Independent Research Project

Will advancements in the understanding of epigenetic mechanisms in the brain affect the future treatment of neurodegenerative diseases?

Put simply the answer to this question is yes. Effective treatment of any disease necessitates a detailed understanding of its pathogenesis. Advancements therefore in the understanding of epigenetic mechanisms, which enable scientists to ascertain the role of epigenetics within pathogenetic pathways, will undoubtedly affect the future treatment of neurodegenerative disease. Epigenetics is widely acknowledged as the 'heritable changes in gene expression that cannot be attributed to differences in the genetic code' . Until this definition was established the perception of DNA as a mechanism through which all biochemical mysteries of the body were explicable was a popular one. It was felt that complete definition of the genome's boundaries could be used as a scaffold on which to build a greater understanding of human phenotypic variation. However DNA alone is unable to provide an explanation for some 'medical mysteries'. Why for example monozygotic twins are discordant in their susceptibility to disease? It has become increasingly clear, as Nessa Carey points out, that to talk about DNA 'as if it's... a mould for a car part in a factory...unless something goes wrong in the process, out pop thousands of identical car parts...' is misleading 'It's more like a scri pt...the same scri pt can result in different productions' . A 'landmark paper' as it was described by Dr. Rajiv Ratan (professor of neuroscience at Burke Research Institute) published in 2005 provided an 'elegant explanation' for the twin 'mystery'; 'although they have similar epigenetic profiles early in life as they age, several epigenetic signatures... diverge'. In a series of experiments during the 1970s, to test his hypothesis that 'as cells become more specialised they undergo an irreversible loss of genetic material', Professor Sir John Gurdon of Cambridge University was led to the conclusion that there 'is something in cells that keeps specific genes turned on or switched off in different cell types' . Carey goes onto make the assertion that 'whatever this something is, it can't be the loss or permanent inactivation of genetic material...Epigenetics is the 'something'', by affecting the translation of mRNA it alters the expression of our genetic material but not the genes themselves . However the extent to which such understanding of epigenetics will affect the future treatment of neurodegenerative disease is limited by a number of issues. The first and perhaps most concerning of these is to do with the lack of information regarding the full implications of changes made at the epigenetic level. This compounded with the idea that such changes are potentially heritable means that progress in the field of epigenetics is limited by how well researchers are able to map the epigenome. Only when it is mapped will researchers be able to progress. This mapping will require meticulous analysis of not only the mechanisms themselves, but also the 'domino' like effects that epigenetic changes could have, both on the individual and possibly their descendents. The second issue is related to the difficulties associated with treating the brain. The intricate matrix of some 100 billion neurones with 100 trillion synapses , the endothelial cells that restrict regular circulation of blood, otherwise known as the blood brain barrier, and the surges in strength of electric fields that sweep across the brain even when it is at rest make it the single most complex organ to treat in the body. Thus the degree to which fresh understanding in the field of epigenetics will affect future treatment is also limited by how well researchers combat wider neurological issues such as the blood brain barrier. Thirdly it is important to assess the advantages of epigenetic treatments compared with those of competing treatment methods such as neural prostheses, a therapy not inhibited by the barrier, and regular enzyme inhibitors. One such advantage maybe the fact that epigenetic treatments are able to target a disease at the earliest stages of its pathogenesis. However as mentioned above there is a fear that interference at the epigenetic level may have wider negative consequences; it may in fact be safer to target a disease at the later or more specialised level of the regular enzyme inhibitor treatments. My intention is to analyse the current understanding of the role of epigenetics within disease and then to make an assessment of its limitations and strengths as a potential treatment for neurodegenerative disease.