Month: December 2017

Epigenetic study methodologies improved in 2017

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Let’s start out 2018 paying more attention to advancements in science that provide sound empirical data and methodology. Let’s ignore and de-emphasize studies and reviews that aren’t much more than beliefs couched in models and memes, whatever their presumed authority.

Let sponsors direct researchers to focus on ultimate causes of diseases. Let’s put research of treatments affecting causes ahead of those that only address symptoms.

Here are two areas of epigenetic research that improved in 2017.

Improved methodologies enabled DNA methylation studies of adenine, one of the four bases of DNA, to advance, such as this 2017 Wisconsin/Minnesota study N6-methyladenine is an epigenetic marker of mammalian early life stress:

“6 mA is present in the mammalian brain, is altered within the Htr2a gene promoter by early life stress and biological sex, and increased 6 mA is associated with gene repression. These data suggest that methylation of adenosine within mammalian DNA may be used as an additional epigenetic biomarker for investigating the development of stress-induced neuropathology.”

Most DNA methylation research is performed on the cytosine and guanine bases.

Other examples of improved methodologies were discussed in this 2017 Japanese study Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies:

“A strategy focusing on CpG sites with high DNA methylation level variability may attain an improved efficacy..estimated to be 3.7-fold higher than that of the most frequently used strategy.

With ~90% coverage of human CpGs, whole-genome bisulfite sequencing (WGBS) provides the highest coverage among the currently available DNAm [DNA methylation] profiling technologies. However, because of its high cost, it is presently infeasible to apply WGBS to large-scale EWASs [epigenome-wide association studies], which require DNAm profiling of hundreds or thousands of subjects. Therefore, microarrays and targeted bisulfite sequencing are currently practicable for large-scale EWASs and thus, effective strategies to select target regions are essentially needed to improve the efficacy of epigenetic association studies.

DNAm levels measured with microarrays are invariable for most CpG sites in the study populations. As invariable DNAm signatures cannot be associated with exposures, intermediate phenotypes, or diseases, current designs of probe sets are inefficient for blood-based EWASs.”

A review of biological variability

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This 2017 UK/Spanish review subject was biological variability:

“No two cells in a cellular population are the same, and no two individuals of a multi-cellular species are identical-not even if they share the same genetic makeup like monozygotic twins or cloned animals.

Epigenetic and gene expression variability are key contributors to phenotypic differences. There are many possible sources of epigenetic and transcriptional variability, which can be divided into three main categories:

  1. individual-intrinsic factors;
  2. environmental factors; and
  3. random fluctuations, also referred to as stochasticity.”

Most of the review cited cell studies. The reviewers cited their own studies in the Introduction section, for example:

“These studies were among the first to classify disease status or aggressiveness based on variability, where the classical comparison of mean DNA methylation or gene expression levels was not informative.”

to help support a later observation:

“It is critical to obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”

The review didn’t cover a pertinent aspect of the subject: how standard research approaches miss detecting biological variability.

For example, from Changing an individual’s future behavior even before they’re born that referred to the methodology of genome-wide association studies (GWAS):

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

Another omission was the point made in A study of DNA methylation and age:

“Due to the methods applied in the present study, not all the effects of DNA methylation on gene expression could be detected; this limitation is also true for previously reported results.

The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”

The reviewers also didn’t cover variability in phenotypic behaviors. I’ll repeat my thoughts from A limited study of parental transmission of anxiety/stress-reactive traits:

“How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions, and in every human’s physiology.”

Perhaps these omissions reflected the reviewers’ focus on their specialties?

Perhaps it isn’t politically correct to discuss or fund research on aspects of biological variability that would advance science by falsifying preferred previous findings? Or advance science by measuring the extent of parental involvement in shaping their offspring’s behavioral and biological variability?

What do you think?

http://onlinelibrary.wiley.com/doi/10.1002/bies.201700148/full “Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity”

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.

What’s an appropriate exercise recovery time?

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This 2017 New Zealand human research studied the effect of one supplement on recovery from exercise-induced muscle damage:

“Eccentric exercise is known to bring about microstructural damage to muscle, initiating an inflammatory cascade involving various reactive oxygen species. This, in turn, can significantly impair physical performance over subsequent days. Taurine, a powerful endogenous antioxidant, has previously been shown to have a beneficial effect on muscle damage markers and recovery when taken for a few days to several weeks prior to eccentric exercise.

The amount of powder was set at 0.1 g∙kg−1 body weight∙day−1, based on several studies that found no adverse effects at levels of up to 10 g∙day. No participant was at a body weight that resulted in consuming more than 10 g∙day.

Supplementation with taurine twice daily for 72 h following eccentric exercise-induced muscle damage may improve eccentric performance recovery of the biceps brachii in healthy males.”

My main takeaway from the study came from this finding:

“Our results show that neither treatment group fully recovered force output by 72 h.”

I was surprised to see that even three days wasn’t enough time for a muscle to fully recover. And the study’s subjects were young males:

“Age = 26.5 ± 6.5 years, height = 180 ± 9.2 cm, mass = 80 ± 11.5 kg. All participants were recreationally fit, engaging in exercise 2–3 times per week.”

This gave me pause to reflect on how inattention to cumulative strain may have produced repetitive stress injuries. I’ve adjusted my workout routines accordingly.

The study listed a number of limitations. An unstated one was that nobody should take supplements in quantities that are many times greater than normal dosages without being informed by quality human experimental evidence.

http://www.mdpi.com/2076-3921/6/4/79/htm “The Effect of Taurine on the Recovery from Eccentric Exercise-Induced Muscle Damage in Males”

How to cure the ultimate causes of migraines?

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Most of the spam I get on this blog comes in as ersatz comments on The hypothalamus couples with the brainstem to cause migraines. I don’t know what it is about the post that attracts internet bots.

The unwanted attention is too bad because the post represents a good personal illustration of “changes in the neural response to painful stimuli.” Last year I experienced three three-day migraines in one month as did the study’s subject. This led to me cycling through a half-dozen medications in an effort to address the migraine causes.

None of the medications proved to be effective at treating the causes. I found one that interrupted the progress of migraines – sumatriptan, a serotonin receptor agonist. I’ve used it when symptoms start, and the medication has kept me from having a full-blown migraine episode in the past year.

1. It may be argued that migraine headache tendencies are genetically inherited. Supporting personal evidence is that both my mother and younger sister have migraine problems. My father, older sister, and younger brother didn’t have migraine problems. Familial genetic inheritance usually isn’t the whole story of diseases, though.

2. Migraine headaches may be an example of diseases that are results of how humans have evolved. From Genetic imprinting, sleep, and parent-offspring conflict:

“Evolutionary theory predicts: that which evolves is not necessarily that which is healthy.

Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.“

Both migraine causes and effects may be traced back to natural lacks of feedback loops. These lacks demonstrate that such physiological feedback wasn’t evolutionarily necessary in order for humans to survive and reproduce.

3. Examples of other processes occurring during prenatal development that also lack feedback loops, and their subsequent diseases, are:

A. Hypoxic conditions per Lack of oxygen’s epigenetic effects are causes of the fetus later developing:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

B. Stressing pregnant dams per Treating prenatal stress-related disorders with an oxytocin receptor agonist caused fetuses to develop a:

and abnormalities:

  • in social behavior,
  • in the HPA response to stress, and
  • in the expression of stress-related genes in the hippocampus and amygdala.”

1. What would be a treatment that could cure genetic causes for migraines?

I don’t know of any gene therapies.

2. What treatments could cure migraines caused by an evolved lack of feedback mechanisms?

We humans are who we have become, unless and until we can change original causes. Can we deal with “changes in the neural response to painful stimuli” without developing hopes for therapies or technologies per Differing approaches to a life wasted on beliefs?

3. What treatments could cure prenatal epigenetic causes for migraines?

The only effective solution I know of that’s been studied in humans is to prevent adverse conditions like hypoxia from taking place during pregnancy. The critical periods of our physical development are over once we’re adults, and we can’t unbake a cake.

Maybe science will offer other possibilities. Maybe researchers could do more than their funding sponsors expect?

Differing approaches to a life wasted on beliefs

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Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their one precious life’s time so far.

Such was my take on beliefs embedded in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future. However, when scrutinized, most human studies have demonstrated NULL effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, his belief seemed driven by something else.

The author cited findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the 300+ cited references concern treatments where patients instead therapeutically addressed their problems’ root causes?

For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence.” He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that he had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior.

So he developed other beliefs instead.

What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.”

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Epigenetic effects of microRNA on fetal heart development

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This 2017 Australian review’s subject was epigenetic impacts involving microRNA in adverse intrauterine environments, and how these affected fetal heart tissue development:

“We describe how an adverse intrauterine environment can influence the expression of miRNAs (a sub-set of non-coding RNAs) and how these changes may impact heart development. Potential consequences of altered miRNA expression in the fetal heart include; Hypoxia inducible factor (HIF) activation, dysregulation of angiogenesis, mitochondrial abnormalities and altered glucose and fatty acid transport/metabolism.

This feedback network between miRNAs and other epigenetic pathways forms an epigenetics–miRNA regulatory circuit that organizes the whole gene expression profile. The human heart encodes over 700 miRNAs.”

A 2016 review Lack of oxygen’s epigenetic effects also provided a details about hypoxia. Those reviewers importantly pointed out the natural lack of a feedback mechanism to the HIF-1α signaling source, and how this evolutionary lack contributed to diseases.

http://www.mdpi.com/1422-0067/18/12/2628/htm “Adverse Intrauterine Environment and Cardiac miRNA Expression”

Do you have your family’s detailed medical histories?

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Imagine that you were a parent who puzzled over the mystery of your pre-teen daughter’s hyperactive behavior. Without detailed family medical histories, would anyone recognize this as a preprogammed phenotype?

Could anyone trace the daughter’s behavior back to her maternal great-grandmother being treated with glucocorticoids near the end of the second trimester of carrying her grandfather?

Such was a finding of a 2017 Canadian guinea pig study that was undertaken to better inform physicians of the transgenerationally inherited epigenetic effects of glucocorticoid treatments commonly prescribed during human pregnancies:

“This study presents the first evidence that prenatal treatment with sGC [synthetic glucocorticoid] results in transgenerational paternal transmission of hyperactivity and altered hypothalamic gene expression through three generations of young offspring. Female offspring appear to be more sensitive than male offspring to the programming effects of sGC, which suggests an interaction between sGC and sex hormones or sex-linked genes. Paternal transmission to F3 strongly implicates epigenetic mechanisms in the process of transmission, and small noncoding RNAs likely play a major role.”

Some details of the study included:

Veh[icle] was the control group initially treated with saline.

The study was informative and conclusive for the aspects studied. From the Methods section:

“Data from same-sex littermates were meaned to prevent litter bias. Sample sizes (N) correspond to independent litters, and not to the total number of offspring across all litters.

Power analyses based on previous studies determined N ≥ 8 sufficient to account for inter-litter variability and detect effects in the tests performed.”

https://www.nature.com/articles/s41598-017-11635-w “Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission”

What is a father’s role in epigenetic inheritance?

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The agenda of this 2017 Danish review was to establish a paternal role in intergenerational and transgenerational epigenetic inheritance of metabolic diseases:

“There are four windows of susceptibility which have major importance for epigenetic inheritance of acquired paternal epigenetic changes:

  1. paternal primordial germ cell (PGC) development,
  2. prospermatogonia stages,
  3. spermatogenesis, and
  4. during preimplantation.”

The review was a long read as the authors discussed animal studies. When it came to human studies near the paper’s end, though, the tone was of a “we know this is real, we just have to find it” variety. The authors acknowledged:

“To what extent the described DNA methylation changes influence the future health status of offspring by escaping remodeling in the preimplantation period as well as in future generations by escaping remodeling in PGC remodeling has yet to be determined.

These studies have not yet provided an in-depth understanding of the specific mechanisms behind epigenetic inheritance or exact effect size for the disease risk in offspring.

Pharmacological approaches have reached their limits..”

before presenting their belief that a hypothetical series of future CRISPR-Cas9 experiments will demonstrate the truth of their agenda.

The review focused on 0.0001% of the prenatal period for what matters with the human male – who he was at the time of a Saturday night drunken copulation – regarding intergenerational and transgenerational epigenetic inheritance of metabolic diseases.

The human female’s role – who she was at conception AND THEN what she does or doesn’t do during the remaining 99.9999% of the prenatal period to accommodate the fetus and prevent further adverse epigenetic effects from being intergenerationally and transgenerationally transmitted  – wasn’t discussed.

Who benefits from this agenda’s narrow focus?

If the review authors sincerely want to:

“Raise societal awareness of behavior to prevent a further rise in the prevalence of metabolic diseases in future generations..”

then EARN IT! Design and implement HUMAN studies to test what’s already known from epigenetic inheritance animal studies per Experience-induced transgenerational programming of neuronal structure and functions. Don’t disguise beliefs with the label of science.

http://jme.endocrinology-journals.org/content/early/2017/12/04/JME-17-0189.full.pdf “DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line”