Bruce Cattanach is a scientist we have met before in these pages. In addition to his work on parent-of-origin effects, he also performed some of the key early experimental studies on the molecular mechanisms behind X inactivation[294]. He would be considered a worthy co-recipient with Mary Lyon by most researchers. Mary Lyon and Bruce Cattanach performed much of their seminal research in the 1960s and are long-since retired. However, Robert Edwards, the pioneer of in vitro fertilisation, received the 2010 Nobel Prize in his mid-eighties, so there is still time and a little hope left for Professors Lyon and Cattanach.
The work of John Gurdon and Shinya Yamanaka on cellular reprogramming has revolutionised our understanding of how cell fate is controlled, and they must be hot favourites for a trip to Stockholm soon. A slightly less mainstream but appealing combination would be Azim Surani and Emma Whitelaw. Together their work has been seminal in demonstrating not only how the epigenome is usually reset in sexual reproduction, but also how this process is occasionally subverted to allow the inheritance of acquired characteristics. David Allis has led the field in the study of epigenetic modifications to histones, and must also be an attractive choice, possibly in combination with some of the leading lights in DNA methylation, especially Adrian Bird and Peter Jones.
Peter Jones has been a pioneer in the development of epigenetic therapies and this is another growth area for epigenetics. Histone deacetylase inhibitors and DNA methyltransferase inhibitors have been in the vanguard of these approaches. The vast majority of clinical trials with these compounds have been in cancer, but this is starting to change. An inhibitor of the sirtuin class of histone deacetylases is in early clinical trials for Huntington’s disease, the devastating inherited neurodegenerative disorder[295]. The greatest excitement, for both cancer and non-oncology conditions, is currently centred around the development of drugs that inhibit more focused epigenetic enzymes. These include enzymes that change just one modification at one specific amino acid position on histone proteins. Hundreds of millions of dollars are being invested worldwide in this sphere, either in new biotech companies, or by the pharmaceutical giants. We are likely to see new drugs from these efforts enter clinical trials for cancer in the next five years, and clinical trials for other less immediately life-threatening conditions within a decade[296].
Our increased understanding of epigenetics, and especially of transgenerational inheritance, may also create problems in drug discovery, as well as opportunities. If we create new drugs that interfere with epigenetic processes, what if these drugs also affect the reprogramming that normally occurs during the production of germ cells? This could theoretically result in physiological changes that don’t just affect the person who was treated, but also their children or grandchildren. We maybe shouldn’t even restrict our concerns to chemicals that specifically target epigenetic enzymes. As we saw in Chapter 8, the environmental pollutant vinclozolin can affect rodents for many generations. If the authorities that regulate the licensing of new drugs begin to insist on transgenerational studies, this will add enormously to the cost and complexity of developing new drugs.
At first glance, this might seem perfectly reasonable; after all, we want drugs to be as safe as possible. But what happens to all the patients who desperately need new drugs to save them from life-threatening diseases, or who need better drugs so that they can live healthy and dignified lives free of pain and disability? The longer it takes to get new drugs to the market, the longer those patients suffer. It’s going to be very interesting to see how drug companies, regulators and patient advocacy groups deal with this issue over the next ten or fifteen years.
Transgenerational effects of epigenetic changes may be one of the areas with the greatest impact on human health over the coming decades, not because of drugs or pollutants but because of food and nutrition. We started this journey into the epigenetic landscape by looking at the Dutch Hunger Winter. This had consequences not just for those who lived through it but for their descendants. We are in the grip of a global obesity epidemic. Even if our societies manage to get control of this (and very few western cultures show many signs of doing so) we may already have generated a less than optimal epigenetic legacy for our children and grandchildren.
Nutrition in general is one area where we can predict epigenetics will come to the fore in the next ten years. Here are just a few examples of what we know at the moment.
Folic acid is one of the supplements recommended for pregnant women. Increasing the supply of folic acid in the very early stages of pregnancy has been a public health triumph, as it has led to a major drop in the incidence of spina bifida in newborns[297]. Folic acid is required for the production of a chemical called SAM (S-adenosyl methionine). SAM is the molecule that donates the methyl group when DNA methyltransferases modify DNA. If baby rats are fed a diet that is low in folic acid, they develop abnormal regulation of imprinted regions of the genome[298]. We are only just beginning to unravel how many of the beneficial effects of folic acid may be mediated through epigenetic mechanisms.
Histone deacetylase inhibitors in our diets may also play useful roles in preventing cancer and possibly other disorders. The data are relatively speculative at the moment. Sodium butyrate in cheese, sulphoraphane in broccoli and diallyl disulphide in garlic are all weak inhibitors of histone deacetylases. Researchers have hypothesised that the release of these compounds from food during digestion may help to modulate gene expression and cell proliferation in the gut[299]. In theory, this could lower the risk of developing cancerous changes in the colon. The bacteria in our intestines also naturally produce butyrate from the breakdown of foodstuffs[300], especially plant-derived materials, which is another good reason to eat our greens.
There’s a speculative but fascinating case study from Iceland on how diet may epigenetically influence a disease. It concerns a rare genetic disease called hereditary cystatin C amyloid angiopathy, which causes premature death through strokes. In the Icelandic families in which some people suffer from the disease, the patients carry a particular mutation in the key gene. Because of the relatively isolated nature of Icelandic societies, and the country’s excellent record keeping, researchers were able to trace this disease back through the affected families. What they found was quite remarkable. Until about 1820, people with this mutation lived until around the age of 60 before they succumbed to the disease. Between 1820 and 1900, the life expectancy for those with the same disorder dropped to about 30 years of age, which is where it has remained. The scientists speculated in their original paper that an environmental change in the period from 1820 onwards altered the way that cells respond to and control the effects of the mutation[301].