The Epigenetics Revolution

The US Department of Defense is providing funding into iPS cells. The military always needs plenty of blood in any combat situation so that it can treat wounded personnel. Red blood cells aren’t like most cells in our bodies. They have no nucleus, which means they can’t divide to form new cells. This makes red blood cells a relatively safe type of iPS cell to start using clinically, as they won’t stay in the body for more than a few weeks. We also don’t reject these cells in the same way that we would a donor kidney, for example, because there are differences in the ways our immune systems recognise these cells. Different people can have compatible red blood cells – it’s the famous ABO blood type system, plus some added complications. It’s been calculated that we could take just 40 donors of specific blood types, and create a bank of iPS cells from those people that would supply all our needs[16]. Because iPS cells can keep on dividing to create more iPS cells when grown under the right conditions, we could create a never-ending bank of cells. There are well-established methods for taking immature blood stem cells and growing them under specific stimuli so that they will differentiate to form (ultimately) red blood cells. Essentially, it should be possible to create a huge bank of different types of red blood cells, so that we can always have matching blood for patients, be these from the battlefield or a traffic accident.

The generation of iPS cells has been one of those rare events in biology that have not just changed a field, but have almost reinvented it. Shinya Yamanaka is considered by most to be a dead cert to share a Nobel Prize with John Gurdon in the near future, and it would be difficult to over-estimate the technological impact of the work. But even though the achievement is extraordinary, nature already does so much more, so much faster.

When a sperm and an egg fuse, the two nuclei are reprogrammed by the cytoplasm of the egg. The sperm nucleus, in particular, very quickly loses most of the molecular memory of what it was and becomes an almost blank canvas. It’s this reprogramming phenomenon that was exploited by John Gurdon, and by Ian Wilmut and Keith Campbell, when they inserted adult nuclei into the cytoplasm of eggs and created new clones.

When an egg and sperm fuse, the reprogramming process is incredibly efficient and is all over within 36 hours. When Shinya Yamanaka first created iPS cells only a miniscule number, a fraction far less than 1 per cent of the cells in the best experiment, were reprogrammed. It literally took weeks for the first reprogrammed iPS cells to grow. A lot of progress has been made in improving the percentage efficiency and speed of reprogramming adult cells into iPS cells, but it still doesn’t come within spitting range of what happens during normal fertilisation. Why not?

The answer is epigenetics. Differentiated cells are epigenetically modified in specific ways, at a molecular level. This is why skin fibroblasts will normally always remain as skin fibroblasts and not turn into cardiomyocytes, for example. When differentiated cells are reprogrammed to become pluripotent cells – whether by somatic cell nuclear transfer or by the use of the four Yamanaka factors – the differentiation-specific epigenetic signature must be removed so that the nucleus becomes more like that of a newly fertilised zygote.

The cytoplasm of an egg is incredibly efficient at reversing the epigenetic memory on our genes, acting as a giant molecular eraser. This is what it does very rapidly when the egg and sperm nuclei fuse to form a zygote. Artificial reprogramming to create iPS cells is more like watching a six-year-old doing their homework – they are forever rubbing out the wrong bit whilst leaving in the mis-spelt words, and then tearing a hole in the page because they rub too vigorously. Although we are starting to get a handle on some of the processes involved, we are a long way from recreating in the lab what happens naturally.

Until now we have been talking about epigenetics at the phenomenon scale. The time has come to move into the molecules that underlie all the remarkable events we’ve talked about so far, and many more besides.

Chapter 3. Life As We Knew It

A poet can survive everything but a misprint.

Oscar Wilde