The Epigenetics Revolution

^{Figure 7.2 A summary of the outcomes from the early work of Azim Surani. The pronucleus was removed from a mouse egg. This donor egg was then injected with two haploid pronuclei and the resulting diploid egg was implanted into a mouse surrogate mother. Live mice resulted only from the eggs which had been reconstituted with one male and one female pronucleus. Embryos from eggs reconstituted with either two male or two female pronuclei failed to develop properly and the embryos died during development.}

To control for the effects of different DNA genomes, the researchers used inbred mouse strains. This ensured that the three types of fertilised eggs shown in the diagram were genetically identical. Yet despite being genetically identical, a series of experiments from Azim Surani and his colleagues[53][54][55], along with other work from the laboratories of Davor Solter[56] and Bruce Cattanach[57] were conclusive. If the fertilised egg contained only two female pronuclei, or two male ones, no live mice were ever born. You needed a pronucleus of each sex.

This is an absolutely remarkable finding. In all three scenarios shown in the diagram, the zygote ends up with exactly the same amount of genetic material. Each zygote has a diploid genome (two copies of every chromosome). If the only factor that was important in the creation of a new individual was the amount of DNA, then all three types of fertilised eggs should have developed to form new individuals.

Quantity isn’t everything

This led to a revolutionary concept – the maternal and paternal genomes may deliver the same DNA but they are not functionally equivalent. It’s not enough just to have the correct amount of the correct sequence of DNA. We have to inherit some from our mother and some from our father. Somehow, our genes ‘remember’ who they come from. They will only function properly if they come from the ‘correct’ parent. Just having the right number of copies of each gene, doesn’t fulfil the requirements for normal development and healthy life.

We know that this isn’t some strange effect that only applies to mice, because of a naturally occurring human condition. In about one in 1500 human pregnancies, for example, there is a placenta in the uterus but there is no foetus. The placenta is abnormal, covered in fluid-filled, grape-like lumps. This structure is called a hydatidiform mole, and in some Asian populations the frequency of these molar pregnancies can be as high as 1 in 200. The apparently pregnant women gain weight, often more quickly than in a normal pregnancy and they also suffer morning sickness, often to a quite extreme degree. The rapidly-growing placental structures produce abnormally high levels of a hormone which is thought to be responsible for the symptoms of nausea in pregnancy.

In countries with good healthcare infrastructure, the hydatidiform mole is normally detected at the first ultrasound scan, and then an abortion-type procedure is carried out by a medical team. If not detected, the mole will usually abort spontaneously at around four or five months post-fertilisation. Early detection of these moles is important as they can form potentially dangerous tumours if they aren’t removed.

These moles are formed if an egg which has somehow lost its nucleus is fertilised. In about 80 per cent of hydatidiform molar pregnancies, an empty egg is fertilised by a single sperm, and the haploid sperm genome is copied to create a diploid genome. In about 20 per cent of cases the empty egg is fertilised simultaneously by two sperm. In both cases the fertilised egg has the correct number of chromosomes (46), but all the DNA came from the father. Because of this, no foetus develops. Just like the experimental mice, human development requires chromosomes from both the mother and the father.

This human condition and the experiments in mice are impossible to reconcile with a model based only on the DNA code, where DNA is a naked molecule, which carries information only in its sequence of A, C, G and T base-pairs. DNA alone isn’t carrying all the necessary information for the creation of new life. Something else must be required in addition to the genetic information. Something epigenetic.