What do our time preferences reveal about our pasts?

This 2016 Swedish human study found:

“Time discounting significantly predicts criminal activity and that high discount rates predict crime more strongly at the extensive margin rather than for total crime. The link is much stronger for property crime and among males with low intelligence.”

The subjects were 13-year-old students in Stockholm County who were asked as a part of a school survey in 1966:

“If you had to choose between SEK 900 [USD 138] now versus SEK 9,000 [USD 1,380] in five years, what would you choose?

  1. Certainly SEK 900 now
  2. Probably SEK 900 now
  3. Cannot choose
  4. Probably SEK 9,000 in five years
  5. Certainly SEK 9,000 in five years”

A choice of Answer 1 to get something immediately and not get ten times the nominal value in five years corresponds to a 58.4% annual discount rate.

These answers to a hypothetical monetary trade-off were correlated to other measures such as intelligence and father’s income. However, the researchers didn’t investigate possible origins:

“We focus on the predictive value of time discounting and avoid claims about causality.”

We know from proper economic theory that time preferences are part of human nature. Discount rates and money don’t necessarily have to be involved because humans will value something today more than a similar item in the future.

I’d guess that most of the answers reflected conditioned behaviors. Did the 13-year olds who answered #1 even roughly calculate the problem? I wonder if they felt they would still be alive at age 18?

http://www.pnas.org/content/113/22/6160.full “Time discounting and criminal behavior”

The persistence of epigenetic marks in Type 1 diabetes

This 2016 California human study found:

“A persistency of DNA methylation over time at key genomic loci associated with diabetic complications. Two sets of DNAs collected at least 16–17 years apart from the same participants are used to show the persistency of DNA-me over time.

Twelve annotated differentially methylated loci were common in both WB [whole blood] and Monos [blood monocytes], including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications.

The top 38 hyperacetylated promoters in cases included 15 genes associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway, which is strongly associated with diabetic complications.”

The researchers built on a series of studies that showed how subjects with early intensive interventions didn’t develop further complications, whereas subjects with later intensive interventions:

“Continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates.

This persistence of benefit from early application of intensive therapy, called ‘metabolic memory,’ is an enigma.”

I’d say that the researchers needed to also consider a point of Enduring memories? Or continuous toxic stimulation? that:

“The lasting epigenomic effect would not be due to memory, but continuous stimulation by persistent pathogens or persistent components.”

Other studies that involved specific genes of this study include:

http://www.pnas.org/content/113/21/E3002.full “Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort”


A limited study of parental transmission of anxiety/stress-reactive traits

BehavioralTraitsThis 2016 New York rodent study found:

“Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring.

We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations.

As the individual traits/pathways each have their own generation-dependent penetrance and gender specificity, the resulting cumulative phenotype is pleiotropic. In the context of genetic diseases, it is typically assumed that this phenomenon arises from individual differences in vulnerability to the various effects of the causative gene. However, the work presented here reveals that pleiotropy can be produced by the variable distribution and segregated transmission of behavioural traits.”

A primary focus was how anxiety was transmitted from parents to offspring:

“The iterative propagation of the male-specific anxiety-like behaviour is most compatible with a model in which proinflammatory state is propagated from H [serotonin1A receptor heterozygote F0] to F1 [first generation] females and in which the proinflammatory state is acquired by F1 males from their H mothers, and then by F2 [second generation] males from their F1 mothers.

We propose that increased levels of gestational MIP-1β [macrophage inflammatory protein 1β] in H and F1 mothers, together with additional proinflammatory cytokines and bioactive proteins, are required to produce immune system activation in their newborn offspring, which in turn promotes the development of the anxiety-like phenotype in males.

In particular, increase in the number of monocytes and their transmigration to the brain parenchyma in F1 and F2 males could be central to the development of anxiety.”

Due to my quick take on the study title – “Behavioural traits propagate across generations..” – I had expectations of this study that weren’t born out. My criticisms below relate to my expectations of what the researchers could have done versus what they did.

The researchers studied parental transmission of behavioral traits and epigenetic changes. Their study design removed prenatal and postnatal parental behavioral transmission of behavioral traits and epigenetic changes as each generation’s embryos were implanted into foster wild-type (WT) mothers.

The study design substituted the foster mothers’ prenatal and postnatal parental environments for the biological parents’ parental environments. So we didn’t find out, for example:

  • What effects the anxious F1 males’ behaviors may have had on their offsprings’ behaviors and epigenetic changes
  • Whether the anxious, hypoactive, overly stress-reactive, hypothermic F2 males’ behaviors affected their offsprings’ behaviors and epigenetic changes
  • To what extents the overly stress-reactive F1 mothers’ prenatal environments and postnatal behaviors induced behaviors and/or epigenetic changes in their children, and whether the F2 children’s parental behaviors subsequently induced behaviors and/or epigenetic changes in the F3 generation.

How did the study meet the overall goal of rodent studies: to help humans?

  1. Only a minority of humans experienced an early-life environment that included primary caregivers other than our biological parents.
  2. Very few of us experienced a prenatal environment other than our biological mothers.
  3. Maybe the researchers filled in some gaps in previous rodent studies, such as determining what is or isn’t a “true transgenerational mechanism.”

As an example of a rodent study that more closely approximated human conditions, the behavior of a mother whose DNA was epigenetically changed by stress induced the same epigenetic changes to her child’s DNA when her child was stressed per One way that mothers cause fear and emotional trauma in their infants:

“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

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 physiology. But when investigating human correlates with behavioral epigenetic changes of rodents in the laboratory, parental behavioral transmission of behavioral traits is often treated the way this study treated it: as a confounder.

I doubt that people who have reached some degree of honesty about their early lives and concomitant empathy for others would agree with this prioritization.

http://www.nature.com/ncomms/2016/160513/ncomms11492/full/ncomms11492.html “Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms”

Enduring epigenetic memories? Or continuous toxic stimulation?

This 2016 review subject was bacterial infections that result in long-lasting memories:

“Virulence factors modify the epigenomic landscape through targeting of host signaling cascades, or chromatin complexes directly. Additionally, some bacterial factors have intrinsic catalytic activity enabling them to directly modify chromatin.

Virus, fungi, and parasites also induce similar processes.

Epigenomic changes are not the only possible marks contributing to epigenetic memory. Every inducible change that is not rapidly reversed has the potential to maintain a lasting effect.

Most studies in this field have been performed in vitro with fully terminally differentiated cells such as epithelial cells. Since in such cell types cell fate is already established and a short lifespan often occurs in vivo, this raises the question of whether such memory would be relevant for these cells. The same can be applied to differentiated innate immune cells, which also have a short lifetime.

Looking at the response of undifferentiated cells such as stem cells appears much more appropriate to further explore the concept of innate immune memory.”

From the Conclusions and Perspectives section:

“The lasting potential of chromatin marks depends not only on the kinetics of the epigenome, but also on the stimulus itself. For example, in contrast to LPS [lipopolysaccharide, the major constituent of the cell wall of Gram-negative bacteria], which is rapidly cleared from the organism, BCG and the anthrax toxin may persist in the host organism.

The lasting epigenomic effect would not be due to memory, but continuous stimulation by persistent pathogens or persistent components.”

This last point emphasized the principle that damaging sources should be addressed. Enduring epigenetic memories may be symptoms rather than causes when toxic conditions persist. One possible reason why therapies that reverse epigenetic changes may not prove to be effective is that these epigenetic memories may not be the only causes of continuing damage.

I downgraded this review’s rating both because it’s behind a paywall, and because the reviewers made this curious statement:

“We apologize to colleagues whose work was not cited here due to reference restrictions.”

Why did the reviewers submit their work to a journal which imposed such restrictions?

“A Lasting Impression: Epigenetic Memory of Bacterial Infections?”

A study of genetic imprinting and neurodevelopmental disorders

This 2016 UK human study assessed the roles of genetic imprinting on diseases that may originate from a certain interval on chromosome 15:

“The 15q11.2-q13.3 region contains a cluster of imprinted genes, which are expressed from one parental allele only as a consequence of germline epigenetic events.

The importance of epigenetic status of duplications at this interval was further underlined by analysis of a number of families. Duplications in two unaffected mothers had a DNA-methylation pattern indicative of being paternally derived, whereas their offspring, who possessed a maternally derived duplication, suffered from psychotic illness.

We clearly implicate 15q11.2-q13.3 interstitial duplications of paternal origin in the aetiology of DD [developmental delay], but do not find them at increased rates in SZ [schizophrenia], which is significantly associated only with duplications of maternal origin.

This study refines the distinct roles of maternal and paternal duplications at 15q11.2-q13.3, underlining the critical importance of maternally active imprinted genes in the contribution to the incidence of psychotic illness.”

The researchers analyzed other studies for better estimates of paternal involvement:

“We show for the first time that paternal duplications are pathogenic. One reason why paternal duplications have been regarded as non-pathogenic in the past is their rare occurrence in patients. Here we demonstrate that they are also rare in the general population as a whole.

Paternal duplications should be less efficiently eliminated from the population by negative selection pressure, due to their lower penetrance for neurodevelopmental disorders. Secondly, some maternal duplications will change to paternal when transmitted from male carriers.

We now suggest one further explanation for their rarity: male patients with SZ and other neurodevelopmental disorders have lower fecundity. Men suffering with SZ have only half the number of offspring compared to women with SZ.”

I would have liked further discussion of the “germline epigenetic events” that apparently contribute to the studied problems. These epigenetic abnormalities may have the potential to be prevented or treated, or at least used as early biomarkers.

The reviewers instead focused on:

“This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.”

http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1005993 “Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders”

Does childhood trauma influence offspring’s birth characteristics?

This 2016 Swedish human study investigated the effects of one specific childhood trauma, parental death:

“Parental (G1) death during (G2) childhood predicts prematurity and lower birthweight in the offspring generation (G3). This response is dependent on G2 gender, G2 age at exposure and G3 parity, but not on G3 gender.

Offspring of women who lost their parent at the age of 0-2 or at the age of 13-17 had an increased risk for prematurity.

Offspring of men who lost a parent at ages 8-12 had an increased risk of prematurity.

For women exposed to a parent’s death at age 0-2, there was no significant deficit in their offspring’s birthweight in any parity class. For women exposed at later ages we observed a deficit in birthweight.

Among children whose fathers experienced parental loss..experiencing parental death at ages 8-12 in particular, or at ages 13-17, but not at ages 0-2 or 3-7, did predict having lighter offspring.”

The study design was unable to produce causal evidence for the putative intergenerational effects. An example of the limitations was:

“We had no information about behaviours and biological markers or genes.”

Its findings were best summarized as:

“Our study fails to refute the hypothesis that a male-line epigenetic mechanism exists which may be triggered by trauma during boys’ slow growth period.”

Still, the study had a firmer foundation than did A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms, which speciously produced politically-correct results from childhood trauma surveys of adults.

http://ije.oxfordjournals.org/content/early/2016/05/03/ije.dyw048.full “Does childhood trauma influence offspring’s birth characteristics?”

Why drugs aren’t ultimately therapeutic

This 2016 Oregon review’s concept was the inadequacy of drug-based therapies, explored with the specific subject of epilepsy:

“Currently used antiepileptic drugs:

  • [aren’t] effective in over 30% of patients
  • [don’t] affect the comorbidities of epilepsy
  • [don’t] prevent the development and progression of epilepsy (epileptogenesis).

Prevention of epilepsy and its progression [requires] novel conceptual advances.”

The overall concept that current drug-based therapies poorly address evolutionary biological realities was illustrated by a pyramid, with the comment that:

“If the basis of the pyramid depicted in Figure 1 is overlooked, it becomes obvious that a traditional pharmacological top-down treatment approach has limitations.”

Why drug ultimately aren't therapeutic

I would have liked the reviewer to further address the “therapeutic reconstruction of the epigenome” point he made in the Abstract:

“New findings based on biochemical manipulation of the DNA methylome suggest that:

  1. Epigenetic mechanisms play a functional role in epileptogenesis; and
  2. Therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.”

As it was, the reviewer lapsed into the prevalent belief that the causes of and cures for human diseases will always be found on the molecular level – for example, the base of the above pyramid – and never in human experiences. This preconception leads to discounting human elements – notably absent in the above pyramid – that generate epigenetic changes.

A consequence of ignoring experiential causes of diseases is that the potential of experiential therapies to effect “therapeutic reconstruction of the epigenome” isn’t investigated.

http://journal.frontiersin.org/article/10.3389/fnmol.2016.00026/full “The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine”