The Epigenetics Revolution полностью

Unfortunately, there are substantial difficulties in doing this. These drugs have side-effects which can include severe fatigue, nausea and a higher risk of infections. These side-effects are considered acceptable if the alternative is an inevitable and fairly near-term death from cancer. But they might be considered less acceptable for treating the early stages of dementia, when the patient still has a relatively reasonable quality of life. And they would certainly be unacceptable for the general population.

There is an additional problem. Most of these drugs are really bad at getting into the brain. In many of the rodent experiments, the drugs were administered directly into the brain, and often into very defined regions such as the hippocampus. This isn’t a realistic treatment method for humans.

There are a few histone deacetylase inhibitors that do get into the brain. A drug called sodium valproate has been used for decades to treat epilepsy, and clearly must be getting into the brain in order to do this. In recent years, we have realised that this compound is also a histone deacetylase inhibitor. This would be extremely encouraging for trying to use epigenetic drugs in Alzheimer’s disease but unfortunately, sodium valproate only inhibits histone deacetylases very weakly. All the animal data on learning and memory have shown that stronger inhibitors work much better than weak ones at reversing these deficits.

It’s not just in disorders like Alzheimer’s disease that epigenetic therapies could be useful if we manage to develop suitable drugs. Between 5 and 10 per cent of regular users of cocaine become addicted to the drug, suffering from uncontrollable cravings for this stimulant. A similar phenomenon occurs in rodents, if animals are allowed unlimited access to the drug. Addiction to stimulants such as cocaine is a classic example of inappropriate adaptations by memory and reward circuits in the brain. These maladaptations are regulated by long-lasting changes in gene expression. Changes in DNA methylation, and in how methylation is read by MeCP2, underpin this addiction. This happens via a set of poorly understood interactions which include signalling factors, DNA and histone modifying enzymes and readers, and miRNAs. Related pathways also underpin addiction to amphetamines[231][232].

If we return to the starting point of this chapter, it’s clear that there’s a major need to stop children who have suffered early trauma from developing into adults with a substantially higher than normal risk of mental illness. It’s very appealing to think we might be able to use epigenetic drug therapies to improve their life chances. Unfortunately, one of the problems in designing therapies for children who have been abused or neglected is that it’s actually pretty difficult to identify those who will be permanently damaged as adults, and those who will have healthy, happy and fulfilled lives. There are enormous ethical dilemmas around giving drugs to children, when we can’t be sure if an individual child actually needs the treatment. In addition, clinical trials to determine if the drugs actually do any good would need to last for decades, which makes them economically almost a non-starter for any pharmaceutical company.

But we mustn’t end on too negative a note. Here’s a great story about an epigenetic event and behaviour. There is a gene called Grb10 that is involved in various signalling pathways. It’s an imprinted gene, and the brain only expresses the paternally inherited copy. If we switch off this paternal copy, the mouse can’t produce any Grb10 protein, and the animals develop a very odd phenotype. They nibble off the face fur and whiskers of other mice in the same cage. This is a sort of aggressive grooming, a bit like a pecking order in chickens. In addition, if faced with a big mouse that they don’t know, the Grb10 mutant mice don’t back away – they stand their ground[233].

Switching off Grb10 in the brain results in what might sound like a rather impressive, kick-ass kind of a mouse. It maybe even seems odd that this gene is normally switched on in the brain. Wouldn’t mice that switched off Grb10 be the butchest, most successful mice? Actually, it’s more likely that they’d be the mice most likely to get themselves beaten up. There are a lot of mice in the world, and they encounter each other pretty frequently. It pays to recognise when you are out-gunned.