The first pluripotent human embryonic stem cells (hESCs) have been generated from somatic cell nuclear transfer, according to a study published today (October 5) in Nature. The findings validate this controversial method, and may one day allow therapeutic stem cells to be created from a patient’s own genetic material.
“The advance here is the proof that somatic cell nuclear transfer can work [in human cells] and can fully reset the donor cell genome to a pluripotent state,” said Harvard Medical School’s George Daley, who was not affiliated with the study.
Somatic cell nuclear transfer typically involves the transfer of genomic information from a somatic cell into an unfertilized egg cell whose nucleus has been removed. The fusion ultimately gives rise to a microscopic embryo, from which embryonic stem cells can theoretically be derived. In contrast, currently existing hESC lines were derived from leftover embryos created for the purposes of in vitro fertilization.
Somatic cell nuclear transfer has shown limited success in animal studies, which have successfully isolated pluripotent cells. Like Dolly the sheep, these microscopic embryos can also be implanted into a host uterus, where they develop into a fetus and grow into adult animals after birth.
In humans, somatic transfer has been less fruitful—the egg cell quits dividing and often dies after nuclear transfer. In the best case, an early embryo consisting of a few cells may form, but these are not capable of giving rise to human life, nor hESCs for therapeutic purposes.
“A couple of studies show some success in generating early microscopic embryos, but this [study] is the first successful pluripotent stem cell line,” said Daley.
To achieve this success, Scott Noggle at the New York Stem Cell Foundation Laboratory took a unique approach to the process. Instead of removing the egg genome prior to nuclear transfer, he and his colleagues added the somatic cell nucleus directly to the intact egg. In the end, the egg cell contained three sets of chromosomes—two from the diploid somatic cell, and one from the haploid egg. The resulting clone developed into a microscopic embryo, which survived long enough for pluripotent stem cell lines to be derived.
The technique provides the first opportunity to make hESCs that carry the same genetic material as the patients. Such cells may help lower the risk of the body rejecting such cells when applied therapeutically. “This could allow us to create cells that are useful for transplantation for a variety of diseases without the problem of immunological rejection,” said Noggle in a press briefing.
Before the technique will ever make it to the clinic, however, researchers must find a way to remove genomic material from the egg cell. “The triploid cells aren’t suitable for therapeutic purposes, and future efforts will be focused on trying to eliminate the [egg cell] genome,” said Daley, who wrote an accompanying News & Views in Nature.
Noggle said the findings may also pave the way for better induced pluripotent stem cells (iPSCs), which form when somatic cells are regressed to a pluripotent state through the use of genetic factors. While iPSCs avoid the ethical issues surrounding embryonic stem cells, the methods used to derive them sometimes induce mutations in cancer causing genes, making them unsuitable for therapeutic purposes.
“Understanding human [eggs’] ability to reprogram could shed light on improved methods for reprograming,” said Noggle. For the first time researchers can now compare iPSC differentiation to the same process an egg goes through after the transfer of a somatic cell genome. This could help researchers identify abnormalities in iPSC differentiation, correct them, and develop pluripotent stem cells that don’t harbor tumorigenic qualities and do not require the use of human embryos.
As part of the study, Noggle and his colleagues developed new protocols that allow women to choose between giving their eggs to research or in vitro fertilization programs. While women have always been paid for donating their eggs for in vitro fertilization, ethical guidelines have prevented researchers from paying women for their eggs. As most women will not donate altruistically, this has left researchers working with the poor-quality eggs rejected from in vitro fertilization. According to the researcher’s new protocols, women are paid to donate, but only later choose whether their eggs should go to research or in vitro fertilization. This gave Noggle better access to high quality eggs, and paved the way for the new discovery.
“This group succeeded because they were highly skillful and had access to a plentiful supply of good quality eggs,” said Daley.
Noggle’s new protocols are among the first based on 2007 guidelines published by the American Society for Reproductive Medicine and the International Society for Stem Cell Research.