Is trauma in our genes? Ethical implications of epigenetic findings

by Neil Levy



Neil Levy is professor of philosophy at Macquarie University, Sydney and deputy director of the Oxford Centre for Neuroethics. He is the author of 7 books, including Neuroethics (2007) and Consciousness and Moral Responsibility (2014), and edits the journal Neuroethics. He is also a member of the AJOB Neuroscience board.



A recent study by Rachel Yehuda et al. in Biological Psychiatry provided further evidence for the genetic transmission of acquired characteristics, by showing that Holocaust survivors passed certain acquired genetic markers to their children. The idea that acquired characteristics can be genetically transmitted is (roughly) equivalent to the doctrine of Lamarckism, and was long considered a heresy in biology. [Editor's note: see also Ryan Purcell's 2014 post for this blog on the relationship between Lamarckism and epigenetics.] According to the Darwinian orthodoxy, traits change because randomly occurring mutations confer a relative fitness advantage on some organisms, not because they change their behaviour, and that change then comes to be encoded in the genes. But the orthodoxy has long been shattered. Scientists now recognize that the story is a lot more complex than that.





This new study is of central interest to neuroethics for many reasons. One is that the trait in question is psychological, or at least very plausibly underlies a disposition to certain psychological responses, given the right circumstances. Children of Holocaust survivors are themselves at higher risk for stress disorders: a propensity to stress disorders is inherited. How does the inheritance work? One possibility is that their parents behave differently, due to the trauma they experienced, and this difference in how they treat their children causes the difference in susceptibility. Another possibility is that the trauma caused an alteration in the genes of the parents, and this alteration was then transmitted biologically – in the DNA or cytoplasm – to children. Of course, these are not exclusive possibilities – its very likely that people who have been massively traumatized have persisting psychological problems that affect their parenting. The new study strongly suggests that in addition to any such transmission of a vulnerability to stress disorders, there is also biological transmission. In effect, the children of Holocaust survivors were born with bodies “prepared” for stress. What might have been (somewhat) protective, had their world been as massively awful as their parents’, proved instead to be maladaptive.

Buchenwald concentration camp, WWII

Studies like this show that many of the subdisciplinary boundaries we are wont to draw – bioethics or even genethics versus neuroethics, for instance – do not mark boundaries that nature respects. While it is a mistake, I think, to identify the mind with the brain, the mind is nevertheless dependent on and realized by entirely physical properties: it falls within the province of those studying the body and how it is constructed. Equally, bioethics doesn’t have an exclusive right to the somatic: in order to understand the mind, we need to be able to understand the somatic too.



The study has an upshot, too, for one of the most cherished distinctions in genethics: between ‘germline’ and ‘somatic’ interventions. Many bioethicists think it is permissible for adults to make changes in themselves so long as they limit those changes to cells that will not be transmitted to future generations. But epigenetic effects, which are only just beginning to be understood, make this distinction extremely hard to draw. In fact, interventions may be transmissible in indirect and unsuspected ways: people may change their environment, which changes their cells in ways that are then transmitted. The very idea that germline interventions are more problematic may be a product of a mistaken view about genes as especially powerful and uniquely segregated units of reproduction. In fact, we transmit all kinds of things to future generations, by all kinds of causal routes, from shared culture to built environment to ideas to DNA and other cellular resources. All these factors are inextricably intertwined and none are causally privileged as the dominant cause of the resulting people.



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Levy, N. (2015). Is trauma in our genes? Ethical implications of epigenetic findings. The Neuroethics Blog. Retrieved on Retrieved on , from http://www.theneuroethicsblog.com/2015/09/is-trauma-in-our-genes-ethical.html

Early Intervention in Schools: A Site for Empirical Neuroethics

By Ilina Singh, MSc



Ilina Singh is a Professor of Science, Ethics, and Society in the department of Social Science, Health, and Medicine at King’s College London, and is cross-appointed to the Institute of Psychiatry. Her work examines the psycho-social and ethical implications of advances in biomedicine and neuroscience for young people and families. She is also a member of the AJOB Neuroscience Editorial Board.

 

The developmental logic of early intervention is currently all the rage across child care-related sectors, including education, mental health, juvenile justice and social policy. It’s not a new logic by any means (witness longstanding programmes such as HeadStart), but it has new energy and justification with the emergence of epigenetic theories of development. Epigenetics has brought attention to ‘environment’ to the fore, particularly in pediatrics and in child psychiatry. While epigenetic theories are still that – theories – the last few years have seen a surge in research and policy focused on children’s early environments: womb, home, school, community. Students and researchers interested in neuroscience ethics, particularly in relation to children and adolescents, should find rich and fruitful ground for research here. In this blog I outline some thoughts about why neuroethicists might be interested in early intervention programmes in one key environment - schools.

From iStockPhoto

Schools have a long history of collaborations with psychiatry, psychology and pediatric medicine. A rich and frequently critical sociological literature details how these collaborations have informed and embedded a range of normative understandings of child development, particularly in the interrelated areas of behaviour, morality, intelligence and attachment. Scientific discoveries have had an important influence on shifting tropes in child education; from the ‘well adjusted’ child in a psycho-analytic framework, to a contemporary focus on child ‘wellbeing’ and ‘flourishing’ informed especially by positive psychology and emerging discoveries in developmental biology and neuroscience. In this context, early years schooling provides both the environmental conditions to kindle the capacities that promote flourishing, and a pre-clinical site in which to monitor and evaluate children and deploy early intervention strategies when a child appears to be at risk of failure to flourish.



From a critical perspective, these educational tropes and the aligned clinical, social, economic and political interests can appear as largely suspect forms of disciplinary “biopower” (to use a Foucaultian concept). The very notion of early intervention could suggest an institutional desire to impress prevailing norms upon the mind and body of the child even before the child has exhibited problems. The presence of formal early mental health identification and intervention procedures in schools can thus be represented as a first step in a ‘psychiatric career’; that is, a path to medicalization, diagnosis and psychiatric treatment. Post-genomic scientific discoveries that highlight the importance of early environments and early interventions with children can be seen to provide biological impetus for an ethically problematic agenda.



It could equally be argued, however, that the move away from pathological labeling of children to a more open and generic vision of ‘wellbeing’ engenders a more ethically sensitive ground on which to identify children at risk. From this perspective, schools can be seen to provide a more neutral site for early identification and intervention, in so far as support on the basis of flourishing is not dependent upon a medical label and therefore does not require or presuppose a pathway to medicalization, diagnosis and treatment. Moreover, school-based early intervention is likely to reduce the potential for a form of reductionism that views a child’s behavioural and developmental difficulties largely in light of individual factors, thereby eliding attention to the ecological conditions that mitigate and potentiate a child’s capacities for key cognitive and emotional skills; e.g. attention, self-regulation and decision-making. Finally, the presence of school-based early intervention may to some extent evade the stigma associated with mental illness labels and treatments, thereby increasing the chances that children in need will themselves engage support at an early stage. Scientific explanatory models are not necessary to support the intuition that children’s early experiences have lasting effects, but such models can engage political and social support for required resources.

From youthtoday.org

It’s probably quite easy to come up with critical arguments about these early intervention programmes (interventions to ‘build character’ in children particularly worry me!), but I predict that criticism alone will shed little light on the substantive social and ethical goods and harms involved. I think empirical neuroethics has an important role to play here, in so far as it can help achieve more nuanced understandings through a ‘bottom-up’ investigation of school-based early intervention. Researchers might study the ‘local ethics’ of a school-based programme, in order to better understand how participation in the programme configures social-biological identities, moralities and futures. The empirical work can then be used to inform a normative analysis (although how one moves between empirical data and normative analysis should be the subject of another blog!)



One of the lovely aspects of working on issues related to children is that the researcher is freed from the confines of ‘the usual ethical concerns’. Child development centrally involves issues of love, care and hope, as well as responsibility, value, freedom and citizenship. The scientific and policy focus on environment in developmental wellbeing opens neuroethics up to research opportunities in new sites, such as schools and other spaces that children frequent and inhabit. I’m hopeful that neuroethics will come to focus more on the lives and experiences of children and young people in the future, particularly as they are increasingly subjects of neuro- and psy-interventions. For those interested in the area, I’ll soon be starting a few projects on early intervention strategies in child and adolescent mental health and wellbeing, funded by the Wellcome Trust. Do get in touch, especially if you have projects and/or experience in talking with young people about moral and ethical concerns.





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Singh, I. (2015). Early Intervention in Schools: A Site for Empirical Neuroethics. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2015/03/early-intervention-in-schools-site-for.html

Do prison sentences alter oxytocin levels?

Editor’s Note: Guest post by NEWest Leader, Livia Merrill



Livia Merrill is a
recent graduate from Tulane University in New Orleans, LA, where she has
received both her B.S. and M.S. in Neuroscience. Her research of 4 years under Dr. Fiona Inglis, PhD, consisted of dendritic morphological changes
in the prefrontal cortex of non-human primates after the administration of PCP.
Having psychomimetic effects, this model was utilized to contribute to the study of
schizophrenia and to provide for more effective anti-psychotics. Her current
pursuit is under Dr. Stacy Drury, PhD to examine cortisol levels of pregnant mothers
in some of the underprivileged neighborhoods of New Orleans and the epigenetic effects on their offspring. Livia’s future plans consist of research
behind deviant behavior and rehabilitating subjects. Ideally, she hopes to
contribute to change in the criminal justice system, where punishment can
transition to rehabilitation, by demonstrating the negative effects of adverse
experiences, including punishment-based systems.



The United States has the largest population of incarcerated individuals in the world; the latest available data from the Bureau of Justice Statistics indicate there are approximately 1.6 million inmates. Such numbers not only reveal the number of imprisoned individuals but also provide an idea of the massive impact on family members, victims, and other members of society. Furthermore, recidivism rates have revealed that one-quarter to two-thirds of released persons from state prisons are rearrested within 3 years.ⁱ Personal accounts, governmental reviews, and actions by prison activists and social workers have unveiled the grave conditions of these institutions. Such examples include a 2012 case where Los Angeles deputies were accused of violently beating inmates of the L.A. County Jail Complexⁱⁱ and a case in 2013 where a Mississippi prison for the mentally ill was accused of being understaffed and having deplorable living conditions, such as rat infestations, rampant diseases, sexual assaults, and malnourishment of food and medicinal treatment.ⁱⁱⁱ

An example of a typical cell in Orleans Parish Prison, New Orleans, LA. (Via therightperspective.org)

Health and concerns for these men and women are virtually non-existent, such as one prison in California^iv that had an appalling amount of suicides last year. A counterargument for lack of concern for incarcerated individuals might include the lack of finances to support such a cause; however, with shorter sentences and reduced willingness to commit nonviolent offenders, there would be funds available to focus on making prison a less negative and oppressing environment, where proper staff, medical care, and basic human rights are concerns. It is important to note that all prison facilities have varying security levels depending on the crime and how violent the offender is considered, with maximum-security prisons undoubtedly having the most questionable conditions concerning the rights of inmates. Under such conditions, we are arguably creating more antisocial individuals than the ones who were originally sentenced. Such transformation can be explicitly seen through past reviews and experiments, like the Stanford Prison Experiment.^v This was designed to mimic prison conditions, where research volunteers played the role as guards or prisoners. The experiment lasted only 6 days, despite its original 14-day plan, due to the anxiety, depression, and overall dehumanizing effects on the “prisoners” and the power and aggressive traits that accompanied the “guards.” This experiment in itself portrays the effects of such drastic hierarchies on human emotion, psychology, and action.




With the increasing evidence of epigenetics demonstrating the effects of the environment on the expression of genes and hormones, I think it is important to realize that the first step of rehabilitating prisoners and transitioning them back into society in a way that minimizes recidivism would be to focus on the conditions of their prison environment. I do believe there is a need for prisons, without such, crime may run rampant, putting the safety of society at risk. However, the corruption in the system lends itself to release inmates back into society and out of prison more hostile than when they entered because of the environment in which they were held throughout their sentence. Typically, such examples includes physical abuse by guards and other prisoners and long-term solitary confinement.^vi




Is this type of environment leading to emotional, physiological, and biological changes within these men and women? And if so, is there a (neuro-)intervention that we can use to further explore harmful effects on prison-mates (and reverberating effects on society)?




A possible candidate for such an exploration is oxytocin. Oxytocin (OT) is a peptide with a wide array of functions in the human body both as a hormone and a neurotransmitter released by the hypothalamus, an area of the brain that is primarily responsible for homeostasis throughout the body. Because recent research has indicated the role of OT in social interaction and behavior, OT is being explored as a potential treatment for antisocial disorders, autism^vii, and psychopathologies.^viii In recent years, OT has been dubbed the “love drug,” via experiments with intranasal administration of OT and its effects on empathy, trust, and generosity. These intranasal deliveries have resulted in improved emotional recognition,^ix cooperation, and social affiliation in human relationships.^x Oxytocin even seems to facilitate romantic attachments and physical intimacy.^xi Higher levels of OT have also been linked to a decrease in anxiety and the release of glucocorticoids^xiii, or stress hormones.

Oxytocin has been socially misconstrued to be the solution to romantic obstacles (Via marriageresourcecentre.org)

The behaviors correlated with OT release, as seen in both human and animal models,^xiv seem to be highly dependent on context and the environment. In positive environments, those with social support and camaraderie, OT release does link to pro-social behavior and an increase in trust. However, in a negative environment, such as experiences with infidelity and dishonesty, without positive social cues, OT has been shown to increase defensiveness and decrease cooperation.^xv Another experiment demonstrated that intranasal OT administration stimulated in-group conformity, when given visual stimuli of “teammates,” while creating a bias against out-groups, when given visual stimuli of the “opposing team.”^xvi Others have shown an increase in defensive aggression towards threatening out-groups.^xvii




Due to the research indicating the potential positive or negative role of OT in societal interactions and how its actions are contextually based, the question arises, how do the levels of OT vary for prisoners–who have engaged in anti-social or negative social behaviors as deemed by our legal system– in comparison to those who are not incarcerated? Would experiencing imprisonment facilitate a decrease or increase in OT release, leading to decreased prosocial behaviors like empathy or increased hostility?

The location of the hypothalamus in the brain (Via MedlinePlus)

Longitudinal studies with individuals during prison sentences would be useful in determining if OT levels vary at the start or end of a prison sentence. To ensure the noninvasive nature needed to conduct such a study, saliva has been used to detect OT levels.^xviii Through personal interviews and salivary samples, exploring the conditions and relationships formed in prison may provide a useful tool for not only physiological changes within a subset of our population but also biological coping mechanisms for the whole of society, such as involvement of immune function and stress responses, which have been shown to improve in the presence of OT with social support.^xix Perhaps by demonstrating changes in OT release, modifications in prison conditions may be recommended, like the elimination of solitary confinement and the death penalty. These types of changes ideally could decrease the recidivism rate, by providing for a smoother transition upon release of prisoners back into society, where the inmates wouldn’t carry the antisocial mindset of proving strength by violence. For example, one prison in Norway is modeled as a respectful and collaborative community, and despite having violent offenders, it boasts one of the lowest reoffending rates. This type of environment removes the culture shock returning to society after engraining an aggressive attitude during prison.^xx




The hope would be to use biological changes, like differing OT levels before and after a prison sentence, as evidence to demonstrate the need for improvements in prison conditions and allow for a more rehabilitative system versus a retributive one.






References




ⁱ Bureau of Justice Statistics

ⁱⁱ Rosas v. Baca. Central District of California. 24 July 2012. The Civil Rights Litigation Clearinghouse.

ⁱⁱⁱ Dockery v. Epps. Southern District of Mississippi. 30 May 2013. The Civil Rights Litigation Clearinghouse.

^iv Rodriguez, S. 15, March 2013. California Prison Conditions Driving Prisoners to Suicide. Solitary Watch: News from a Nation in Lockdown.

^v Zimbardo, P. 1971. Stanford Prison Experiment. A Simulation Study of the Psychology of Imprisonment Conducted at Stanford University.

^vi Ridgeway, J. and Casella, J. 14, May 2013. America’s 10 Worst Prisons. MotherJones.

^vii Opar, A. 2008. Search for potential autism treatments turns to ‘trust hormone.’ Nature Medicine 14: 353.

^viii Feifel, D., et al. 2010. Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. 68(7):678-670.

^ix Di Simplicio, M., et al. 2009. Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers. Journal of Pyschopharmacology 23(3): 241-248.

^x Ross, HE., and Young, LJ. 2009. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Frontiers in Neuroendocrinology 30(4):534-547.

^xi Schneiderman, I., et al. 2012. Oxytocin during the initial stages of romantic attachment: relation to couples’ interactive reciprocity. Psychoneuroendocrinology 37(8): 1277-1285.

^xii Missig, G., et al. 2010. Oxytocin reduces background anxiety in a fear-potentiated startle paradigm. Neuropsychopharmacology 35(13): 2607-2616.

^xiii Heinrichs, M., et al. 2003. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biological Psychiatry 54(12): 1389-1398.

^xiv Reviewed in Yamasue, H., et al. 2012. Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction. The Journal of Neuroscience 32(41):14109-14117.

^xv Declerck, C., et al. 2010. Oxytocin and cooperation under conditions of uncertainty: the modulating role of incentives and social information. Hormones and Behavior 57(3): 3368-374.

^xvi Stallen, M., et al. 2012. The herding hormone: oxytocin stimulates in-group conformity. Psychological Science 23(11): 1288-1292.

^xvii De Dreu, C., et al. 2010. The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 328(5984):1408-1411.

xviii White-Traut et al. 2009. Detection of salivary oxytocin levels in lactating women. Developmental Pyschobiology 51(4):367-373.

^xix Chen, F., et al. 2011. Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans. Proceedings of the National Academy of Sciences 108:19937-19942.

^xx James, Erwin. 24, Feb. 2013. The Norwegian prison where inmates are treated like people. The Guardian.






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Merrill, L. (2014). Do prison sentences alter oxytocin levels? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/07/do-prison-sentences-alter-oxytocin.html

Lamarckian sh*t? Why epigenetics is not eugenics

An argument could be made that communicating scientific advances to the public has never been more important. As the NIH budget stagnated, and then was cut by Sequestration, many of us have realized what a poor job we have been doing convincing the public of the importance of basic science research. Neuroscience itself has been under more scrutiny recently. As Adam Gopnik of The New Yorker wrote in a review of three new books bashing brain research, “Neuroscience can often answer the obvious questions but rarely the interesting ones.” If that is the way that the public sees it, then clearly we are losing something in translation. Recently there has been a push to reverse this trend and reaffirm biomedical research as a source of inspiration and hope for the public. The actor and author Alan Alda, who has long held a passion for science, has made it a personal mission to improve communication about science because “How are scientists going to get money from policy makers, if our leaders and legislators can’t understand what they do?”¹

Late last year, Brian Dias, a postdoctoral fellow in Kerry Ressler’s laboratory at Emory, found out just how difficult communicating his work to the public can be. Dias and Ressler had been working on testing whether olfactory fear conditioning would transmit a sensitivity to the conditioned odor across generations. That is, using a mouse model they were exploring whether an experience in your lifetime could affect your children or grandchildren’s response to their environment. They studied the olfactory system because it is extraordinarily well-mapped (thanks in large part to work that Dr. Ressler did in Nobel Laureate Linda Buck’s lab as a graduate student) and shows gross structural changes in mice when they learn to associate an odor with an unpleasant experience¹. Recently, there has been a great deal of interest in understanding how an organism’s environment can affect the way in which genes are expressed via a phenomenon call epigenetics.



Epigenetics refers to chemical modifications to the genome that do not affect the DNA sequence itself. Normally, the DNA molecule of each chromosome is tightly packed in a highly complex yet orderly fashion so that it can fit inside the nucleus of the cell. Several types of chemical modifications can be made to DNA that affect how tightly it packs and in turn, the ability of enzymes to transcribe the sequence and initiate the production of the proteins that it codes for. Epigenetic marks do not affect the letters in the code, just how often it is read. Genes can effectively be silenced or activated by these mechanisms, which are still not completely understood.



Researchers have found that the early life environment can have long term effects on individuals and even their offspring² – so called inter-generational epigenetics³. Lately, interest has even shifted to assessing trans-generational epigenetic effects. In 2010, an Australian group reported that in rodents, paternal high-fat diet can lead to dysfunction in pancreatic insulin-producing β-cells in female offspring⁴. More recently, a study of pre-diabetic mice found that epigenetic marks in the pancreas and, importantly, in sperm persisted for multiple generations as did a pre-disposition to impaired glucose metabolism⁵. Trans-generational epigenetic inheritance has been reported to affect lifespan in the nematode C. elegans⁶, and now some studies suggest that the effects of stress or abuse can be passed to the next generation in mice⁷ and humans⁸.



In this special Neuroethics Journal Club focused on “Neuroscience in the News”, the group was fortunate to get to hear the story of publishing this exciting paper⁹ first hand from Dr. Dias. One of the most interesting aspects of the discussion was the timing of the initial presentation of the results and publication of the paper. Dias gave a presentation at Neuroscience 2013 on November 12^th that created a great deal of buzz, so much so that Virginia Hughes of National Geographic’s “Only Human” blog reported on the presentation and also on the Twitter activity itself. Reponses ranged from “Astonishing if true” to “Crazy Lamarkian [sic] shit”.



The Nature Neuroscience editors themselves may have been thinking something along the same lines as the latter commenter as they made a portrait of Jean-Baptiste Lamarck – the champion of the contentious evolutionary theory that acquired adaptations during life shape subsequent generations – the cover image for the issue with Dias and Ressler’s article. The trouble with associating Lamarck and trans-generational epigenetics is that it could lead to the same type of reasoning that gave rise to eugenics in the early to mid-20^th century. Disadvantaged individuals who have lived with hunger and been exposed to violence or other trauma could be seen as permanently damaged and may be dissuaded from having children to avoid perpetuating some sort of “bad epigenetics”. The fact is, genes simply code for proteins and the jump from the molecular level to behavior is complex to say the least. Dias and Ressler were careful to describe the behavioral phenomenon in the offspring of the fear-conditioned mice as an increased sensitivity, not specifically a fear of the odor. At this point, they were not able to determine a molecular mechanism or specific cause of the behavioral change.



The paper appeared online December 1^st, almost three weeks after Dias’ SfN talk and the ensuing controversy and armchair critiquing. However, during most of that time the authors were essentially handcuffed by the journal’s press embargo policy until the paper was published online on December 1^st. Granted, it is rare that a presentation at a conference would generate this much excitement before the paper was published, but it seems that even with early online publication of articles, peer-reviewed journals have trouble keeping up with 21^st century, 140-character communication. The rapid, yet accurate dissemination of results will likely be an issue that journals continue to struggle with, while occasionally leaving authors in limbo.



In addition to the discussion surrounding publication of a controversial paper, the journal club also delved into some of the ethical issues that may arise from studies such as this one. For example, should the children of veterans who have suffered from PTSD be treated as an “at-risk” group, and what would that entail? Or, should members of the military be screened for a family history of trauma based on the idea that those individuals whose parents experienced traumatic events may be more vulnerable to adverse outcomes during or after their tour of duty? It seemed that there was agreement that when a plausible mechanism for how a fear memory – and particularly one associated with a certain smell – could impact the epigenetic marks in sperm cells in order to be passed on to subsequent generations, and then tested, the field would be better able to understand intervention opportunities. Trauma and stress are major public health issues just based on what we know about how they can shape an individual’s behavioral and physiological responses to later challenges in life^10,11. If in fact trauma and adversity can also shape our children’s sensory experience of the world through heritable, epigenetic changes, then it will be even more important to understand how the effects can be mitigated.



Additionally, accurate and clear communication of results to the public remains as important as ever. While the avenues for communication have changed drastically in recent years, and in many ways have made communicating easier, publishers and authors will likely continue to grapple with the new speed and power of social media. What role, if any, should these platforms play in the communication of science? If one of the goals is to engage the public’s interest then it seems that social media presents a great opportunity to do that but there are obvious concerns. While it may not be possible to fit detailed methods and results into 140 characters, new initiatives such as PubMed Commons may help reduce the formality and finality associated with published papers and increase discussion among scientists. Still, it will be interesting to see how social media is adopted by scientists and whether it helps at all in bridging our current communication gap with the public.





References



1. Jones, S. V., Choi, D. C., Davis, M. & Ressler, K. J. Learning-dependent structural plasticity in the adult olfactory pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 13106-13111, doi:10.1523/JNEUROSCI.4465-08.2008 (2008).

2. Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nature reviews. Genetics 8, 253-262, doi:10.1038/nrg2045 (2007).

3. Heard, E., Martienssen, R.A. Transgenerational Epigenetic Inheritance: Myths and Mechanisms. Cell 157, 95-109 (2014).

4. Ng, S. F. et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963-966, doi:10.1038/nature09491 (2010).

5. Wei, Y. et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proceedings of the National Academy of Sciences of the United States of America 111, 1873-1878, doi:10.1073/pnas.1321195111 (2014).

6. Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365-371, doi:10.1038/nature10572 (2011).

7. Dietz, D. M. et al. Paternal transmission of stress-induced pathologies. Biological psychiatry 70, 408-414, doi:10.1016/j.biopsych.2011.05.005 (2011).

8. Jovanovic, T. et al. Physiological markers of anxiety are increased in children of abused mothers. Journal of child psychology and psychiatry, and allied disciplines 52, 844-852, doi:10.1111/j.1469-7610.2011.02410.x (2011).

9. Dias, B. G. & Ressler, K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature neuroscience 17, 89-96, doi:10.1038/nn.3594 (2014).

10. Gluckman, P. D., Hanson, M. A., Cooper, C. & Thornburg, K. L. Effect of in utero and early-life conditions on adult health and disease. The New England journal of medicine 359, 61-73, doi:10.1056/NEJMra0708473 (2008).

11. Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature neuroscience 12, 1559-1566, doi:10.1038/nn.2436 (2009).





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Purcell, R. (2014). Lamarckian sh*t? Why epigenetics is not eugenics. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/03/lamarckian-sht-why-epigenetics-is-not.html

Refried serotonin lunch

That title sounds like the prequel to a William Burroughs novel. I wish I'd come up with it myself, but I'm actually plagiarizing almost word for word from Dr. Steven Hyman, Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Last week, Emory awarded Dr. Hyman this year's Neuroscience and Ethics Award. Dr. Hyman spoke on "Addiction as a Window on Volitional Control", which shouldn't be surprising, given his molecular and genetic studies of the dopaminergic system.



Earlier in the day, Dr. Hyman stopped by the Emory Center for Ethics to have lunch with faculty and students from several schools and programs. He held forth on the state of translational neuropsychiatric research for an hour and a half, while the rest of us prevented him from eating by constantly barraging him with questions. I have a feeling I'm not the only one who found what he had to say both thought-provoking and provocative. He liberally spiced up his comments with colorful phrases like the aforementioned "refried serotonin meal" (which I will put in context at the end of this post).

Before I talk about what Hyman talked about, though, I have to put the man himself in context. Here's an interview with him and a talk he gave at a benefit, if you want to check them out. And here's the Cliff's Notes version of his career: Hyman started college as a philosopher, and then realized that neuroscientists were the ones working on the questions he wanted to answer, and so he snuck into the field through the back door of med school. Eventually he established his own lab. He then went on to head the National Institutes of Mental Health (NIMH) for five years, and followed that with a stint as provost at Harvard before becoming director of the Stanley Center. Let's relate all that to what he had to say at lunch. I guess his background explains, in part, his ability to turn a phrase. And his C.V. explains why those phrases tend to cast psychiatry and big pharma in a pretty harsh light.

Hyman leapt right into why we've had such a hard time curing mental health disorders. According to him, there's two main reasons. One is that research, for a long time, focused on drugs--the "paradigm dominate[d] the field". He conceded that research on drugs initially made sense: the drugs helped people with mental health problems when nothing had before. As he pointed out, Thorazine was just one of many antihistamines, which had great sedative properties, until doctors noticed it ameliorated some psychotic symptoms. The other reason we’ve had such a hard time curing mental health disorders, according to Dr.Hyman, is that psychoanalytics still casts a long shadow over psychiatry. He pointed to the DSM-III, released in 1980 (if you don't know, that's Diagnostic and Statistical Manual of Mental Disorders), which he said was based on "1970s science". With the DSM-III, he said, you had a case of extremely "bright people becom[ing] guardians of the holy writ". Even now, as the American Psychological Association puts together the DSM-V, "people will kill each other over the placement of a semi-colon".

The end result of the DSM is that disorders are defined in terms of symptoms. The problem with this is that human beings, especially those struggling with mental disorders, are not likely to be easily divided into groups based on their symptoms. No one who is depressed thinks, "Oh, it's been two weeks and I've only had three episodes of suicidal thoughts--I'd better get some stinkin' thinkin' goin’ to meet my quota." Yet, this is exactly the way that scientific studies were being framed when Hyman became head of the NIMH, and, because of the DSM, they’re still being framed that way. Hyman tried to change that. “I felt I was responsible for two billion dollars of taxpayer money--and if we are [funding] biological characterization of something that is not a natural kind, the study [was] stillborn.” In other words, we’ll never come up with a therapy for a mental disorder that doesn’t really exist.



In contrast, Hyman feels that “the genetics of neuropsychiatric disease is going to work”. The cost of sequencing genomes has come down something like 10-million fold. “It makes Moore’s law look pretty lazy.” He pointed out that we know that mental health issues run in families, even if the symptoms don’t always look the same. There are shared genes that put people at risk for mental health disorders in general: bi-polar patients show up in families with high incidence of schizophrenia. By the same token, Hyman said, all this genetic data has shown that phenotyping—i.e., looking at symptoms—is “worthless”. For example, there’s no correlations between genes and symptoms of schizophrenia that show that we can divide the disease into sub-classes. And while we do see a clear correlation between certain genes and the presence or absence of mental health problems in general in families, we still have to deal with 100s or 1000s of genes of small effect. “The hard problem is the genes to biology problem” in Hyman’s view.

There were a lot of other topics Dr.Hyman covered during the hour and a half that he talked with us. A couple of people asked questions about epigenetics, and I thought his answers came off as a bit glib. In case you don’t already know, the field of epigenetics studies changes in gene expression that are inherited but don’t require changes in DNA sequence. For example, DNA methylation patterns can be transferred from one generation of cells to the next, and these patterns affect transcription of genes. Epigenetics provides a way for the environment to affect the genome. In other words, this field could explain why one man suffers from a mental disorder when his identical twin doesn’t. Shouldn’t we be studying that, and worrying a little less about those 1000s of “genes of small effects”?



I also was a little taken aback to hear someone in Hyman’s position say that big pharma had woken up from its “refried serotonin meal”. I mean, I thought SSRIs were not so efficacious when I was watching my depressed friends in high school crush them up and smoke them, but I wasn’t head of the NIMH at the time. (And I guess I won’t be after writing this paragraph.) With the benefit of age and wisdom and stuff, I realize that they represent about the best we can do right now. So I have to agree with Dr. Hyman when he says “no one’s improved on Lithium,” in terms of efficacy, “and that was 1949.” To improve our therapies, we’ll have to overcome a lot of the baggage left over from that time in psychology when Freud stopped studying crawfish and started prescribing cocaine. (That’s my cynicism you hear in that sentence, not his.) Hyman’s take-home message is that we have an opportunity right now to make big leaps forward in treating psychiatric disorders. I think we can all agree on that.



--David Nicholson Neuroscience Graduate Student, Sober Lab







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Nicholson, D. (2012). Refried serotonin lunch. The Neuroethics Blog. Retrieved on
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