It is no longer science fiction: human embryos have now been made from DNA in skin cells that were fertilised with sperm, a move that redrafts the biological limits of reproduction. At an Oregon Health & Science University (OHSU) laboratory, scientists have shown for the first time that a nucleus from a typical skin cell can be reprogrammed within a donor egg to act like a natural gamete, mapping out possible avenues for treating infertility and allowing same-sex couples to have children genetically related to one another.
The method is based on somatic cell nuclear transfer (SCNT), the same fundamental technique that was employed to clone Dolly the Sheep in 1996, but with a significant difference. Rather than creating a genetic replica of the donor, the OHSU researchers sought to produce a viable egg that could be fertilised. The procedure starts by extracting the nucleus from a mature metaphase II (MII) oocyte donated by a healthy volunteer. Into this empty egg, researchers insert the nucleus of a skin fibroblast that has been halted in the G0/G1 stage of the cell cycle, with chromosomes in the non-replicated state a prerequisite for what is to come.
In the cytoplasm of the egg, the somatic nucleus is tricked into shedding half of its chromosomes using an artificial method the researchers refer to as “mitomeiosis,” a mix of mitosis and meiosis. In natural meiosis, homologous chromosomes pair, undergo crossover recombination, and segregate precisely to produce haploid gametes. In mitomeiosis, however, segregation is random and no recombination occurs, a fundamental difference that currently limits the technique’s accuracy. Sequencing analysis of 113 SCNT-derived embryos identified only approximately half as having an even somatic chromosome split between the egg and extruded polar body, and many retained or lost whole pairs of chromosomes, resulting in aneuploidy.
Activation of these reconstructed eggs was another technical challenge. Fertilisation with sperm alone induced normal cell cycle exit in less than 25% of SCNT oocytes, the majority of which arrested at the two-cell stage. To counteract this, the team used a sequential artificial activation protocol: electroporation in a calcium-containing buffer to imitate fertilisation-induced Ca²⁺ oscillations, followed by treatment with roscovitine, an inhibitor of cyclin-dependent kinases that suppresses Maturation Promoting Factor (MPF) activity. This sequence rescued most SCNT oocytes from metaphase arrest, allowing for polar body extrusion and pronuclear formation in more than 75% of instances. Nevertheless, a mere 8.8% of the fertilized SCNT embryos reached the blastocyst stage, as opposed to virtually 60% of the controls.
Ignoring these constraints, the proof-of-concept is impressive. In 82 viable eggs produced, some of which were fertilised with sperm from a donor, a number achieved early embryonic stages. Chromosome tracing revealed that homologs from sperm incorporated into the embryonic genome in addition to somatic-derived chromosomes in some embryos, with other embryos becoming mosaics with blastomeres containing only sperm or only somatic chromosomes. The somatic genome, though semi-haploid and aneuploid, was able to replicate and segregate through early mitotic cycles.
The possible uses are vast. In vitro gametogenesis (IVG) with mitomeiosis may enable women of older maternal age, cancer survivors, or those without functional gametes to create eggs from their own somatic cells. For gay men, the skin cells of one partner might be used to produce an egg, which could be fertilized by the other’s sperm, giving rise to a child genetically linked to both. “In addition to offering hope for millions of people with infertility due to lack of eggs or sperm, this method would allow for the possibility of same-sex couples to have a child genetically related to both partners,” said OHSU Prof. Paula Amato.
But the path to clinical application is long. The stochastic segregation of chromosomes during mitomeiosis needs to be substituted with accurate pairing and allocation in order to provide embryos with precisely one set of each of the 23 types of chromosomes. Natural meiosis does so through intricate molecular choreography that includes programmed DNA double-strand breaks, homolog recognition, and crossover recombination processes probably not in the MII oocyte cytoplasm used in this work. As Prof. Shoukhrat Mitalipov put it, “We have to perfect it. Eventually, I think that’s where the future will go because there are more and more patients that cannot have children.” Ultimately, I believe that is where the future lies because there are increasingly more and more patients who cannot have children.
Ethical and regulatory issues dominate. The UK’s Human Fertilisation and Embryology Authority has already identified IVG as a technology “on the threshold of viability,” with implications varying from increased fertility choice to controversial situations like “multiplex parenting.” The potential for producing large numbers of embryos in vitro also opens up concerns regarding genetic selection, extending beyond prevention of disease. Public debate and legislative regulation will be necessary prior to such techniques proceeding from experimental research into reproductive medicine.
For the present, the OHSU study remains a landmark in reproductive biology: the first to prove that human skin cell DNA can be reprogrammed into an egg, fertilized, and coaxed into embryonic growth. It is a technical achievement haunted by biological subtlety and a preview of a time when the meaning of parenthood could be redefined in terms of cell engineering.
