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Why is the topic of the biological embedding of experiences important for translation?

Published online by Cambridge University Press:  03 October 2016

Michael Rutter*
Affiliation:
Institute of Psychiatry, Psychology and Neuroscience
*
Address correspondence and reprint requests to: Michael Rutter, Institute of Psychiatry, Psychology and Neuroscience, PO Box 80, SGDP Centre, De Crespigny Park, Denmark Hill, London SE5 8AF, UK; E-mail: michael.rutter@kcl.ac.uk.

Abstract

Translational research focuses on innovation in healthcare settings, but this is a two-way process that may have implications for either treatment or prevention. Smoking and lung cancer and the fetal alcohol syndrome are used as examples. Experimental medicine that budges basic and clinical science often constitutes a key way forward. Areas of scientific progress and challenge are discussed in relation to drug action, social cognition, cognitive neuroscience, molecular genetics, gene–environment interaction, and epigenetics. Key concepts and challenges in relation to stress include toxicity, allostatic load, the hypothalamus–pituitary–adrenal axis, and objectives versus subjective stress. The reasons for the need to test causal inferences are discussed. Various kinds of “natural experiments” are discussed in illustration using the assisted conception design, the discordant monozygotic twin design, and the study of universal exposure. Animal models are discussed in relation to enrichment and deprivation effects and the effects of infant separation experiences, epigenetic effects, and the biological embedding of experiences. Translational issues are discussed in relation to the hypothalamic–pituitary–adrenal axis, epigenetics, and inflammation. In conclusion, it is suggested that there are immediate possibilities for experimental medicine but caution is needed with respect to moving into translation too quickly.

Type
Special Section Articles
Copyright
Copyright © Cambridge University Press 2016 

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References

Academy of Medical Sciences. (2007). Identifying the environmental causes of disease: How should we decide what to believe and when to take action? London: Author.Google Scholar
Arseneault, L., Cannon, M., Fisher, H. L., Polanczyk, G., Moffitt, T. E., & Caspi, A. (2011). Childhood trauma and children's emerging psychotic symptoms: A genetically sensitive longitudinal cohort study. American Journal of Psychiatry, 168, 6572.Google Scholar
Ayd, F. J., & Blackwell, B. (Eds.) (1970). Discoveries in biological psychiatry. Philadelphia, PA: Lippincott.Google Scholar
Baddeley, A. (2007). Working memory, thought, and action. Oxford: Oxford University Press.CrossRefGoogle Scholar
Basu, A., Pereira, J., & Aitchison, K. J. (2007). The pharmacological management of schizophrenia. In Stein, G. & Wilkinson, G. (Eds.), Seminar series in general adult psychiatry (2nd ed., pp. 238294). London: Gaskell.Google Scholar
Battaglia, M., Ogliari, A., D'Amato, F., & Kinkead, R. (2014). Early-life risk factors for panic and separation anxiety disorder: Insights and outstanding questions arising from human and animal studies of CO2 sensitivity. Neuroscience & Biobehavioral Reviews, 46, 455464.Google Scholar
Blakemore, S. J. (2008). The social brain in adolescence. Nature Reviews Neuroscience, 9, 267277.Google Scholar
Bliss, T., Collingridge, G., & Morris, R. (Eds.) (2003). Long-term potentiation. Oxford: Oxford University Press.Google ScholarPubMed
Bowlby, J. (1969). Attachment and loss: Vol. 1. Attachment. London: Hogarth Press.Google Scholar
Bowlby, J. (1973). Attachment and loss: Vol. 2. Separation, anxiety and anger. London: Hogarth Press.Google Scholar
Bowlby, J. (1980). Attachment and loss: Vol. 3. Loss, sadness and depression. New York: Basic Books.Google Scholar
Brett, Z. H., Humphreys, K. L., Smyke, A. T., Gleason, M. M., Nelson, C. A., Zeanah, C. H., et al. (2015). Serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates the longitudinal impact of early caregiving on externalizing behavior. Development and Psychopathology, 27, 718.Google Scholar
British Academy. (2010). Social science and family policies. London: Author.Google Scholar
Cahan, S., & Cohen, N. (1989). Age versus schooling effects on intelligence development. Child Development, 60, 12391249.Google Scholar
Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010). Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509527.CrossRefGoogle Scholar
Caspi, A., Moffitt, T. E., Morgan, J., Rutter, M., Taylor, A., Arseneault, L., et al. (2004). Maternal expressed emotion predicts children's antisocial behavior problems: Using monozygotic-twin differences to identify environmental effects on behavioral development. Developmental Psychology, 40, 149161.Google Scholar
Champagne, F. A. (2010). Early adversity and developmental outcomes interaction between genetics, epigenetics, and social experiences across the life span. Perspectives on Psychological Science, 5, 564574.Google Scholar
Cohen, S., Alper, C., Adler, N. E., Treanor, J. J., & Turner, R. B. (2008). Objective and subjective socioeconomic status and susceptibility to the common cold. Health Psychology, 27, 268274.CrossRefGoogle ScholarPubMed
Cooksey, D. (2006). A review of UK health research funding. London: Stationary Office.Google Scholar
Costello, J. E., Compton, S. N., Keeler, G., & Angold, A. (2003). Relationships between poverty and psychopathology: A natural experiment. Journal of the American Medical Association, 290, 20232029.CrossRefGoogle ScholarPubMed
Costello, J. E., Erkanko, A., Copeland, W., & Angold, A. (2010). Association of family income supplements in adolescence with development of psychiatric and substance use disorders in adulthood among an American Indian population. Journal of the American Medical Association, 303, 19541960.Google Scholar
Croning, M. D. R., Marshall, M. C., McLaren, P., Armstrong, J. D., & Grant, S. G. N. (2009). G2Cdb: The genes to cognition database. Nucleic Acids Research (Vol. 37, Database issue), D846D851.Google Scholar
Danese, A., & McCrory, E. (2015). Child maltreatment. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, E. (Eds.) Rutter's child and adolescent psychiatry (6th ed., pp. 364375). Oxford: Wiley–Blackwell.Google Scholar
Danese, A., Moffitt, T. E., Pariante, C. M., Ambler, A., Poulton, R., & Caspi, A. (2008). Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Archives of General Psychiatry, 65, 409415.Google Scholar
Doll, R., & Hill, A. B. (1950). Smoking and carcinoma of the lung. British Medical Journal, 2, 739748.Google Scholar
Doll, R., & Hill, A. B. (1954). The mortality of doctors in relation to their smoking habits. British Medical Journal, 1, 14511455.Google Scholar
Draganski, B., & May, A. (2008). Training-induced structural changes in the adult human brain. Behavioural Brain Research, 192, 137142.Google Scholar
Duncan, G. J., Magnuson, K. A., & Ludwig, J. (2004). The endogeneity problem in developmental studies. Research in Human Development, 1, 5980.Google Scholar
Essex, M. J., Boyce, W. T., Hertzman, C., Lam, L. L., Armstrong, J. M., Neumann, S. M. A., et al. (2013). Epigenetic vestiges of early developmental adversity: Childhood stress exposure and DNA methylation in adolescence. Child Development, 84, 5875.CrossRefGoogle ScholarPubMed
Fergusson, D. M., Horwood, L. J., & Lynskey, M. T. (1992). Family change, parental discord and early offending. Journal of Child Psychology and Psychiatry, 33, 10591075.CrossRefGoogle ScholarPubMed
Fisher, P. A., van Ryzin, M. J., & Gunnar, M. R. (2011). Mitigating HPA axis dysregulation associated with placement changes in foster care. Psychoneuroendocrinology, 36, 531539.Google Scholar
Fraga, M. F., Ballestar, E., Paz, M. F., Ropero, S., Setien, F., Ballestar, M. L., et al. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences, 102, 1060410609.Google Scholar
Frick, P. J., Ray, J. V., Thornton, L. C., & Kahn, R. E. (2014). Can callous–unemotional traits enhance the understanding, diagnosis, and treatment of serious conduct problems in children and adolescents? A comprehensive review. Psychological Bulletin, 140, 157.Google Scholar
Frith, C. (2007). Making up the mind: How the brain creates our mental world. Malden, MA: Blackwell.Google Scholar
Gallese, V., Fadiga, L., Fogassi, L., & Rizzolatti, G. (1996). Action recognition in the premotor cortex. Brain, 119, 593609.Google Scholar
Gianaros, P. J., Horenstein, J. A., Cohen, S., Matthews, K. A., Brown, S. M., Flory, J. D., et al. (2007). Perigenual anterior cingulate morphology covaries with perceived social standing. Social Cognitive and Affective Neuroscience, 2, 161173.Google Scholar
Glaser, D. (2015). Child sexual abuse. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, E. (Eds.), Rutter's child and adolescent psychiatry (6th ed., pp. 376388). Oxford: Wiley–Blackwell.Google Scholar
Gray, R., & Henderson, J. (2006). Review of the fetal effects of prenatal alcohol exposure: Report to the Department of Health. Oxford: National Perinatal Epidemiology Unit.Google Scholar
Gunnar, M. R., & Vazquez, D. M. (2006). Stress, neurobiology and developmental psychopathology. In Cicchetti, D. & Cohen, D. (Eds.), Developmental psychopathology (Vol. 2, pp. 533577). Hoboken, NJ: Wiley.Google Scholar
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400403.CrossRefGoogle ScholarPubMed
Harlow, H. F., & Zimmermann, R. R. (1959). Affectional responses in the infant monkey. Science, 130, 421432.Google Scholar
Harris, T., Brown, G. W., & Bifulco, A. (1986). Loss of parent in childhood and adult psychiatric disorder: The role of lack of adequate parental care. Psychological Medicine, 16, 641659.Google Scholar
Heijmans, B. T., & Mill, J. (2012). Commentary: The seven plagues of epigenetic epidemiology. International Journal of Epidemiology, 41, 7478.Google Scholar
Hickok, G. (2014). The myth of mirror neurones: The real neuroscience of communication and cognition. London: Norton.Google Scholar
Hinde, R. A., & McGinnis, L. (1977). Some factors influencing the effects of temporary mother–infant separation: Some experiments with rhesus monkeys. Psychological Medicine, 7, 197212.Google Scholar
Hinde, R. A., & Spencer-Booth, Y. (1970). Individual differences in the responses of rhesus monkeys to a period of separation from their mothers. Journal of Child Psychology and Psychiatry, 11, 159176.Google Scholar
Hodgson, K., Uher, R., Crawford, A. A., Lewis, G., O'Donovan, M. C., Keers, R., et al. (2014). Genetic predictors of antidepressant side effects: A grouped candidate gene approach in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. Journal of Psychopharmacology, 28, 142150.Google Scholar
Hubel, D. H., & Wiesel, T. N. (2005). Brain and visual perception: The story of a 25-year collaboration. New York: Oxford University Press.Google Scholar
Hyde, L. W., Lerch, J., Norton, A., Forgeard, M., Winner, R. L., Evans, A. C., et al. (2009). The effects of musical training on structural brain development. Annals of New York Academy of Sciences, 1169, 182186.Google Scholar
Hyman, S. E. (2007). Can neuroscience be integrated into the DSM-V? Nature Reviews Neuroscience, 8, 725732.Google Scholar
Iacoboni, M., & Dapretto, M. (2006). The mirror neuron system and the consequences of its dysfunction. Nature Reviews Neuroscience, 7, 942951.Google Scholar
Insel, T. R., & Scholnick, E. M. (2006). Cure therapeutics and strategic prevention: Raising the bar for mental health research. Molecular Psychiatry, 11, 1117.Google Scholar
Iyegbe, C., Campbell, D., Butler, A., Ajnakina, O., & Sham, P. (2014). The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for G × E research. Social Psychiatry and Psychiatric Epidemiology, 49, 169182.Google Scholar
Jenkins, J., Madigan, S., & Arseneault, L. (2015). Psychosocial adversity. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, E. (Eds.), Rutter's child and adolescent psychiatry (6th ed., pp. 330340). Oxford: Wiley–Blackwell.Google Scholar
Kandel, E. R. (2007). In search of memory: The emergence of a new science of mind. New York: Norton.Google Scholar
Kapur, S., Zipursky, R., & Remington, G. (1999). Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. American Journal of Psychiatry, 156, 286293.Google Scholar
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444454.Google Scholar
Kilner, J. M., & Lemon, R. N. (2013). What we know currently about mirror neurons. Current Biology, 23, R1057R1065.Google Scholar
Kumsta, R., Sonuga-Barke, E., & Rutter, M. (2012). Adolescent callous–unemotional traits and conduct disorder in adoptees exposed to severe early deprivation. British Journal of Psychiatry, 200, 197201.Google Scholar
Lilienfeld, S. O., Ritschel, L. A., Lynn, S. L., Cautin, R. L., & Latzman, R. D. (2014). Why ineffective psychotherapies appear to work: A taxonomy of causes of spurious therapeutic effectiveness. Perspectives on Psychological Science, 9, 355387.Google Scholar
Loman, M. M., & Gunnar, M. R. (2010). Early experience and the development of stress reactivity and regulation in children. Neuroscience and Biobehavioral Reviews, 34, 867876.CrossRefGoogle ScholarPubMed
Maguire, E. A., Woollett, K., & Spiers, H. J. (2006). London taxi drivers and bus drivers: A structural MRI and neuropsychological analysis. Hippocampus, 16, 10911101.Google Scholar
McEwen, B. S., & Lasley, E. N. (2002). The end of stress as we know it. Washington, DC: Dana Press.Google Scholar
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342348.Google Scholar
McGowan, P. O., Sasaki, A., Huang, T. C., Unterberger, A., Suderman, M., Ernst, C., et al. (2008). Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLOS ONE, 3, e2085.Google Scholar
McLellan, J. M., Susser, E., & King, M.-C. (2006). Maternal famine, de novo mutations, and schizophrenia. Journal of the American Medical Association, 296, 582584.Google Scholar
Meaney, M. J. (2010). Epigenetics and the biological definition of Gene × Environment interactions. Child Development, 81, 4179.Google Scholar
Merton, R. K. (1973). The sociology of science: Theoretical and empirical investigations. Chicago: University of Chicago Press.Google Scholar
Meyer-Lindenberg, A., Buckholtz, J. W., Kolachana, B., Hariri, A. R., Pezawas, L., Blasi, G., et al. (2006). Neural mechanisms of genetic risk for impulsivity and violence in humans. Proceedings of the National Academy of Sciences, 103, 62696274.Google Scholar
Milner, B. S., Corkin, S., & Teuber, H.-L. (1968). Further analysis of the hippocampal amnesic syndrome: 14-year-follow-up of HM. Neuropsychologia, 6, 215234.CrossRefGoogle Scholar
Milner, B. S., Squire, L. R., & Kandel, E. R. (1998). Cognitive neuroscience and the study of memory. Neuron, 20, 445468.Google Scholar
National Research Council. (2002). Scientific research in education. Washington, DC: National Academy Press.Google Scholar
Obradović, J., Bush, N. R., Stamperdahl, J., Adler, N. E., & Boyce, W. T. (2010). Biological sensitivity to context: The interactive effects of stress reactivity and family adversity on socio-emotional behavior and school readiness. Child Development, 81, 270289.Google Scholar
Peters, K. (2004). Exceptional matters: Clinical research from bedside to bench. Clinical Medicine, 4, 551566.Google Scholar
Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. A., Munoz, K. E., Kolachana, B. S., et al. (2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience, 8, 828834.Google Scholar
Randall, C. L. (2001). Alcohol and pregnancy: Highlights from three decades of research. Journal of Studies on Alcohol, 62, 554561.Google Scholar
Redondo, R. L., Kim, J., Arons, A. L., Ramirez, S., Liu, X., & Tonegawa, S. (2014). Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature, 513, 426430.Google Scholar
Rice, F., Harold, G. T., Boivin, J., Hay, D. F., Van Den Bree, M., & Thapar, A. (2009). Disentangling prenatal and inherited influences in humans with an experimental design. Proceedings of the National Academy of Sciences, 106, 24642467.Google Scholar
Rietveld, C. A., Conley, D., Eriksson, N., Esko, T., Medland, S. E., Vinkhuyxen, A. A. E., et al. (2014). Replicability and robustness of genome-wide-association studies for behavioral traits. Psychological Science, 25, 19751986.Google Scholar
Rosenzweig, M. R., & Bennett, E. L. (1996). Psychobiology of plasticity: Effects of training and experience on brain and behavior. Behavioural Brain Research, 78, 5765.Google Scholar
Rosenzweig, M. R., Krech, D., Bennett, E. L., & Diamond, M. C. (1962). Effects of environmental complexity and training on brain chemistry and anatomy: A replication and extension. Journal of Comparative and Physiological Psychology, 55, 429437.Google Scholar
Rutter, M. (2012). Achievements and challenge in the biology of environmental effects (Sackler Symposium). Proceedings of the National Academy of Sciences, 109, 1714917153.Google Scholar
Rutter, M. (2014). Biomarkers: Potential and challenges. In Singh, I., Sinnoff-Armstrong, W. P., & Sarnlesan, J. (Eds.), Bioprediction, biomarkers and bad behavior: Scientific, legal and ethical challenges (pp. 188205). New York: Oxford University Press.Google Scholar
Rutter, M., & Azis-Clauson, C. (2015). Biology of environmental effects. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, E. (Eds.), Rutter's child and adolescent psychiatry (6th ed., pp. 287302). Oxford: Wiley–Blackwell.Google Scholar
Rutter, M., & Pickles, A. (2015). Threats to the validity of child psychiatry and psychology. Journal of Child Psychiatry and Psychology. Advance online publication.Google Scholar
Rutter, M., & Plomin, R. (2009). Pathways from science findings to health benefits. Psychological Medicine, 39, 529542.Google Scholar
Rutter, M., & Rutter, M. (1992). Developing minds: Challenge and continuity across the life span. London: Penguin Books.Google Scholar
Rutter, M., & Solantaus, T. (2014). Translation gone awry: Unexpected scientific findings and misleading inferences. European Child & Adolescent Psychiatry, 23, 247255.Google Scholar
Sapolsky, R. M. (2004). Why zebras don't get ulcers (3rd ed.). New York: W. H. Freeman.Google Scholar
Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421427.Google Scholar
Scoville, W. B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery and Psychiatry, 20, 1121.Google Scholar
Shonkoff, J. P. (2010). Building an enhanced bio-developmental framework to guide the future of early childhood policy. Child Development, 81, 343353.Google Scholar
Shonkoff, J. P., Richter, L., Gaag, J. V. D., & Bhutta, Z. A. (2012). An integrated scientific framework for child survival and early childhood development. American Academy of Pediatrics, 129, 113.Google ScholarPubMed
Singh-Manoux, A., Marmot, M., & Adler, N. E. (2005). Does subjective social status predict health and change in health status better than objective status? Psychosomatic Medicine, 67, 855861.Google Scholar
Southgate, V., & Hamilton, A. F. (2008). Unbroken mirrors: Challenging a theory of autism. Trends in Cognitive Science, 12, 225229.CrossRefGoogle ScholarPubMed
St. Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., et al. (2005). Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. Journal of the American Medical Association, 294, 557562.Google Scholar
Stein, Z. A., Susser, M., Saenger, G., & Marolla, F. (1975). Famine and human development: The Dutch Hunger Winter of 1944–1945. New York: Oxford University Press.Google Scholar
Takizawa, R., Danese, A., Maughan, B., & Arseneault, L. (2015). Bullying victimization in childhood predicts inflammation and obesity at mid-life: A five-decade birth cohort study. Psychological Medicine. Advance online publication.Google Scholar
Thapar, A., & Rutter, M. (2015). Using natural experiments and animal models to study causal hypotheses in relation to child mental health problems. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, A. (Eds.), Rutter's child and adolescent psychiatry (6th ed., pp. 145162). Oxford: Wiley–Blackwell.Google Scholar
Tobi, E. W., Slagboom, P. L., van Dongen, J., Kremer, D., Stein, A. D., Putter, H., et al. (2012). Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLOS ONE, 7 e37933.Google Scholar
Tulving, E. (2002). Episodic memory: From mind to brain. Annual Review of Psychology, 52, 125.Google Scholar
Uher, R., Caspi, A., Houts, R., Sugden, K., Williams, B., Poulton, R., et al. (2011). Serotonin transporter gene moderates childhood maltreatment's effects on persistent but not single-episode depression: Replications and implications for resolving inconsistent results. Journal of Affective Disorders, 135, 5665.Google Scholar
Viding, E., & McCrory, E. J. (2015). Genetic and neurocognitive contributions to the development of psychopathy. In Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., & Taylor, E. (Eds.), Rutter's child and adolescent psychiatry (6th ed.). Oxford: Wiley–Blackwell.Google Scholar
Volkow, E., & Swanson, J. (2008). Basic neuropsychopharmacology. In Rutter, M., Thapar, A., Pine, D., Leckman, J. F., Scott, S., Snowling, M., et al. (Eds.), Rutter's child and adolescent psychiatry (5th ed., pp. 212233). Oxford: Blackwell.Google Scholar
Von Senden, M. (1960). Space and sight: The perception of space and shape in the congenitally blind before and after operation. Glencoe, IL: Free Press.Google Scholar
Weaver, I. C. G., Meaney, M. J., & Szyf, M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proceedings of the National Academy of Sciences, 103, 34803485.Google Scholar
Woollett, K., Spiers, H. J., & Maguire, E. A. (2010). Talent in the taxi: A model system for exploring expertise. In Happé, F. & Frith, U. (Eds.), Autism and talent (pp. 89104). Oxford: Oxford University Press.Google Scholar
Wootton, B. (1959). Social science and social pathology. London: Allen & Unwin.Google Scholar