The Epigenetics Revolution

Epigenetic modifications control cell fate – it’s these processes by which liver cells, for example, stay as liver cells and don’t turn into other cell types. Cancer represents a breakdown in normal control of cell fate, because liver cells stop being liver cells and become cancer cells, suggesting that epigenetic regulation has become abnormal in cancer. We should therefore aim to develop drugs that influence this epigenetic mis-regulation. Such drugs may be useful for treating or controlling cancer.

That’s a neat and tidy process, and makes a lot of sense. In fact, hundreds of millions of dollars are being spent in the global pharmaceutical industry to develop epigenetic drugs for exactly this purpose. But the clear-cut thought process outlined above is not how this process of cancer drug discovery started.

There are already licensed drugs which treat cancer and which work by inhibiting epigenetic enzymes. These compounds were shown to be active against cancer cells before they were shown to work on epigenetic enzymes. In fact, it’s the success of these compounds that has really stirred up interest in epigenetic therapies, and in the whole field of epigenetics itself – so much for a neat narrative arc.

The accidental epigeneticist

Back in the early 1970s, a young South African scientist called Peter Jones was working with a compound called 5-azacytidine. This compound was already known to have anti-cancer effects because it could stop leukaemia cells from dividing, and had some beneficial effects when tested in childhood leukaemia patients[167].

Peter Jones is now recognised as the founding father of epigenetic treatments for cancer. Tall, thin, tanned and with thick close-cropped white hair, he is an instantly recognisable presence at any conference. Like so many of the terrific scientists mentioned in this book, he has researched for decades in an ever-evolving field. He remains at the forefront of efforts to understand the impact of the epigenome on health. He is currently spearheading efforts to characterise all the epigenetic modifications present in a vast number of different cell types and diseases. These days he is able to call on technologies that allow his team to analyse millions of read-outs from highly specific and specialised equipment. Back in the early 1970s, he made his first breakthrough by being incredibly observant and thorough – a classic case of a prepared mind.

Forty years ago, nobody was quite sure how 5-azacytidine worked. It’s very similar in chemical structure to base C (cytidine) from DNA and RNA. It was assumed that 5-azacytidine got added into DNA and RNA chains. Once there, it somehow disrupted normal copying of DNA, and transcription or activity of RNA. Cancer cells such as the ones found in leukaemia are extremely active. They need to synthesise lots of proteins, which means they need to transcribe a lot of mRNA. Because they divide quickly they also need to replicate their DNA very efficiently. If 5-azacytidine was interfering with one or both of these processes, it would probably hamper the growth and division of the cancer cells.

Peter Jones and his colleagues were testing the effects of 5-azacytidine on a range of cells from mammals. It’s remarkably fiddly to get many types of cells to grow in the laboratory if you just take them straight out of a human or another animal. Even when you can get them to grow, they often stop dividing after a few cell divisions and die off. To get around this, Peter Jones worked with cell lines. Cell lines are derived originally from animals, including humans, but as a result of chance or experimental manipulation, they are able to grow indefinitely in culture, if given the right nutrients, temperature and environmental conditions. Cell lines are not exactly the same as cells in the body, but they are a useful experimental system.

The type of cells that Peter Jones and his colleagues were testing are usually grown in a flat plastic flask. This looks a little like a see-through version of a hip flask for whisky or brandy, lying on its side. The mammalian cells grow on the flat inside surface of the flask. They form a single layer of cells, tightly packed side by side, but never growing on top of one another.