Dec. 9, 2010
Using a very roundabout technique, scientists have created mice with two genetic fathers. But don't look for this to be applicable any time soon with humans. The convoluted technique needs flow charts to explain (thankfully provided by the authors in their paper.)
In their first try, they derived embryonic stem (ES) cells from a destroyed male mouse embryo (Father #1). Over time in culture, some ES cells lose the Y chromosome (1.3% in this experiment.) These "XO" (one X chromosome, no second sex chromosome) cells are then injected into female mouse embryos, creating a chimeric organism composed of some cells from the original embryo (XX) and some XO cells. Those embryos are then gestated to birth. Some of the chimeric mice have oocytes produced from their XO cell contribution. These female mice are bred with male mice (Father #2) and the resulting pups thus have two genetic fathers.
Of course, there's a little catch, in that Father #1 was destroyed as an embryo. As the authors note:
"ES cell lines are derived by disassembling the inner cell mass of a blastocyst, thus the individual that would have been generated from that particular blastocyst does not exist."
So in their second experiment, they generated iPS cells (embryonic-like stem cells) from mouse skin (Father #1 in this case was still not an adult, but was a mouse fetus.) Because iPS cells behave like ES cells, some of these cells also lost the Y chromosome in culture (0.9%), resulting in "XO" cells. As before, these were injected into female (XX) mouse embryos to create chimeric embryos, which were gestated to birth and then at maturity bred to male mice (Father #2), resulting in some pups that had two genetic fathers.
So they did indeed derive mice that have the genetic complement of two fathers. But then they engage in some "what if" speculation regarding use in humans that is stretched, at the least. Since their current experiments relied on forming chimeric embryos and then culling to get the mice with XO genotype, then breeding, the technique is a real Rube Goldberg process. They note that it might be possible to generate eggs or sperm from human iPS cells and use those in IVF. While there is some evidence this might be possible, the authors themselves point out that deriving functional gametes from ES and iPSC cells has yet to be achieved, as well as the concern that lab-generated gametes might lack the maturation needed for normal development.
"It is also not clear if in vitro differentiated germ cells would acquire the appropriate epigenetic marks required for normal development. Perhaps in the future, it may be possible to generate human oocytes from iPS cells in vitro or through human-animal chimeras. However, in humans, a 45,X karyotype results in infertility."
That last little bit is also a problem. Mice with XO genotype are fertile females. Humans with XO genotype have Turner syndrome, a syndrome that includes infertility. So then a greater speculation--maybe they could add back an X or Y chromosome to the cells. Conceivable perhaps, but extremely difficult technically.
Maybe senior author Richard Behringer summed it up best:
"It has been a weird project, but we wanted to see if it could be done."