We could hypothesise that the reason why mammals all have a mother and father is because that’s what we need to introduce two haploid genomes to one another, to create a new cell with a full complement of chromosomes. Certainly it’s true that this is what normally happens but this model would also imply that the only reason why biologically we need a parent of each sex is because of a delivery system.
In 2010 Professor Robert Edwards received the Nobel Prize in Physiology or Medicine for his pioneering work in the field of in vitro fertilisation, which led to the so-called test tube babies. In this work, eggs were removed from a woman’s body, fertilised in the laboratory, and re-implanted back into the uterus. In vitro fertilisation was hugely challenging, and Professor Edwards’ success in human reproduction was built on years of painstaking work in mice.
This mouse work laid the foundation for a remarkable series of experiments, which demonstrated there’s a lot more to mammalian reproduction than just a delivery system. The major force in this field is Professor Azim Surani, from Cambridge University, who started his scientific career by obtaining his PhD under the supervision of Robert Edwards. Since Professor Edwards received his early research training in Conrad Waddington’s lab, we can think of Azim Surani as Conrad Waddington’s intellectual grandson.
Azim Surani is another of those UK academics who carries his prestige very lightly, despite his status. He is a Fellow of the Royal Society and a Commander of the British Empire, and has been awarded the prestigious Gabor Medal and Royal Society Royal Medal. Like John Gurdon and Adrian Bird, he continues to break new ground in a research area that he pioneered over a quarter of a century ago.
Starting in the mid 1980s, Azim Surani carried out a programme of experiments which showed unequivocally that mammalian reproduction is much more than a matter of a delivery system. We don’t just need a biological mother and a biological father because that’s how two haploid genomes fuse to form one diploid nucleus. It actually matters enormously that half of our DNA comes from our mother and half from our father.
Figure 7.1 shows what a just-fertilised egg looks like, before the two genomes meet. It’s simplified and exaggerated, but it will serve our purpose. The haploid nuclei from the egg and the sperm are called pro-nuclei.
Figure 7.1 The mammalian egg just after it has been penetrated by a sperm, but before the two haploid (half the normal chromosome number) pronuclei have fused. Note the disparity in size between the pronucleus that came from the egg, and the one that originated from the sperm.
We can see that the female pronucleus is much bigger than the male one. This is very important experimentally, as it means that we can tell the different pronuclei apart. Because we can tell them apart, scientists can transfer a pronucleus from one cell to another, and be certain about which one they transferred. They know if they transferred a pronucleus that came from the father’s sperm (male pronucleus) or from the mother’s egg (female pronucleus).
Many years ago Professor Gurdon used tiny micropipettes to transfer the nuclei from the body cells of toads into toad eggs. Azim Surani used a refinement of this technology to transfer pronuclei between different fertilised eggs from mice. The manipulated fertilised eggs were then implanted into female mice and allowed to develop.
In a slew of papers, mainly published between the years of 1984 and 1987, Professor Surani demonstrated that it’s essential to have a male and a female pronucleus in order to create new living mice. This is shown graphically in Figure 7.2.
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.
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.