Turning skin into sperm

Eggs and sperm are pretty special cells. They are the chains that link one generation to the next. In a sense they are our immortal parts, with some living on in our children, and some of theirs carrying on in yet the following generation, and so on. The scientists that study these cells consider them the most important cells of the body. Without them our species would cease to exist.

Infertility is a devastating condition for couples that desire children. They will go to great lengths to overcome the problem. About one percent of all births in the US are the result of in vitro fertilization procedures. But even these so called test tube babies can only be made if the parents produce eggs and sperm. If the male, for example, makes no sperm, then all current procedures fail.

A remarkable breakthrough in the test tube creation of sperm has been reported in the Aug. 19 issue of the prestigious science journal “Cell”. A group working at Kyoto University, including Katsuhiko Hayashi and Mitinori Saitou, discovered how to turn stem cells into sperm. They worked with the mouse model organism, but there is no reason to think that the same developed methods won’t also apply to humans.

This group and others had been previously studying the normal progressive process that creates sperm. It had been shown that in the embryo the stem cells that will normally give rise to sperm are sequentially exposed to a series of signals including the Wnt, Activin and FGF, BMP4 and LIF growth factors. By recapitulating this natural plan in the petri dish they found they were able to convert a small percentage of stem cells into primordial germ cells, the precursors to sperm. They were able to actually sort out just the primordial germ cells based on their surface properties, and then they injected them into the testicles of mice that could not make their own sperm. Amazingly, the injected cells made sperm and the mice became fertile.

This work was first carried out using embryonic stem cells, which are natural stem cells that were isolated from mouse embryos. This is great from a science perspective, but it wouldn’t be of much use for an adult male, with his embryonic stem cells long gone. The Kyoto group therefore repeated the experiments starting with stem cells that had been made from adult cells. Yamanaka had shown previously that it is possible to treat adult cells, such as skin cells, with a special gene expression cocktail and to turn them into the functional equivalent of embryonic stem cells. See my blog on “Why Yamanaka will win the Nobel Prize” for details. Anyway, they showed that the procedure worked just as well with stem cells made from adults.

The implications of the work are enormous. In a few years, as these procedures are translated from the mouse to the human, it might become possible for men that don’t make sperm to father children. This could provide considerable benefit for otherwise infertile couples.

It also opens up some interesting possibilities concerning designer genes children. Scientists are already incredibly proficient at the genetic engineering of stem cells. Over ten thousand genes have been modified in mouse stem cells, and then the cells were used to make mice, which then revealed the functions of the genes. It now appears possible to take skin cells from adults, to turn them into stem cells, which can then be genetically manipulated, and turned into sperm. That is, it now appears possible to make designer genes sperm.

As we better learn the complex relationships between DNA sequence and traits, such as longevity, health, looks, athletic performance and intelligence, it will become possible to engineer sperm that will produce children with desired features. This strategy is much more ethically appealing than more traditional designer genes baby approaches, which typically involve the genetic screening of many embryos to find those with the preferred gene combinations. The problem, of course, is that those embryos without the wanted features are discarded.

But the designer genes production of sperm, and eventually eggs, avoids these ethical concerns. All of the genetic engineering and selection occurs before any embryos are made. No life is lost. No embryos are harmed. What is not to like?

2 thoughts on “Turning skin into sperm”

  1. Amazing article,as an engineering genetics student, I hope this would become as an alternative to those infertile couples!

  2. Nice entry, thank you for posting.

    Just a few comments:

    1) for many infertile couples third party donation is a real possibility. If a man des not produce sperm a sperm donor can be found, same thing with oocyte donors. It’s very common in some countries, not so much (or illegal) in other. Those countries in which it is illegal (like mine), however, also usually tend to discourage pluripotent cell research as well.

    2) Apart for the ethical issues involved, according to current regulation in the Europian Union and to some extent in north America, no reaserch that aims at genetic modification of human cells in a way that is inheritable to the following generation(s) can be funded by public money. As this is the main source of funding for research in many countries, it will probably be a long time before any of this will become available to any infertile couple.

    3) Because of the inherent difference in stem cell (and iPS) state between mouse and human (I am referring to the more “epiblast-like” nature of human stem cells), it is not a safe assumption to make that making gametes from human cells will be more or less the same as for mouse cells. Human pluripotent cells are actually known to be quite bad at differentiating towards gametes.

    4) It is important to always remember that during physiological gametogenesis a very large amount of sperm and eggs are lost, possibly due to a very carefull quality control mechaism. This is impossible to mimic in vitro (since we know almost nothing about it), and the only way we have to know if we made good quality sperms in vitro is to see if they work (can fertilize), and the fetus develop more or less normally. Not the kind of QC you want to have in a patient…

    5) we have become very good at genetically modifying mouse stem cells. With human ones, it’s a complete different ballgame. It’s highly inefficient, the genes get silenced very fast, it is much harder to direct insertion into specific loci, etc…so much that people are trying very hard to make human stem cells behave like mouse ones so that they can actually do some decent genetic engineering with them.

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