Stuck in the wrong paradigm

This 2019 article questioned the paradigm of determining substance carcinogenicity:

“In the absence of robust epidemiological data, the final arbiter of whether a chemical is considered to be a carcinogen or not has been based on the outcome of long-term rodent bioassays. This approach is incompatible with the current knowledge of the etiology of cancer. The current view of the etiology of cancer suggests that it is not useful to consider carcinogenicity as a single hazardous property with its own hazard category.

There is no bright line between carcinogens and non-carcinogens but rather there is a continuum with some chemicals having high potential, some having no potential, and others having potential at a point along the continuum. This continuum exists alongside other adverse effects. One problem is being stuck in the old practice of wishing to reproduce the binary “carcinogen/non-carcinogen” results of the long-term bioassay rather than move to a new paradigm in assessing the chemical’s position on the spectrum of carcinogenic potential.

The two-year bioassay has such high variability (because of the variability of the carcinogenic process it is trying to measure and the interplay between dose limiting toxicity and cell proliferation inducing toxicity) that the outcome of the assay for compounds with low to intermediate carcinogenic potential is little more than a lottery. After half a century, it has only been used to evaluate less than 5% of chemicals that are in use. It is not reproducible because of the probabalistic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design.”

Unscientific research paradigms will eventually collapse because they can’t withstand the scrutiny of the scientific method. Too bad the coauthors didn’t kill off this one while they were still in positions at the U.S. Environmental Protection Agency, World Health Organization, etc. “Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible” (not freely available)


Epigenetic causes of sexual orientation and handedness?

This 2018 Austrian human study subject was various associations of prenatal testosterone levels to fetal development:

“The available evidence suggests, albeit not conclusively, that prenatal testosterone levels may be one cause for the association of sexual orientation with handedness. Associations among women were consistent with predictions of the Geschwind–Galaburda theory (GGT), whereas those among men were consistent with predictions of the callosal hypothesis. However, research on the associations between sexual orientation and handedness appears to be compromised by various methodological and interpretational problems which need to be overcome to arrive at a clearer picture.

The GGT posits that high prenatal testosterone levels cause a delay in the fetal development of the left cerebral hemisphere which results in a right-hemisphere dominance and hence in a tendency for left-handedness. According to the GGT, high prenatal testosterone levels entail not only a masculinization of the female fetus, but also a feminization of the male fetus (contrary to neurohormonal theory). Overall, the male fetus is subjected to higher levels of intrauterine testosterone than the female fetus. The GGT is thus consistent with the higher prevalence of left-handedness among men than among women.

The callosal hypothesis applies to men only and assumes, in line with neurohormonal theory, that low prenatal testosterone levels are associated with later homosexuality. According to the CH, high prenatal testosterone enhances processes of cerebral lateralization through mechanisms of axonal pruning, thereby resulting in stronger left-hemisphere dominance and a smaller corpus callosum. Consistent with this, women have a larger corpus callosum than men.”

The study’s Limitations section included the following:

  1. “Limitations of the current study pertain to the self-report nature of our data. Behavioral data may provide differing results from those obtained here.
  2. Assessment of sexual orientation relied on a single-item measure. Utilization of rating scales (e.g., the Kinsey Sexual Orientation Scale) or of multi-item scales, and assessing different components of sexual orientation, would have allowed for a more fine-grained analysis and for a cross-validation of sexual orientation ratings with sexual attraction.
  3. Albeit both our samples were large, the proportions of bisexual and homosexual individuals were, expectedly, only small, as were effects of lateral preferences. Thus, in analysis we could not differentiate bisexual from homosexual individuals. Bisexual and homosexual individuals may differ with regard to the distribution of lateral preferences.
  4. Some effect tests in this study have been underpowered. Independent replications with even larger samples are still needed.”

The largest unstated limitation was no fetal measurements. When a fetus’ epigenetic responses and adaptations aren’t considered, not only can the two competing hypotheses not be adequately compared, but causes for the studied phenotypic programming and other later-life effects will also be missed. “Associations of Bisexuality and Homosexuality with Handedness and Footedness: A Latent Variable Analysis Approach”

Fear of feeling?

Here’s a 2018 article from two researchers involved in the Dunedin (New Zealand) Longitudinal Study. They coauthored many studies, including People had the same personalities at age 26 that they had at age 3.

The paper’s grand hypothesis was:

“A single dimension is able to measure a person’s liability to mental disorder, comorbidity among disorders, persistence of disorders over time, and severity of symptoms.”

The coauthors partially based this on:

“Repeated diagnostic interviews carried out over 25 years, when the research participants were 11, 13, 15, 18, 21, 26, 32, and 38 years old, and include information about seven diagnostic groups: anxiety, depression, attention deficit hyperactivity disorder, conduct disorder, substance dependence, bipolar disorder, and schizophrenia.” “All for One and One for All: Mental Disorders in One Dimension” (not freely available)

More about the coauthors:

Two psychologists followed 1000 New Zealanders for decades. Here’s what they found about how childhood shapes later life

“Dunedin and other studies show that most people have at least one episode of mental illness during their lifetime.”

What compels people to search for “universal truths” instead of personal truths? Are we afraid of our feelings?

What if the grand hypothesis worth proving was: For one’s life to have meaning, each individual has to regain their feelings?

Chronological age by itself is an outdated clinical measurement

This 2018 editorial in the New England Journal of Medicine concerned a clinical trial of an osteoporosis treatment:

“When measurement of bone density was first introduced 25 years ago, absolute bone mineral density (g per square centimeter) was considered as too onerous for clinicians to understand. Ultimately, these events led to a treatment gap in patients who had strong clinical risk factors for an osteoporotic fracture (particularly age) but had T scores in the osteopenic range.

The average age of the participants in the current trial was approximately 3.5 years older than that in the Fracture Intervention Trial. Owing to the interaction between age and bone mineral density, the results of the current trial should not be extrapolated to younger postmenopausal women (50 to 64 years of age) with osteopenia.

This trial reminds us that risk assessment and treatment decisions go well beyond bone mineral density and should focus particularly on age and a history of previous fractures.”

The time has passed for physicians and clinicians to consider only chronological age when evaluating a patient’s clinical age. More effective human age measurements covering the entire person as well as their body’s components include:


This editorial provided the history of how a still-generally-accepted set of diagnostic measurements were selected for their relative convenience instead of chosen for their efficacy. Add chronological age to such ineffective measurements.

Let’s recognize better aging and diagnostic measurements, then incorporate them. How else will we advance past this uninformative averaging and unhelpful recommendation based on chronological age?

“The average age of the participants in the current trial was approximately 3.5 years older than that in the Fracture Intervention Trial. Owing to the interaction between age and bone mineral density, the results of the current trial should not be extrapolated to younger postmenopausal women (50 to 64 years of age) with osteopenia.” “A Not-So-New Treatment for Old Bones”

A slanted view of the epigenetic clock

The founder of the epigenetic clock technique was interviewed for MIT Technology Review:

“We need to find ways to keep people healthier longer,” he says. He hopes that refinements to his clock will soon make it precise enough to reflect changes in lifestyle and behavior.”

The journalist attempted to dumb the subject down “for the rest of us” with distortions such as the headline. The varying correlation of epigenetic age to chronological age was somewhat better reported in the story:

“The epigenetic clock is more accurate the younger a person is. It’s especially inaccurate for the very old.”

The journalist inappropriately used luck as a synonym for randomness/stochasticity:

“He estimates that about 40% of the ticking rate is determined by genetic inheritance, and the rest by lifestyle and luck.”

A third example of less-than-straightforward journalism started with:

“Such personalization raises questions about fairness. If your epigenetic clock is ticking faster through no fault of your own..”

Were MIT Technology Review readers unable to comprehend a straightforward story on the epigenetic clock? What was the purpose of slants and distortions in an introductory article? “Want to know when you’re going to die?”

The role of recall neurons in traumatic memories

This 2018 Swiss rodent study found:

“Our data show that:

  • A subset of memory recall–induced neurons in the DG [dentate gyrus] becomes reactivated after memory attenuation,
  • The degree of fear reduction positively correlates with this reactivation, and
  • The continued activity of memory recall–induced neurons is critical for remote fear memory attenuation.

Although other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated, these results suggest that fear attenuation at least partially occurs in memory recall–induced ensembles through updating or unlearning of the original memory trace of fear.

These data thereby provide the first evidence at an engram-specific level that fear attenuation may not be driven only by extinction learning, that is, by an inhibitory memory trace different from the original fear trace.

Rather, our findings indicate that during remote fear memory attenuation both mechanisms likely coexist, albeit with the importance of the continued activity of memory recall–induced neurons experimentally documented herein. Such activity may not only represent the capacity for a valence change in DG engram cells but also be a prerequisite for memory reconsolidation, namely, an opportunity for learning inside the original memory trace.

As such, this activity likely constitutes a physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans: the engagement, rather than the suppression, of the original trauma.”

The researchers also provided examples of human trauma:

“We dedicate this work to O.K.’s father, Mohamed Salah El-Dien, and J.G.’s mother, Wilma, who both sadly passed away during its completion.”

So, how can this study help humans? The study had disclosed and undisclosed limitations:

1. Humans aren’t lab rats. We can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments.

2. It’s a bridge too far to go from neural activity in transgenic mice to expressing unfounded opinions on:

“A physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans.”

Human exposure therapies have many drawbacks, in addition to being applied externally to the patient on someone else’s schedule. A few others were discussed in The role of DNMT3a in fear memories:

  • “Inability to generalize its efficacy over time,
  • Potential return of adverse memory in the new/novel contexts,
  • Context-dependent nature of extinction which is widely viewed as the biological basis of exposure therapy.”

3. Rodent neural activity also doesn’t elevate recall to become an important goal of effective human therapies. Clearly, what the rodents experienced should be translated into human reliving/re-experiencing, not recall. Terminology used in animal studies preferentially has the same meaning with humans, since the purpose of animal studies is to help humans.

4. The researchers acknowledged that:

“Other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated.”

A study that provided evidence for basic principles of Primal Therapy determined another brain area:

“The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”

The study I curated yesterday, Organ epigenetic memory, demonstrated organ memory storage. It’s hard to completely rule out that other body areas may also store traumatic memories.

The wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address the whole person, the whole body, and each individual’s entire history. “Reactivation of recall-induced neurons contributes to remote fear memory attenuation” (not freely available)

Here’s one of the researchers’ outline:

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.

Prenatal programming of human HPA axis development

This 2017 UC Irvine human review subject provided details of how fetal hypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:

“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.

Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.

Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”

Every time I read a prenatal study I’m in awe of all that has to go right, and at the appropriate time, and in sequence, for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for any human to escape epigenetic damage.

1. The reviewers referenced human research performed with postnatal subjects, as well as animal studies, despite the disclaimer:

This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”

This led to blurring of what had been studied or not with human fetuses regarding the subject.

2. The reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. It’s more appropriate for reviewers to offer informed reviews of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

3. It would have been preferable had the researchers stayed with their stated intention and critically reviewed only a few dozen studies with solid evidence of the review title: “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover older humans, animals, and questionable evidence.

I asked the reviewers to provide a searchable file so that their work could be better used as a reference. “Developmental origins of the human hypothalamic-pituitary-adrenal axis” (registration required)