The Epigenetics Revolution

Okay, we’d still have to find a way of putting them into a surrogate mother, but we only have to go down the surrogate mother route if we want to generate a complete individual. Sometimes this is exactly what we want – to re-create a prize bull or prize stallion, for example, but this is not what most sane people want to do with humans. Indeed cloning humans (reproductive cloning) is banned in pretty much every country which has the scientists and the infrastructure to undertake such a task. But actually for most purposes we don’t need to go as far as this stage for cloning to be useful for humans. What we need are cells that have the potential to turn into lots of other cell types. These are the cells that are known as stem cells, and they are metaphorically near the top of Waddington’s epigenetic landscape. The reason we need such cells lies in the nature of the diseases that are major problems in the developed world.

In the rich parts of our planet the diseases that kill most of us are chronic. They take a long time to develop and often they take a long time to kill us when they do. Take heart disease, for example – if someone survives the initial heart attack they don’t necessarily ever go back to having a totally healthy heart again. During the attack some of the heart muscle cells (cardiomyocytes) may become starved of oxygen and die. We might imagine this would be no problem, as surely the heart can create replacement cells? After all, if we donate blood, our bone marrow can make more red blood cells. Similarly, we have to do an awful lot of damage to the liver before it stops being able to regenerate and repair itself. But the heart is different. Cardiomyocytes are referred to as ‘terminally differentiated’ – they have gone right to the bottom of Waddington’s hill and are stuck in a particular trough. Unlike bone marrow or liver, the heart doesn’t have an accessible reservoir of less specialised cells (cardiac stem cells) that could turn into new cardiomyocytes. So, the long-term problem that follows a heart attack is that our bodies can’t make new cardiac muscle cells. The body does the only thing it can and replaces the dead cardiomyocytes with connective tissue, and the heart never beats in quite the same way it did before.

Similar things happen in so many diseases – the insulin-secreting cells that are lost when teenagers develop type 1 diabetes, the brain cells that are lost in Alzheimer’s disease, the cartilage producing cells that disappear during osteoarthritis – the list goes on and on. It would be great if we could replace these with new cells, identical to our own. This way we wouldn’t have to deal with all the rejection issues that make organ transplants such a challenge, or with the lack of availability of donors. Using stem cells in this way is referred to as therapeutic cloning; creating cells identical to a specific individual in order to treat a disease.

For over 40 years we’ve known that in theory this could be possible. John Gurdon’s work and all that followed after him showed that adult cells contain the blueprints for all the cells of the body if we can only find the correct way of accessing them. John Gurdon had taken nuclei from adult toads, put them into toad eggs and been able to push those nuclei all the way back up Waddington’s landscape and create new animals. The adult nuclei had been – and this word is critical – reprogrammed. Ian Wilmut and Keith Campbell had done pretty much the same thing with sheep. The important common feature to recognise here is that in each case the reprogramming only worked when the adult nucleus was placed inside an unfertilised egg. It was the egg that was really important. We can’t clone an animal by taking an adult nucleus and putting it into some other cell type.

Why not?

We need a little cell biology here. The nucleus contains the vast majority of the DNA/genes that encode us – our blueprint. There’s a miniscule fraction of DNA that isn’t in the nucleus, it’s in tiny structures called mitochondria, but we don’t need to worry about that here. When we’re first taught about cells in school it’s almost as if the nucleus is all powerful and the rest of the cell – the cytoplasm – is a bag of liquid that doesn’t really do much. Nothing could be further from the truth, and this is especially the case for the egg, because the toads and Dolly have taught us that the cytoplasm of the egg is absolutely key. Something, or some things, in that egg cytoplasm actively reprogrammed the adult nucleus that the experimenters injected into it. These unknown factors moved a nucleus from the bottom of one of Waddington’s troughs right back to the top of the landscape.