and unchanging. The epigenome, which is the assortment of chemical and protein tags that mark which parts of that sequence should be read, is a different story… “If we disrupt the epigenetic programming during these critical periods or windows of susceptibility, we carry a disturbed epigenome with us for the rest of our lives,” Walker said. “This is thought to contribute to the root cause of many conditions, such as metabolic syndrome, diabetes, and obesity.”

Windows of susceptibility

Epigenetic marks come in two basic varieties — chemical tags that are attached to DNA and protein tags attached to histones — around which the DNA is spooled. These tags, referred to as chromatin marks, are placed, recognized, and removed by molecules that Walker calls “epigenetic readers, writers, and erasers,” respectively.

Epigenetic marks are particularly active during certain periods of development, such as when eggs and sperm are being formed, when a fetus is developing in the womb, and during childhood. During those times, the epigenome can be reprogrammed in response to environmental cues like diet, air pollution, and estrogen-disrupting chemicals…”

A silent epidemic

Walker’s latest research, yet unpublished, is looking at how exposure to a class of chemicals called endocrine-disrupting compounds, including the estrogen-disrupting chemical bisphenol A (BPA), early in life can cause changes in the epigenome that have effects much later in life. Specifically, she is interested in the role BPA may play in the growing epidemic of nonalcoholic fatty liver disease (NAFLD), which now affects 30 percent of American adults. NAFLD can raise the risk of heart disease, diabetes, cirrhosis, and liver cancer.

…What they saw is explained by a relatively new idea known as epigenetic aging. Just as the functioning of cells and tissues changes naturally as we age, so do the epigenetic marks on genes governing our body’s processes (see related story). Walker found that the natural aging of the epigenome was accelerated by early life exposure to BPA… “The delayed manifestation of the effects of epigenetic reprogramming means that there may be things we can do to prevent the onset of disease,” said Walker. “In other words, epigenetic reprogramming may be a ticking time bomb, but later-life exposures are necessary to light the fuse.”

Environmental Factor - March 2019: Early life exposures can jumble DNA’s epigenetic marks

Lipton, communicate by energy

Excerpts from Bruce H. Lipton The Biology of Belief [2005]:

“[The] reductionist model suggests that if there is a problem in the system, evident as a disease or dysfunction, the source of the problem can be attributed to a malfunction in one of the steps along the chemical assembly line. By providing the cell with a functional replacement part for the faulty element, by prescribing pharmaceutical drugs for example, the defective single point can theoretically be repaired and health restored. This assumption spurs the pharmaceutical industry’s search for magic-bullet drugs and designer genes.

“However, the quantum perspective reveals that the universe is an integration of interdependent energy fields that are entangled in a meshwork of interactions. Biomedical scientists have been particularly confounded because they do not recognize the massive complexity of the intercommunication among the physical parts of the energy fields that make up the whole. The reductionist’s perception of a linear flow of information is a characteristic of the Newtonian universe. In contrast, the flow of information in a quantum universe is holistic. Cellular constituents are woven into a complex web of crosstalk, feedback and feedforward communication loops. A biological dysfunction may arise from a miscommunication along any of the routes of information flow. To adjust the chemistry of this complicated interactive system requires a lot more understanding than just adjusting one of the information pathway’s components with a drug…

“Once I realized the nature of the complex interactions between matter and energy, I knew that a reductionist, linear (A>B>C>D>E) approach could not even come close to giving us an accurate understanding of disease. While quantum physics implied the existence of such interconnected information pathways, recent groundbreaking research in mapping protein-protein interactions in the cell now demonstrates the physical presence of these complex holistic pathways. [Li, et al, 2004; Giot, et al, 2003; Jansen, et al, 2003]… Clearly biological dysfunctions can result from miscommunication anywhere within these complex pathways. When you change the parameters of a protein at one point in such a complex pathway, you inevitably alter the parameters of other proteins at innumerable points within the entangled networks… ‘Newtonian’ research scientists have not fully appreciated the extensive interconnectivity among the cell’s biological information networks.[pp103-104]

“The mapping of these information network pathways underscores the dangers of prescription drugs… When a drug [gmo-gene or chemical pollutant] is introduced into the body to treat a malfunction in one protein, that drug inevitably interacts with at least one and possibly many other proteins… For example, when a drug is prescribed to correct a dysfunction in a signaling pathway of the heart, that drug is delivered by the blood to the entire body. This ‘cardiac’ medicine can unintentionally disturb the function of the nervous system if the brain also uses components of the targeted signaling pathway. While this redundancy complicated the effects of prescription drugs, it is another remarkably efficient result of evolution. Multicellular organisms can survive with far fewer genes than scientists once thought because the same gene products (protein) are used for a variety of functions… similar to using the twenty-six letters of the alphabet to construct every word in our [English] language [ listed at over 400,000 words]. [pp105-106]

…”A recent example of tragic adverse reactions to drug therapy is the debilitating and life-threatening side effects associated with synthetic hormone replacement therapy (HRT). Estrogen’s best-known influence is on the function of the female reproductive system. However, more recent studies on the distribution of estrogen receptors in the body reveal that they, and of course their complementary estrogen signal molecules, play an important role in the normal function of blood vessels, the heart and the brain. Doctors have routinely precscribed synthetic estrogen to alleviate menopausal symptoms… However, pharmaceutical estrogen therapy does not focus the drug’s effects on the intended target tissues. The drug also impacts and disturbs the estrogen receptors of the heart, the blood vessels and the nervous system. Synthetic [estrogen] replacement therapy has been shown to have disturbing side effects that result in cardiovascular disease and neural dysfunctions such as strokes. [Shumaker, et al, 2003; Wasserthiel-Smoller, et al, 2003; Anderson, et al, 2003; Cauley, et al, 2003].[p107]

…[And]”what great and marvelous advances in biomedical sciences can we attribute to the quantum revolution? Let’s list them in order of their importance: It is a very short list—there haven’t been any…[p109]

“There have, thankfully, been some visionary biologists who have advocated this integration. More than [fifty] years ago the renowned Nobel Prize-winning physiologist Albert Szent-Gyorgi published a book called Introduction to a Submolecular Biology [1960]… Biologists in the main have still not recognized the importance of Szent-Gyorgi’s book, but research suggests that sooner or later they will have to because the weight of scientific evidence is toppling the old materialist paradigm. [p110]

…”Hundreds upon hundreds of other scientific studies over the last fifty years have consistently revealed that ‘invisible forces’ of the electromagnetic spectrum profoundly impact every facet of biological regulation. These energies include microwaves, radio frequencies, the visible light spectrum, extremely low frequencies, acoustic frequencies and even a newly recognized form of force known as scalar energy. Specific frequencies and patterns of electromagnetic radiation regulate DNA, RNA and protein synthesis, alter protein shape and function, and control gene regulation, cell division, cell differentiation, morphogenesis (the process by which cells assemble into organs and tissues), hormone secretion, nerve growth and function. Each one of these cellular activities is a fundamental behavior that contributes to the unfolding of life. Though these research studies have been published in some of the most respected mainstream biomedical journals, their revolutionary findings have not been incorporated into the medical school curriculum. [Liboff 2004; Goodman and Blank 2002; Sivitz 2000; Jin, et al, 2000; Blackman, et al, 1993; Rosen 1992; Blank 1992; Tsong 1989; Yen-Patton, et al, 1988].[p111]

“An important study [fifty] years ago by Oxford University biophysicist C.W.F. McClare calculated and compared the efficiency of information transfer between energy signals and chemical signals in biological systems. His research, ‘Resonance in Bioenergetics’ published in the Annals of the New York Academy of Science, revealed that energetic signaling mechanisms such as electromagnetic frequencies are a hundred times more efficient in relaying environmental information than physical signals such as hormones, neurotransmitters, growth factors, etc. [McClare 1974]… The speed of electromagnetic energy signals is 186,000 miles per second, while the speed of a diffusible chemical is considerably less than 1 centimeter per second. Energy signals are 100 times more efficient and infinitely faster than physical chemical signaling. What kind of signaling would your trillion-celled community prefer? [or what others would prefer done to you?] Do the math!” [p112]