1. Beyond nature / nurture: Epigenetics and the legacy of environment Michael Arribas-Ayllon Philosophy Café, Cardiff, 15 th February 2010

2. Part 1 Överkalix

3. The Överkalix Study (2001) Randomly selected 99 children born in 1905 Their parents and grandparents traced back to birth Birth dates correlated with regional harvest statistics – classified periods of ‘poor’, ‘moderate’ and ‘good’ availability to food Calculated the availability of food during the child’s ‘Slow Growth Period’ (SGP) – 8-10 years for girls – 9-12 years for boys Proband’s age of death used as a variable in a statistical model Causes of death recorded

4. Availability of food Crop failure – 1800 – 1809 – 1812 – 1829 – 1821 – 1831-6 – 1851 – 1856 – 1867 – 1877 – 1881 – 1888 – 1889 Crop abundance – 1799 – 1801 – 1813-15 – 1825-6 – 1828 – 1841 – 1844 – 1846 – 1853 – 1860-1 – 1863 – 1870 – 1876 – 1879-80

5. Findings There was a deleterious effect on the survival of the proband if the paternal grandfather was ‘overfed’ at least once during a ‘good’ harvest when he was 9-10 years old Probands benefited from the paternal grandfather experiencing at least one ‘poor’ harvest during the SGP when they were 9-12 years old Difference in survival between grandchildren, whose paternal grandfather experienced these two extremes, was 32 years Moderate availability of food produced no effect

6. Author’s claims ‘Over nutrition’ seems to have altered the DNA when the paternal grandfather and perhaps the paternal grandmother are affected only, but not the maternal ancestor The impact ‘skipped’ a generation which could be consistent with genomic imprinting Supports the possibility of an intergenerational ‘feedforward loop’

7. Second study - causes of death Cardiovascular disease (n=123) – incidence was lower when PGF exposed to poor harvest – incidence was higher when PGF exposed to good harvest Diabetes (n=19) – Incidence increased when PGF exposed to poor harvest – Incidence higher when PGF exposed to good harvest

8. Author’s claims Nutrition-related circumstances has a transgenerational association on cardiovascular and diabetes-related deaths Transmission follows the paternal line No evidence for a specific mechanism

9. ALSPAC study (2006) 1.Survey of 14,024 pregnancies – fathers who reported smoking (n=9886) – age of exposure to smoking (SGP) – offspring measured for BMI at 7 and 9 years 2.Reanalysed Överkalix data for sex-specific effects – re-examined data pertaining to paternal grandmother

10. Findings ALSPAC Found strong association between age of paternal father smoking (onset) and the BMI of boys at 9 years Överkalix The effect of food supply on the paternal grandmother during SGP (0-3 years) showed the largest transgenerational response: – two-fold higher mortality rate when paternal grandmother experienced food abundance

11. Author’s claims Found a clear sex specific, male-line transgenerational effect across both data sets Little known about the specific mechanism responsible for effect They hypothesise that sex chromosome (X and Y) may play a role: – father to son and paternal grandfather to grandson (Y chromosome) – grandmother to granddaughter (X chromosome) SGP is a critical period of development So a one-off environmental event affecting prepubescent boys can alter the phenotype of their sons and grandson – supported by animal studies

12. Do genes have memory? In the past low birth weight and morbidity has been linked to maternal undernutrition The molecular mechanism is not know but an increasingly popular hypothesis is ‘epigenetics’ Genomic imprinting – ‘switching’ genes on or off

13. Part 2 Nature / Nurture

14. N / N debate is a tedious ritual of discussion Unreasonably persistent dichotomy Two common claims: – N / N = universal – not N or N, but both Product of 19 th c. Language of genetics

15. A ‘convenient jingle’ “The phrase ‘nature and nurture’ is a convenient jingle of words, for it separates under two distinct heads the innumerable elements of which personality is composed. Nature is all that a man brings with himself into the world; nurture is every influence from without that affects him after his birth... When nature and nurture compete for supremacy on equal terms... the former proves to be the stronger... [although] neither is self- sufficient” (Galton, 1874: 12). Francis Galton

16. Classical genetics Particulate theory of inheritance Powerful model capable of explaining: – transmission of hereditary characteristics – biodiversity over time – dominant and recessive inheritance Also amenable to: – relatively simple universal laws – reductionist explanations of inheritance Gregor Mendel

17. Lamarckism Soft inheritance Folk wisdom Partly accommodated by Darwin (pangenesis) Galton sought to disprove Darwin’s theory Eventually ruled out by Mendelian genetics Germ plasm theory (1892) Weismann’s barrier Jean-Baptiste Lamarck

18. Grammar of Science If the views of Weismann be correct—if the bad man can by the influence of education and surroundings be made good, but the bad stock can never be converted into good stock—then we see how grave a responsibility is cast at the present day upon every citizen, who directly or indirectly has to consider problems relating to the state endowment of education, the revision and administration of the Poor Law, and, above all, the conduct of public and private charities (Pearson, 1892: 26-7). Karl Pearson

19. The return of epigenetics Epigenome introduces another level of complexity ‘Sits on top’ of the genome Challenges natural selection as the only mechanism of heredity Specific environmental exposures (drugs, alcohol, psychosocial stress, etc) or disease states (depression, etc) may be correlated with specific epigenomic changes

20. Ethics of epigenetics Epigenetics may lead to unique ethical challenges: – intensify obligations concerning lifestyle decisions – increase blame arising from choice – liability for future illness in offspring – multigenerational liability for mortgages, employment or insurance – increase discrimination? – privacy of information regarding epigenetic influences – compensation for exposure to environmental risks – highlight social inequalities