Welcome to the epigenetic revolution

3 March 2018
 
The first time that the term epigenetics was mentioned in the economic literature was in the year 2007 when the Nobel prize winner James Heckman wrote the article “The economics, technology, and neuroscience of human capability formation (2007).” Heckman wanted to emphasize how the caretaking by the parents (also called early childhood environment) has an effect on the intellectual and emotional capabilities of people that show up later in their life. Heckman argues that it is best to conceive these early lifehood years as “critical periods,” in which the brain develops neural connections. These connections once formed are difficult to change and affect how a person interacts with the social environment.

The question however is what actually is parental care (or education) and what has this to do with epigenetics? Perhaps a more important question for the reader what is epigenetics? I answer these questions stepwise.

What is genetics? Before I explain what is epigenetics it is first important to explain what is genetics. I like to explain these concepts based on the research we did accomplish some years ago.

Our research was founded, using a specific hypotheses, whether there was an association between specific candidate genes and a phenotype? Neuro-economists already have discovered that the formation of expectations around rewards in an environment (rewarding environments) versus non rewarding environments involves the activation of the dopamine system (Schultz et al., 1997). This theory we then used as a hypothesis in our research in genetics. We did investigate whether the variant of a gene (specific the well-known variant DRD4 7R+ gene) could have an effect on the way dopamine receptors are shaped which would affect people’s experiences in regard to how they respond to rewards in their environment. This experience of rewards then is known as a “phenotype” and concretely implies that a person is more or less prone to respond to rewards. Another hypothesis we proposed had to do with the oxytocin system functioning which affects how people develop relationships with each other. Here a well-known variant of the oxytocin receptors gene (the OXTR AA versus AG/GG variant) is assumed to play a role. The variants of this gene is associated with how people develop relationships with each other. Carriers of the OXTR AA are known to be less social (Donaldson and Young, 2008). In different studies we found such association but not in other studies. Differently put, we could not always replicate the findings and in genetics the inability to replicate research findings is known as false positives.

Low replicability of genetic research: the low replicability is a well known phenomenon in genetics: meta-studies have shown that neither the DRD4 gene nor the OXTR gene has a significant association with respectively the reward responses in the environment nor with the social behavior (Pappa et al., 2014; Bakermans-Kranenburg en Van IJzendoorn, 2014).  Note that the researchers who performed these meta-studies are quite though to people who preach the so-called universal truth about candidate genes and its association with phenotypes. The following expression by professor Tiemeier of Erasmus MC is striking: “In summary, this systematic review indicates that it is not yet possible to draw definitive conclusions about the functionality of DRD4 VNTRs polymorphisms. Despite the wealth of studies, we appear to remain in the discovery phase of behavioral research employing DRD4 VNTRs. A moratorium should be declared on the singling out of the 7-repeat – the “Magnificent Seven” – at least until the application of multidisciplinary principles shed light on the functionality of the different variants.” (Pappa et al., 2015, p. 184). So we should be aware of the limitations of gene testing and its commercial use.

There are many reasons why it is difficult to replicate genetic findings. First, in genetics researchers do not study a gene, but base pairs which form the genes, also known as SNP’s. The length of such genes vary from a hundred base-pairs to a few millions. In addition, people in general possess 20.500 genes. When we are aware that genes produce proteins who have an influence on the complex dynamics in a cell, then it is very difficult to make a step from an SNP and behavioral phenotype. In addition, for different phenotypes the same genes also play an important role (and also called polygenic).

Note also that the social environment plays an important role how a gene and social behavior (the phenotype) are associated: for instance when administering the hormone oxytocin nasally then depending on the environment the hormone oxytocin either facilitates in-group formation effect but it also has an out-group formation effect (De Dreu, et al., 2010).



What is epigenetics? This brings us to the topic what is epigenetics. Note that we presented some insights around genetics which is also known as the genetic dogma. This dogma implies that there is a genetic code, the DNA in other terms, which consists of base-pairs who are coupled to a phosphate-deoxyribose bone. The activation of a gene is triggered by the activation of the promotor part of the gene via transcription factors, which then translates into RNA, which then is transformed into amino acids. From there proteins are formed which affect how cells or neurons are functioning. The well-known DNA-chain is shown hereunder.

http://www.ks.uiuc.edu/Research/methylation/



Epigenetics and early life caring practices: Years ago a famous group of scientists led by Michael Meaney (Meaney, 2001) investigated how the caring practices of young mice by their mums during early life affected their stress levels later on in life. Important it is unethical do experimentally induce changes in child rearing practices with humans. Therefore researchers do animal experiments – mice in this case. Young mice (pups) of the same off spring was split in two groups: one group was raised by a stable mouse mother (dams) and the other group raised by a neurotic mouse mother (dams). When mammals experience stress they activate the hypothalamus-pituitary-adrenal cortex (HPA) axis which produces cortisol. In order to reduce the stress they seek proximity by the mother (dam); hence they experience neuro-ception of safety. This reduction of the stress system takes place in the hippocampus because of well-functioning glucocorticoid receptors.

https://www.nature.com/articles/nrn2649

Interesting, it was found that in mice which were reared properly by a good mouse mother, the glucocorticoid receptor gene (the NR3C1) functioned well because methylation on the promotor was removed. In poorly reared mice, however, methylation was found to be retained and the gene could not be read and translated to receptors. This discovery led to new research on how nurture affects epigenetic mechanisms in both animals and humans. 

Epigenetic discovery in humans: based on the studies in mice, we looked at attachment styles, and in particular, whether attachment styles are related to the methylation of the glucocorticoid receptor, which is required to block activation of the HPA axis in the hippocampus – that is, to prevent the stress response.

Attachment styles arise during parenting at a young age. In the attachment literature a distinction is made between three styles: secure, avoidant and anxious attachment styles. Secure attachment means that people were raised in a warm nest in which they found protection from their parents when experiencing stress. Avoidant attachment occurs when parents provided little support in times of need and they responded in a cold manner when their children experienced stress. Anxious attachment arises when parents are inconsistent, which means that they are sometimes warm, but at other moments act cold again which causes fearful insecurity in people as to whether others can provide them the security then they need so. 



https://welldoing.org/article/how-your-attachment-style-affects-your-relationships

We investigated whether for anxious and avoidant attached people a methyl-ring would be attached to the promotor of the glucocorticoid receptors (Ein-Dor et al., 2018). To our amazement this phenomenon only occurred with the avoidant attached people. Remember it is likely that these attachment styles are not easily modifiable which is why we mentioned “earlier critical moments.” Therefore we did set a first step in what Heckman calls the role of parent caring practices for the economic status and welfare of a person. We now also better understand why genetics in and by itself brings so much false positive because these studies do not take into consideration the epigenetic mechanisms which activate or deactivate the functioning of genes.  

From the perspective of economics this might be important: avoidant attached people experience much stress but they do not seek proximity with others when stressed. This then might imply an advantage: when these avoidant people do encounter innovations (which at times is experienced as threatening) they might well be the first to adopt them as they do not wait for others to adopt them which in turn creates a safe bet. Remind however that avoidant people not always the most pleasant people to work with. But in any way we now can better understand the cellular mechanisms behind the attachment styles and why it affect their social behaviors.

At this moment we are applying for a grant in order to analyze these initial findings. Indeed, if we can understand these epigenetic mechanisms related to attachment styles, probably we can change the attachment styles would that be desirable.

Bibliography


Bakermans-Kranenburg, M. J., & Van IJzendoorn, M. H. (2014). A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans. Psychiatric genetics, 24(2), 45-51.

Beauchamp, Jonathan P., David Cesarini, Magnus Johannesson, Matthijs JHM van der Loos, Philipp D. Koellinger, Patrick JF Groenen, James H. Fowler, Niels J. Rosenquist, Roy A. Thurik, and Nicholas A. Christakis. "Molecular genetics and economics." The Journal of Economic Perspectives 25, no. 4 (2011): 57-82.

Belsky, J., & Pluess, M. (2009). Beyond Diathesis-Stress: Differential Susceptibility to Environmental Influences. Psychological Bulletin, 135(6), 885-908.
 
De Dreu, C. K., Greer, L. L., Handgraaf, M. J., Shalvi, S., Van Kleef, G. A., Baas, M., ... & Feith, S. W. (2010). The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science, 328(5984), 1408-1411.
 
Donaldson, Z. R., & Young, L. J. (2008). Oxytocin, vasopressin, and the neurogenetics of sociality. Science, 322(5903), 900-904.
Ein-Dor, T., W. JMI Verbeke, M. Mokry, & P. Vrticka (2018). "Epigenetic Modification of the Oxytocin and Glucocorticoid Receptor Genes is linked to Attachment Avoidance in young Adults." (2018).
 
Heckman, J. J. (2007). The economics, technology, and neuroscience of human capability formation. Proceedings of the national Academy of Sciences, 104(33), 13250-13255.
 
Landecker, H., & Panofsky, A. (2013). From social structure to gene regulation, and back: A critical introduction to environmental epigenetics for sociology. Annual Review of Sociology, 39, 333-357.
 
Meaney, M. J. (2001). Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annual review of neuroscience, 24(1), 1161-1192.

Pappa, I., Mileva-Seitz, V. R., Bakermans-Kranenburg, M. J., Tiemeier, H., & van Ijzendoorn, M. H. (2015). The magnificent seven: A quantitative review of dopamine receptor d4 and its association with child behavior. Neuroscience & Biobehavioral Reviews, 57, 175-186.

Schultz, W., Dayan, P., & Montague, P. R. (1997). A neural substrate of prediction and reward. Science, 275(5306), 1593-1599.
 
Shamay-Tsoory, S. G., & Abu-Akel, A. (2016). The social salience hypothesis of oxytocin. Biological psychiatry, 79(3), 194-202.

https://nos.nl/artikel/2212001-stop-meer-geld-en-aandacht-in-de-herhaling-van-wetenschappelijk-onderzoek.html

Illustration is extracted from: http://www.salariuspharma.com/epigenetics.html


 

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