The Epigenetics Revolution

That’s why there was such a furore in 1996 when Keith Campbell and Ian Wilmut at the Roslin Institute created the first mammalian clone, Dolly the sheep[8]. Like John Gurdon, they used SCNT. In the case of Dolly, the scientists transferred the nucleus from a cell in the mammary gland of an adult ewe into an unfertilised sheep egg from which they had removed the original nucleus. Then they transplanted this into the uterus of a recipient ewe. Pioneers of cloning were nothing if not obsessively persistent. Campbell and Wilmut performed nearly 300 nuclear transfers before they obtained that one iconic animal, which now revolves in a glass case in the Royal Scottish Museum in Edinburgh. Even today, when all sorts of animals have been cloned, from racehorses to prize cattle and even pet dogs and cats, the process is incredibly inefficient. Two questions have remained remarkably pertinent since Dolly tottered on her soon to be prematurely arthritic legs into the pages of history. The first is why is cloning animals so inefficient? The second is why are the animals so often less healthy than ‘natural’ offspring? The answer in both cases is epigenetics, and the molecular explanations will become apparent as we move through our exploration of the field. But before we do, we’re going to take our cue from H. G. Wells’s time traveller and fast-forward over thirty years from John Gurdon in Cambridge to a laboratory in Japan, where an equally obsessive scientist has found a completely new way of cloning animals from adult cells.

Chapter 2. How We Learned to Roll Uphill

Any intelligent fool can make things bigger and more complex … It takes a touch of genius and a lot of courage to move in the opposite direction.

Albert Einstein

Let’s move on about 40 years from John Gurdon’s work, and a decade on from Dolly. There is so much coverage in the press about cloned mammals that we might think this procedure has become routine and easy. The reality is that it is still highly time-consuming and laborious to create clones by nuclear transfer, and consequently it’s generally a very costly process. Much of the problem lies in the fact that the process relies on manually transferring somatic nuclei into eggs. Unlike the amphibians that John Gurdon worked on, there’s the additional problem that mammals don’t produce very many eggs at once. Mammalian eggs also have to be extracted carefully from the body, they aren’t just ejected into a tank like toad eggs. Mammalian eggs have to be cultured incredibly delicately to keep them healthy and alive. Researchers need to remove the nucleus manually from an egg, inject in a nucleus from an adult cell (without damaging anything), then keep culturing the cells really, really carefully until they can be implanted into the uterus of another female. This is incredibly intensive and painstaking work and we can only do it one cell at a time.

For many years, scientists had a dream of how they would carry out cloning in an ideal world. They would take really accessible cells from the adult mammal they wanted to clone. A small sample of cells scraped from the skin would be a pleasantly easy option. Then they would treat these cells in the laboratory, adding specific genes, or proteins, or chemicals. This treatment would change the way the nuclei of these cells behaved. Instead of acting like the nucleus of a skin cell, they would act the same way as nuclei from newly fertilised eggs. The treatment would therefore have the same ultimate effect as transferring the nuclei from adult cells into fertilised eggs, from which their own nuclei had been removed. The beauty of such a hypothetical scheme is that we’d have bypassed most of the really difficult and time-consuming steps that require such a high level of technical skill in manipulating tiny cells. This would make it an easily accessible technique and one that could be carried out on lots of cells simultaneously, rather than just one nuclear transfer at a time.