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The report of sperm cells created from skin cells may appear amusing at first blush. I was certainly guilty of a reflexive guffaw, which was promptly replaced by shame as I realize what it meant for male infertility caused by cancer or chemotherapy. I cannot stress enough what a significant step this is in stem cell biology because making germ cells in a lab has been notoriously difficult, and is even harder to prove.
Previous studies relied heavily on protein or gene expression changes to track germ cell development. But when they are investigated further, the cells are found to be trapped in an immature state and don't progress to form functional, mature cells (a very common problem in stem cell biology). Why is that?
First, any gene/protein expression changes are only temporal and may be caused by any number of reasons other than changes in cell identity. In other words, gene/protein expression changes are like putting on a costume and makeup to play a character. But the get-up doesn't do anything to change the underlying identity of the player.
Another reason for the difficulty is because nature has taken special care to separate germ cells from all the other cells in the same organism, mainly because germ cells are the repository of genetic information for an entire species. But how is that possible when cells in the same organism share the same genetic code? The answer is epigenetics, which essentially places chemical tags directly onto the DNA in distinct patterns. These tags form the basis to molecularly distinguish germ cells from somatic cells (the same is true for stem cells/pluripotent cells, which also have a unique pattern of chemical tags on their DNA to set them apart from other classes of cells). For previous studies that produced only immature cells, it's often found that the epigenetic patterns of those cells were not consistent with those of the matured cells, indicating their underlying identity didn't change even though they expressed the expected protein markers.
The fact that Easley et al. found a similar epigenetic pattern between normal sperm and lab-made sperm was a significant breakthrough, and makes this paper special because it strongly suggests an underlying change in cell identity. However, they compared the epigenetic patterns of only two separate DNA loci and that's just too few to call it solid evidence. But their claim for producing mature sperm cells is certainly bolstered by the data presented on both the epigenetic and protein levels.
But my suspicions were raised by their claim to have directly differentiated their pluripotent cells into matured sperm cells, without going through pre-germ cell intermediates. Think of it as an express train that's able to go directly from Point A to Point B without stopping at all the other stops along the way. Why is this important, you may ask? It's all for the sake of efficiency. Cells tend to be lost in a long differentiation process, especially if it has multiple stops. The cells may simply die along the way, or some cells may spontaneously differentiate into cell types you don't want and will have to be separated out and discarded later. If you can get a lot of high-quality cells from the get-go, then it's more likely to be applicable in a clinic and may yield a better success rate when introduced to patients.
I just can't help wondering if the direct differentiation claim may be a bit overblown because it may be we simply can't see those earlier stops, rather than because there are actually fewer stops. If you look at the data in Figure 1, you'll see roughly 40%-60% of the cells were positive for the germ cell marker VASA. While those percentage are quite impressive; what about the rest? What did those turn into? It is also possible for their pluripotent cells to develop faster in a dish, and their speedy progress mask the existence of brief stops.
Bottom line: the claim for making mature sperm cells is probably true, but I'm not convinced that direct differentiation is actually taking place. In any case, direct differentiation is more of a technical concern and doesn't mean a whole lot in practical terms when the goal is to make viable and functional sperm cells.
References
Easley CA 4th, et al. Direct Differentiation of Human Pluripotent Stem Cells into Haploid Spermatogenic Cells. Cell Rep. 2012 Aug 21. [Epub ahead of print]
