Epigenetics

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”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

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”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

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”

Fear extinction is the learned inhibition of retrieval of previously acquired responses

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory

This 2014 rodent study showed that fear extinction doesn’t depend on memory retrieval:

“These results show that extinction and retrieval are separate processes and strongly suggest that extinction is triggered or gated by the conditioned stimulus even in the absence of retrieval.”

Key to my understanding this finding came from a definition in another summary study by the authors, The learning of fear extinction, where they stated:

“Extinction is the learned inhibition of retrieval of previously acquired responses.”

These two studies and Hippocampal mechanisms involved in the enhancement of fear extinction caused by exposure to novelty should inform researchers of studies such as If rodent training has beneficial epigenetic effects, how can the next step be human gene therapy? of desirable alternative treatments, rather than proceeding from rodent training directly to human gene therapy.

http://www.pnas.org/content/112/2/E230.full “Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval”

A biologically relevant event can drive long-term memory in a single training session

gettingwell4 2-3 stars Required further work, Brain development, Dopamine, Epigenetics, Memory, Neurochemicals

This 2014 fruit fly study found:

“A biologically relevant event such as finding food under starvation conditions or being poisoned can drive long-term memory in a single training session.”

I don’t think that we need to discover at these extremes, though, whether or not the finding has human applicability.

We do know from the Dutch hunger winter of 1944 study referenced in the Non-PC alert: Treating the mother’s obesity symptoms positively affects the post-surgery offspring study that prenatal exposure to famine had lifelong ill effects on the children. The exposed children had epigenetic DNA changes – a form of long-term memory – from their mothers’ starvation, which resulted in relative obesity compared with their unexposed siblings.

http://www.pnas.org/content/112/2/578.full “Distinct dopamine neurons mediate reward signals for short- and long-term memories”

If rodent training had beneficial epigenetic effects, how can the next step be human gene therapy?

gettingwell4 0-1 star Wasted resources, Epigenetics, Memory , ,

This 2014 rodent study detailed significant and lasting epigenetic DNA methylation in the hippocampus part of the limbic system as a result of fear-extinction training.

The researchers missed the boat when explaining in interviews how their research could apply to humans. What I understood from the interviews was that the researchers were focused on targeting human genes with some outside action.

Recommending human gene therapy smelled like an agenda. If these epigenetic modifications were induced by training in rodents, wouldn’t the next step be research into reversal training or therapeutic activity for humans?

The researchers also found:

“Importantly, these effects were specific to extinction training and did not occur in mice that had been fear conditioned, followed by a single reactivation trial, therefore arguing against the possibility that such epigenetic modifications are nonspecifically induced by the retrieval or reconsolidation of the original fear memory.”

This was fine for rodent studies where the origins of both the disease and the cure were all exerted externally. I didn’t see that it necessarily applied to humans.

After all, we’re not lab rats. We can perform effective therapy that doesn’t involve some outside action being done to us.

http://www.pnas.org/content/111/19/7120.full “Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation”