Epigenetics

A possible link between stress responses and human cancers?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Neurochemicals, Primal Therapy, Stress ,

This 2015 UK rodent study found:

“An unexpected role for the GR [glucocorticoid receptor] in promoting accurate chromosome segregation during mitosis.

We also identify reduced GR expression in several common human cancers, thereby implicating GR as a novel tumor suppressor gene.”

One of the researchers said:

“Cancer is caused by cell division going wrong, but no one has previously looked at the role GR has to play in this process. It’s now clear that it is vital.”

From the study:

“Our findings now show that GR function regulates accurate mitotic progression, with clear implications for human health.

Add a previously unidentified perspective to GR action in cell division, affecting mitotic spindle function.

It may be that this action can be targeted by specific ligands, potentially opening up new therapeutic approaches to treat common cancers.”

The Translating PTSD research findings from animals to humans study also found reduced expression of glucocorticoid receptor genes, which appeared in some rodents after stress. Unfortunately, those researchers’ priorities weren’t to research the causes of this reduced expression.

One relevant hypothesis of Primal Therapy is that trauma in the earliest parts of human life epigenetically impairs the proper functioning of human development processes. A follow-on hypothesis is that the arrival of diseases in later life may be traceable back to the damage done during early-life development processes.

An example of this would be that a developing fetus adapts to being constantly stressed by an anxious and stressed mother. When the changes persist after birth, they may present as maladaptations of the infant to a non-stressful environment. These enduring changes may be among the causes of symptoms decades later such as over- and/or under-reactions to stress.

It seems possible that further research in these areas may find links among human stress responses and human cancers. The current study suggested that the glucocorticoid receptor may play a part in these links.

http://www.pnas.org/content/112/17/5479.full “Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy”

Epigenetic production of new brain neurons in the hippocampus

gettingwell4 2-3 stars Required further work, Epigenetics, Hippocampus, Limbic system ,

This 2015 La Jolla rodent study provided further details on the production of new neurons in the adult hippocampus:

“We propose that SOX2 sets a permissive epigenetic state in neural progenitor cells, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.”

The researchers stated that the functions of these new brain neurons were:

“Newborn granule neurons generated from neural progenitor cells in the adult hippocampus play a key role in spatial learning and pattern separation.”

http://www.pnas.org/content/112/15/E1936.full “SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis“

A common dietary supplement that has rapid and lasting antidepressant effects

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Neurochemicals, Stress , , ,

This 2012 Italian rodent study found that a common dietary supplement had rapid and lasting antidepressant effects:

“Remarkably, L-acetylcarnitine displayed a clear-cut antidepressant effect already after 3 and 7 d[ays] of daily dosing. No tolerance was developed to the action of L-acetylcarnitine. The drug was even more effective after 21 d[ays], and the effect persisted for at least 2 w[ee]k[s] after drug withdrawal.”

The researchers studied stressed mice and rats to determine that:

  1. An effect of the stress was to epigenetically change the hippocampus to produce less of an important molecule – type 2 metabotropic glutamate (mGlu2).
  2. A reduction of the mGlu2 molecule decreased the hippocampus’ regulation of the glutamate neurotransmitter.
  3. Under-regulation of glutamate, in turn, caused symptoms of depression.

L-acetylcarnitine reversed the immediate causes of stress-induced symptoms by acetylating histone proteins. These control the transcription of the brain-derived neurotrophic factor (BDNF) and mGlu2 receptors in the hippocampus and prefrontal cortex.

LAC putative action

A commentary on this research, Next generation antidepressants, had the above graphic that showed possible mechanisms for the effects of L-acetylcarnitine. Epigenetic histone modifications seem to be more easily reversible than epigenetic DNA methylation.

“Currently, depression is diagnosed only by its symptoms,” Nasca says. “But these results put us on track to discover molecular signatures in humans that may have the potential to serve as markers for certain types of depression.”

It’s tempting to extrapolate this study to humans and test whether depression symptoms could be effectively treated with some multiple of a normal acetyl-L-carnitine dietary supplement dose of 500 mg at $.25 a day. This dietary supplement is better for depression symptoms than placebo analyzed randomized control trials that tested and demonstrated its efficacy.

To cure stress-induced illnesses in humans, though, ultimate causes of stress should be removed or otherwise addressed.

http://www.pnas.org/content/110/12/4804.full “L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors”

Adaptations to stress encourage mutations in a DNA area that causes diseases

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress

This 2015 Baylor human cell study subject was the underlying mechanisms of cellular responses to environmental stressors of cold, heat, hypoxia, and oxidation:

“Because trinucleotide repeats are overrepresented in gene-regulatory proteins, stress-induced trinucleotide repeat mutagenesis may provide a path for the environment to subtly alter gene regulatory networks – with attendant changes in cell behavior – during development, disease, and evolution.”

The study’s overarching framework was that human cells will adapt to best survive in their environment. The study found that the cells’ responses to stress encouraged the creation of mutations in a DNA area that’s:

“The cause of multiple human diseases. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential.”

It’s a logical inference to likewise understand how stressors in a mother’s environment for a developing fetus will cause the fetus to adapt at the cellular level. If, for example, the fetus is stressed by inadequate oxygen – hypoxia – this study shows how cells will adapt in ways that foster mutations and diseases.

When the stressed fetus arrives in a different environment after birth, the newborn’s cells are maladapted to certain aspects of a normal environment – to adequate oxygen in this example. Many of the cells’ adjustments to the old environment persist in the new environment. Pathways epigenetically adapted to best survive during the fetus’ development in the womb may impact the infant’s development in a normal environment.

Researchers could make significant contributions to science by investigating treatments and therapies that potentially reverse causes of epigenetic changes.

http://www.pnas.org/content/112/12/3764.full “Environmental stress induces trinucleotide repeat mutagenesis in human cells”

If research doesn’t provide causal evidence for effects, can epigenetics be forced in to explain everything?

gettingwell4 < 0 Detracted from science, Epigenetics, Telomeres

This 2015 UK bird study found that older mothers had female children who had fewer offspring than did the rest of the house sparrow population. The finding applied also to older fathers and their male children.

In general, if a study didn’t directly demonstrate cause and effect, it isn’t appropriate to force the use of epigenetics to explain everything. That’s what this study did with epigenetic inheritance.

Did the study:

“Demonstrate that this parental age effect..potentially is epigenetically inherited.”

by analyzing DNA across generations?

No!

The researchers ran some numbers that tested the effect of older foster parents where the model’s only other possible explanation was epigenetic inheritance.

Several other things about this study were off:

  • The researchers used the term “fitness” 28 times as shorthand to mean the number of offspring, but only twice was it explained as “reproductive fitness.” This was potentially misleading in some of the contexts of the term’s other uses. For example, several of the cited references used “fitness” in a different context.
  • The researchers went into a long exposition of telomeres, punctuated by citing 11 references, only to say:

    “However it is unclear how telomere dynamics could affect fitness.”

    The next sentence was:

    “An alternative explanation might be the accumulation of deleterious mutations as individuals age.”

    which was additionally irritating because “alternative” assumed that telomeres presented a factual explanation of the study’s findings in the first place. Was this section an artifact of a struggle with the reviewer?

After forcing epigenetic inheritance as an explanatory factor and potentially misleading readers about reproductive fitness and telomeres, the researchers had little basis to conclude that their research had “important implications.”

http://www.pnas.org/content/112/13/4021.full “Reduced fitness in progeny from old parents in a natural population”

Epigenetic DNA methylation and demethylation with the developing fetus

gettingwell4 5+ stars Premium, Brain development, Cortisol, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Oxytocin, Serotonin , ,

This extremely dense and informative 2014 UK summary study provided details about genomic imprinting:

“An unusual epigenetic process in that it is heritable and results in autosomal gene expression according to parent of origin.”

Several notes of interest:

  • Figure 3 had a fascinating sketch of how the fetus caused the mother’s hypothalamus to:

    “Determine forward maternal planning by directing/orchestrating maternal physiology and postnatal maternalism to synchronize with development of the fetus.”

  • Figure 4 followed up with a flowchart of how – with a female fetus – coexistence of three matrilineal generations in the pregnant female (her, the fetus, and the grandmother’s influence on the developing fetus’ ovarian oocytes) enabled intergenerational forward planning.
  • The study briefly noted significance of genomic imprinting on male sexual behavior, where, if processes didn’t proceed normally at this early stage of a male fetus’ development, could result in suboptimal adult behavior that didn’t change with experience.

F4.large

I’ll quote a few other unrelated passages that caught my eye.

“Reproductive success of mammals also places a considerable burden on matrilineal time and energy, with some 95% of mammalian female adult life committed to pregnancy, lactation, and maternal care.

Offspring that receive optimal nourishment and improved maternal care will be predisposed to develop a hypothalamus that is both genetically and epigenetically predisposed to this same type of good mothering.

The fetus controls its own destiny in times of acute starvation, especially in the last trimester of pregnancy, by short-term sacrifice of its placenta to preserve resources critical for brain development.”

http://www.pnas.org/content/112/22/6834.full “Genomic imprinting, action, and interaction of maternal and fetal genomes”

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Epigenetic DNA methylation of the oxytocin receptor gene affected the perception of anger and fear

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Brain development, Brain hemispheres, Cerebrum, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Oxytocin, Thalamus ,

This 2015 Virginia human study:

“Reveals how epigenetic variability in the endogenous oxytocin system impacts brain systems supporting social cognition and is an important step to better characterize relationships between genes, brain, and behavior.”

The researchers did a lot of things right:

  • They studied a priori selected brain areas, followed by whole brain analyses;
  • Their subjects were carefully selected

    “Because methylation levels have been shown to differ as a function of race, we restricted our sample to Caucasians of European descent”

    but they didn’t restrict subjects to the same gender;

  • They acknowledged as a limitation:

    “A lack of behavioral evidence to reveal how these epigenetic and neural markers impact the overt social phenotype.”

One thing on which I disagree with the researchers is their assessment of what needs to be done next. Their news release stated:

“When imagining the future possibilities and implications this DNA methylation and oxytocin receptor research may have, the investigators think a blood test could be developed in order to predict how an individual may behave in social situations.”

Nice idea, but the next step should be to complete the research. The next step is to develop evidence for how the oxytocin receptor gene became methylated.

The subjects had a wide range of DNA methylation at the studied gene site – from 33% to 72% methylated!

Why?

At the same gene site:

“There was a significant effect of sex such that females have a higher level of methylation than males.”

Why?

Given these significant effects, why was there no research into likely causes?

Aren’t early periods in people’s lives the most likely times when the “Epigenetic modification of the oxytocin receptor gene” that “influences the perception of anger and fear in the human brain” takes place?

Wouldn’t findings from research on the subjects’ histories potentially help other people?

http://www.pnas.org/content/112/11/3308.full “Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain”

Would you deprive your infant in order to be in a researcher’s control group?

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Epigenetics , , , ,

This 2015 Harvard study found that exposing extremely premature babies to sounds of their mothers enlarged their auditory cortex.

The lead researcher stated:

“Our findings do not prove that the brains of these babies are necessarily better, and we cannot conclude that they will end up with no developmental disabilities.

We don’t know the advantages of having a bigger auditory cortex.”

It’s too bad that studies like this one have to take deprived infants and further deprive them for use as a control group. I suppose it’s possible that the control group members’ development could just be shifted, similar to the Maternal depression and antidepressants epigenetically change infant language development study.

However, given the findings of the Our early experiences are maintained and unconsciously influence us for years, if not indefinitely study, it’s also possible that the last trimester of womb life is a critical period for a child’s auditory cortex. If timely development doesn’t take place within the environment provided by the mother, there may not be another period to fully catch up on growth and learning, even given the effects of neural plasticity.

http://www.pnas.org/content/112/10/3152.full “Mother’s voice and heartbeat sounds elicit auditory plasticity in the human brain before full gestation”

Neural plasticity trumps genetics in the hippocampus part of the limbic system

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Hippocampus, Limbic system, Memory , ,

This 2015 rodent study used a genetic strain of mice that was bred to not express a gene that enabled long-term memory in the hippocampus. The mice were not memory-impaired, however, due to their brains’ neural plasticity.

The researchers found:

“Deletion of genes in organisms does not always give rise to phenotypes because of the existence of compensation.

The current work provides an example of how a complex brain system may adjust to the effects of gene deletion to recover function.”

The Early human brain development can be greatly modified by environmental factors study showed even greater plasticity in another part of the human brain where the people faced much larger obstacles than gene deletion.

I view this finding as a cautionary tale to reference any time a study comes out stating that A and B genes are found to cause X and Y symptoms or behavior. Researchers don’t have enough evidence in 2015 to unequivocally describe what rodent brains are capable of, much less human brains.

The researchers implied how they kept faith in their work with the phrase:

“The compensatory mechanism is imperfect and does not fully restore cGKII-dependent function.”

Is perfection the standard to which their research is also held?

http://www.pnas.org/content/112/10/3122.full “Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors”

Do the impacts of early experiences of hunger affect our behavior, thoughts, and feelings today?

gettingwell4 5+ stars Premium, Epigenetics, Primal Therapy , , , , , , ,

This 2015 worldwide human study Hunger promotes acquisition of nonfood objects found that people’s current degree of hungriness affected their propensity to acquire nonfood items.

The researchers admitted that they didn’t demonstrate cause and effect with the five experiments they performed, although the findings had merit. News articles poked good-natured fun at the findings with headlines such as “Why Hungry People Want More Binder Clips.”

The research caught my eye with these statements:

“Hunger’s influence extends beyond food consumption to the acquisition of nonfood items that cannot satisfy the underlying need.

We conclude that a basic biologically based motivation can affect substantively unrelated behaviors that cannot satisfy the motivation.”

The concept of the quotes relates to a principle of Dr. Arthur Janov’s Primal Therapy – symbolic satisfaction of needs.

I stated two fundamentals of Primal Therapy in An agenda-driven study on beliefs, smoking and addiction that found nothing of substance:

  1. The physiological impacts of our early unmet needs drive our behavior, thoughts, and feelings.
  2. The painful impacts of our unfulfilled needs impel us to be constantly vigilant for some way to fulfill them.

Corollary principles of Primal Therapy are:

  • Our present efforts to fulfill our early unmet needs will seldom be satisfying. It’s too late.
  • We acquire substitutes now for what we really needed back then.
  • Acquiring these symbols of our early unmet needs may, at best, temporarily satisfy derivative needs.

But the symbolic satisfaction of derived needs – the symptoms – never resolves the impacts of early unfulfilled needs – the motivating causes:

  • We repeat the acquisition behavior, and get caught in a circle of acting out our feelings and impulses driven by these conditions.
  • The unconscious act-outs become sources of misery both to us and to the people around us.

In his book “Primal Healing” Dr. Arthur Janov gives two examples of critical periods only during which early needs can be satisfied:

  1. Being touched in the first months of life is crucial to a child’s development. The lack of close contact after the age of 5 wouldn’t have the same effect.
  2. Conversely, the need for praise at 6 months of age may not be essential, but it’s crucial for children at age 5.

As this study’s finding showed, there’s every reason for us to want researchers to provide a factual blueprint of causes for our hunger sensation effects, such as “unrelated behaviors that cannot satisfy the motivation.”

Why not start with hunger research? Objectives of the research should include answering:

  • What enduring physiological changes occurred as a result of past hunger?
  • How do these changes affect the subjects’ present behaviors, thoughts, and feelings?

Hunger research that would likely provide causal evidence for the effect of why people acquire “items that cannot satisfy the underlying need” should include studying where to start the timelines for the impacts of hunger. The impacts would potentially go back at least to infancy when we were completely dependent on our caregivers.

Infants can’t get up to go to the refrigerator to satisfy their hunger. All a hungry infant can do is call attention to their need, and feel pain from the deprivation of their need.

Is infancy far back enough, though, to understand the beginnings of potential impacts of hunger? The Non-PC alert: Treating the mother’s obesity symptoms positively affects the post-surgery offspring study referenced an older study of how the hunger of mothers-to-be had lifelong ill effects for the fetuses they carried during the Dutch hunger winter of 1944. The exposed children had epigenetic DNA changes from their mothers’ starvation, which resulted in relative obesity compared with their unexposed siblings.

Is it science, or is it a silly and sad farce when researchers “make up” missing data?

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Hippocampus, Limbic system, Stress , , ,

This 2014 French study was a parody of science.

The researchers “made up” missing data on over 50% of the men and over 47% of the women! All to satisfy their model that drove an agenda of the effects of adverse childhood experiences.

As an example of how silly and sad this was:

  • Two of the seven subject ages of interest were 23 and 33 consecutively, and
  • One of the nine factors was education level.

If I was a subject, and wasn’t around to give data at age 33 and later, how would the researchers have extrapolated a measurement of my education level of “high school” at age 23?

I’m pretty sure their imputation method would have “made up” education level data points for me of “high school” for ages 33 and beyond. I doubt that the model would have produced my actual education levels of a Bachelors and two Masters degrees at age 33.

Everything I said about the Problematic research on stress that will never make a contribution toward advancing science study applied to this study, including the “allostatic load” buzzword and the same compliant reviewer.

Studies like this both detract from science and are a misallocation of scarce resources. Their design and data aren’t able to reach levels where they can provide etiologic evidence.

Such studies also have limiting effects on how we “do something” about real problems, because the researchers won’t be permitted to produce findings that aren’t politically correct.

http://www.pnas.org/content/112/7/E738.full “Adverse childhood experiences and physiological wear-and-tear in midlife: Findings from the 1958 British birth cohort”

One possible way that epigenetic DNA changes can pass from one generation to the next generation

gettingwell4 2-3 stars Required further work, Epigenetics

This 2015 roundworm study showed one possible way that epigenetic DNA changes could pass from one generation to the next generation:

  • The researchers caused nerve cells to transmit double-stranded RNA to germline cells.
  • The RNA changed the germline cells, and
  • The changes were passed down to the next 25 generations.

This was a new direction that had several known limitations ahead. The researchers didn’t show that this transmission mechanism worked in nature. Also, more complex species don’t retain most epigenetic changes between generations.

However:

http://www.pnas.org/content/112/7/2133.full “Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing”

Dr. Arthur Janov interview on his 2011 book Life Before Birth: The hidden script that rules our lives

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Limbic system, Lower brain, Neurochemicals, Primal Therapy, Stress, Telomeres , , , , , ,

Dr. Arthur Janov’s 2011 book “Life Before Birth: The hidden script that rules our lives” describes problems that start in the earliest parts of our lives, when epigenetic changes due to trauma in the womb affect our development.

“The science has changed. When I first started out 44 years ago, there was nobody who could understand it, or agree, especially the professionals. Now all, or a great deal of the current research, is backing up everything I say.

I’m saying that this therapy is really a matter of life and death now. I should probably start at the beginning and say that there’s trauma in the womb. We need to set back the clock so that we take account of trauma that occurs while our mother is carrying that has lifelong consequences for how long we live, for example. There’s a current research study that shows that as you get more traumatized in the womb, your life expectancy is much shorter.

When you get rid of the childhood pain that happened way back when – and there are ways to do it – you will live much longer. So truly, a proper therapy now is a matter of life and death. Not only because your life expectancy is shorter when you have trauma, but you get sick earlier, you have diabetes, Alzheimer’s, all kinds of diseases on your way to your death, which makes life very uncomfortable.

But that’s just part of what we do. The idea is that we found a way to take the pain out of the system, going all the way back. And what we’re finding is that pain starts way, way earlier than we thought.

I used to think that the greatest point was the birth trauma. Well that’s no longer true. Way before the birth trauma there are traumas from the smoking mothers, the anxious mothers, the depressed mothers, that have lifelong effects on the baby, the offspring.”

“https://www.youtube.com/watch?v=dbUhjZhpEyct”

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If research treats “Preexisting individual differences” as a black box, how can it find causes for stress and depression?

gettingwell4 0-1 star Wasted resources, Epigenetics, Immune system, Stress ,

This 2014 research studied both humans and rodents to provide further evidence on the physiology of defeat. The researchers demonstrated that with mice:

“Bone marrow transplants of stem cells that produce leucocytes lacking IL-6 (the cytokine interleukin 6) or when injected with antibodies that block IL-6 prior to stress exposure, the development of social avoidance was reduced.”

The researchers also showed in humans that standard antidepressants didn’t act to lower IL-6.

So, what were we to make of this finding?

“Preexisting differences in the sensitivity of a key part of each individual’s immune system to stress confer a greater risk of developing stress-related depression or anxiety.”

  • Was it sufficient for the researchers and the news articles covering the research to treat “preexisting differences” as a black box that nobody could enter to find causes for the effects of “developing stress-related depression or anxiety?”
  • Did things happen in each individual’s history to cause the “preexisting differences” or was each individual born that way?
  • Why was the research directed at symptoms with no mention of any underlying causal factors?

It wasn’t sufficient for the researchers to carry on their experiments with assumptions that there weren’t early-life causes for the above symptoms. Such a pretense leads to the follow-on pretense that later-life consequences weren’t effects of causes, but were instead, mysteries due to “preexisting individual differences.”

http://www.pnas.org/content/111/45/16136.full “Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress”

The degree of epigenetic DNA methylation may be used as a proxy to measure biological age

gettingwell4 4-5 stars Advanced knowledge, Epigenetics

This fascinating 2014 human study developed the new use of a somewhat intuitive marker of aging. The researchers used the degree of methylation – an epigenetic chemical modification of DNA – as an epigenetic clock to measure biological age.

The researchers found that, on average, the epigenetic age of the liver increased by 3.3 years for every increase in 10 body mass index (BMI) units. Other studied tissue areas weren’t similarly affected.

http://www.pnas.org/content/111/43/15538.full “Obesity accelerates epigenetic aging of human liver”