Masterpieces of Epigenetics: The Missing Link between Nature and Nurture
Presented by Dr Nessa Carey
Conference Auditorium, University of Leeds, Leeds LS2 9JT, UK
Tuesday 11 December 2012
'Beautiful science' was how Dr Nessa Carey described epigenetics at the Biochemical Society Annual Symposium Public Lecture, held at the University of Leeds on 11 December. Dr Carey, who works at Pfizer, explained that while the DNA double helix remains one of the most iconic images of biology, we are only now beginning to gain a clearer picture of how specialised cells 'wriggle in the troughs of specialisation'; retaining their functions but also responding to the environment.
In 2000, US President Bill Clinton proclaimed that 'Today we are learning the language in which God created life', following an announcement about progress on the Human Genome Project. Dr Carey explained that it can take just one problem with any of the three billion nucleotide pairs that make up our DNA for us to have a debilitating disease. Would knowing the human genome sequence allow us to combat such diseases? Unfortunately for this theory, genotype does not always equate to phenotype. DNA, Dr Carey used the analogy, is a script, not a template.
Dr Carey gave several examples of so-called 'intangible variation'. Identical mice kept under standardised conditions will not be identical. A maggot and a fly must use the same genetic script. In some crocodiles, you cannot tell from the DNA whether individuals are male or female. Where genetic identity does not equal phenotypic identity, epigenetics is at play, and we are 'masterpieces of epigenetics', she explained. Up until now we have only been able to describe these phenomena. Now we are starting to understand how they actually happen.
The modification of histones (proteins around which DNA winds to be compacted into cells) and the methylation (the binding of methyl chemical groups) of DNA are two important epigenetic mechanisms, we heard. For example, the brain does not produce haemoglobin because the high levels of methylation around the genes that code for this become completely inaccessible to the protein-producing machinery of the cell. Dr Carey explained that there are around 70 known types of histone modification, which all have subtle effects on the accessibility of genes. Through all this, the genome itself remains unchanged.
Epigenetics is starting to become a fertile area for designing new drugs. 'Why else would Pfizer be interested in this area', noted Dr Carey. Using the analogy of a bicycle being chained up without you holding the key, she explained that in many chronic conditions there is nothing wrong with the genes, but they are locked into inappropriate patterns of expression.
Cancer is a particularly fruitful field for this kind of research, we heard. Zolinza affects proteins which contribute to the modification of histones, for the treatment of cutaneous T Cell lymphoma. Vidaza interferes with the DNA methylation process and ribosome function for the treatment of myelodysplastic syndrome.
It is a well-known phenomenon that having a stressful childhood can have a significant impact on adulthood, even when the child is moved to a nurturing environment following an initial period of maltreatment. The traditional explanation for this is 'psychological damage'. This is a return to us describing, rather than explaining the issue. Dr Carey encouraged us to question what the true physical basis for this is. This phenomenon has been investigated in rats. Experiments have shown that rats who are nurtured through childhood shrug off minor stresses in adulthood. 'Unloved' rats, on the other hand, 'jump out of their skin'. Investigation demonstrates that this is because the 'fight or flight' response becomes over-activated.
What other diseases could this type of mechanism be applied to? Epigenetics can be implicated in chronic or persistent diseases which place a great burden on our society. For example, rheumatoid arthritis, post-traumatic stress disorder, diabetes and heart disease could all be treated before serious manifestation, Dr Carey convincingly suggested, if we had drugs to pre-emptively counter the epigenetic effects.
No drugs are free of side effects, and we are not able to pre-empt most disease cases to a significant degree of accuracy. So how could clinical trials be run for these scenarios? On an ethical level, would any eventual 'treatment' for childhood neglect distract from the search for sociological solutions? These are vitally important questions. When applied to treatment, who would we treat and when?
There are still many unanswered questions. The only part of the genome that gets more complicated in higher organisms is what was formerly known as 'junk DNA'. We now know that this actually provides the 'molecular velcro' to make things stick to histones, but we are nowhere near unlocking its power. In the mean time, we risk epigenetics becoming a catch-all phrase for everything we don't understand! This is a burgeoning field, which could lead to exciting but complex medical implications. But we need to play the long game and debate it appropriately.