There may also be an aspect of pure bad luck in who develops cancer. We probably all have random fluctuations in the levels, activity or localisation of proteins that target, write, interpret and erase our epigenetic codes. And there are the non-coding RNAs too.
The 3′ UTRs of both DNMT3A and DNMT3B mRNA contain binding sites for a family of miRNAs called miR-29. Normally, these miRNAs will bind to the DNMT3A and DNMT3B mRNA molecules and down-regulate them. In lung cancer, the levels of these miRNAs drop and as a consequence DNMT3A and DNMT3B mRNA and subsequently protein expression is elevated. This is likely to increase the amount of de novo methylation of susceptible tumour suppressor promoters[203].
It is likely that there will also be feedback loops between miRNAs and the epigenetic enzymes they control, if one component of the pathway becomes mis-regulated. This will reinforce abnormal control mechanisms in the cell, leading to yet another vicious cycle, and is shown in Figure 11.4. In this example, a miRNA regulates a specific epigenetic enzyme, which itself modifies the promoter of the miRNA. In this case, the epigenetic enzyme creates a repressive modification.
Figure 11.4 A positive feedback loop which constantly drives down expression of a miRNA which would normally control expression of an epigenetic enzyme that creates a repressed chromatin state.
There is still much that we need to understand if we are to develop the next generation of epigenetic drugs to treat cancer patients. We need to know which drugs will work best in which diseases and which patients will benefit the most. We want to be able to work this out in advance, so that we don’t have to hope for the best when running large numbers of clinical trials. At least 5-azacytidine and SAHA have given us the comfort of knowing that epigenetic therapy is possible in cancer, even if improvements are needed.
As we shall see in the next chapter, epigenetic problems are not restricted to cancer. But sadly we are even further away from knowing how to use epigenetic therapies in one of the greatest unmet clinical needs in the western world – psychiatric disease.
Chapter 12. All in the Mind
The mind is its own place, and in itself can make a Heaven of Hell, a Hell of Heaven.
One of the most noticeable publishing trends of the last ten years has been the rise and rise of the ‘misery memoir’. In this genre, the authors recount the tough times of their childhood and how they have risen above them to be successful and fulfilled individuals. The genre can be sub-divided into two categories. The first is the poor-but-happy tale, the ‘we had nothing but we had love’ story. The second, which may or may not also include poverty, tends to be much more disturbing. It focuses on harrowing tales of childhood neglect and childhood abuse, and some of these memoirs have been hugely successful. A Child Called It by Dave Pelzer, possibly the most famous of this category of books, spent over six years on the New York Times bestsellers list.
A substantial amount of their appeal seems to lie in the triumph-over-adversity aspects of these memoirs. Readers seem to take heart from the stories of individuals who, despite a terrible start in life, finally grow up to be happy, well-balanced adults. We applaud those who become winners ‘against the odds’.
This tells us something quite revealing. It shows that, as a society, we believe that early childhood events are extremely important in influencing adult life. It also shows that we believe that it is very difficult to get over the effects of early trauma. As a readership, we possibly value these successful survivors because of what we perceive as their relative rarity.
In many ways, we are correct in our assumptions as it is true that dreadful early childhood experiences really can have a dramatic impact on adult life. There are all sorts of ways in which this has been measured and the precise figures may vary from study to study. Despite this, certain clear trends have emerged. Childhood abuse and neglect result in adults with a three times greater risk of suicide than the general population. Abused children are at least 50 per cent more likely than the general population to suffer from serious depression as adults, and will find it much harder to recover from this illness. Adults who were subjected to childhood abuse and neglect are also at significantly higher risk of a range of other conditions including schizophrenia, eating disorders, personality disorders, bipolar disease and generalised anxiety. They are also more likely to abuse drugs or alcohol[204].
An abusive or neglectful environment when young is clearly a major risk factor for the development of later neuropsychiatric disorders. We are so aware of this as a society that sometimes we almost forget to question why this should be the case. It just seems self-evident. But it’s not. Why should events that lasted for two years, for example, still have adverse consequences for that individual several decades later?
One explanation that is often given is that the children are ‘psychologically damaged’ by their early experiences. Whilst true, this isn’t that helpful a statement. The reason why it’s not helpful is that the phrase ‘psychologically damaged’ isn’t really an explanation at all – it’s a description. It sounds quite convincing but on certain levels it doesn’t really tell us anything.
Any scientist addressing this problem will want to take this description and probe it at another level. What are the molecular events that underlie this psychological damage? What happens in the brains of the abused or neglected children, that leaves them so prone to mental health problems as adults?
There is sometimes resistance to this approach from other disciplines, which work within different conceptual frameworks. This seems rather puzzling. If we don’t accept there is a molecular basis to a biological effect, what are we left with? A religious person may prefer to invoke the soul, just as a Freudian therapist may invoke the psyche. Both of these refer to a theoretical construct that has no defined physical basis. Moving into such a model system, where it is impossible to develop the testable hypotheses that are the cornerstone of all scientific enquiry, is deeply unattractive to most scientists. We prefer to probe for a mechanism that has a physical foundation, rather than defaulting to a scenario in which there is something which is assumed, somehow, to be a part of us, without having any physical existence.
This can generate a cultural clash, but it’s one that’s based on a misunderstanding. A scientist will expect that observable events have a physical basis. For the topic of this chapter, our proposed hypothesis is that terrible early childhood experiences change certain physical aspects of the brain during a key developmental period. This in turn affects the likelihood of mental health problems in adult life. This is a mechanistic explanation. It’s lacking in details, admittedly, but we’ll fill in some of these in this chapter. Mechanistic explanations often sit uncomfortably in our society, because they sound too deterministic. Mechanistic explanations are misinterpreted and taken to imply that humans are essentially robots, wired and programmed to respond in certain ways to certain stimuli.
But this doesn’t have to be the case. If a system has enough flexibility, then one stimulus doesn’t always have to result in the same outcome. Not every abused or neglected child develops into a vulnerable, unwell adult. A phenomenon can have a mechanistic basis, without being deterministic.