Germ cells from “ethical” stem cells

What expertise I have is not in cell or developmental biology, nor in stem cell research.  But I try to follow developments.  As I do, I’m learning two humbling lessons:  it’s next to impossible to keep up, and you can’t make this stuff up.

Consider the work, summarized in a report in Nature last week (accessible to the public without subscription), regarding the use of stem cells to study how germ cells (sperm and eggs) arise in embryonic development.  Over the past decade or so, scientists in Japan have been studying germ cell development in mice.  It turns out that oocytes develop in the ovaries, and sperm in the testes, from more primitive germ cells called primordial germ cells, or PGCs for short.  It further turns out that mouse embryonic stem cells can be coaxed to develop into PGCs in the laboratory by applying a single protein, called bone morphogenic protein 4, at just the right time.  Once the scientists had found this out, they wanted to know whether the PGCs they had developed in the lab were for real.  The “proof of the pudding” in this case is to show that the PGCs can develop into mature sperm or eggs.  This, they cannot do in the lab (at least not yet).   So they injected their PGCs into the sperm or ovaries of otherwise infertile male and female mice, respectively.  And, lo and behold, they not only got mature sperm and eggs, but those sperm and eggs were able to fertilize eggs or sperm (more conventionally obtained) in vitro to generate mouse embryos, which developed to full term mouse pups when implanted into the uterus of a female mouse.

Now, initially, they started with mouse embryonic stem cells, obtained from an actual embryo (a process likely, at least, to destroy the embryo).  But they got the same results when they started with skin cells from mature mice and “reprogrammed” them into the “ethical” stem cells, induced pluripotent stem cells (iPSCs).  So, one could conceive of starting with a skin cell from a male and deriving an egg—a female gamete—from it through the iPSC route, while, conversely, sperm could be derived starting with skin cells from a female.  The possibilities, reports Nature, led the researchers to be deluged with inquiries from infertile couples, as well as from gays and lesbians interested in the ultimate prospects.

Well, the here to there—from mouse experiments to a new human assisted reproductive technology (ART)—is far from straightforward.  The Nature report lays out some of the issues:

  • Mice are not people (i.e., humans—they say “humans,” I say “people”), and in a very real sense, getting the same results in humans means going back to the beginning.  There is no guarantee that the step(s) from human pluripotent cells to human PGCs is as simple as it turns out to be for mice.
  • The scientists have not figured out, even for mice, how to get mature gametes from PGCs without implantation into ovaries or testes—kind of a critical step.
  • A next step would be to try to repeat the same thing in monkeys.  The scientists have gotten monkey embryos, and think that it will take another 5-10 years to repeat the work in monkeys.  It is assumed that going from monkeys to humans will only require “small tweaks,” because we’re both (humans and monkeys) primates, after all, and humans are biologically much closer to monkeys than to mice, but how easily monkey results would be translated to man remains to be determined.
  • Oh, one other thing—in the mice, the pups born from the stem-cell-derived PGCs→germ cells appear normal, but their offspring are not; their PGCs often produce fragile, abnormal eggs that give rise less frequently to normal third-generation offspring.  Translation: it’s conceivable that your kids by this method might turn out OK, but no guarantees about the grandkids.

This is an example of new science raising ethical concerns that are not urgent today, but can creep up on us eventually if neglected while the technical work proceeds.  We can bet the work will proceed.  There is no guarantee it will give rise to a viable human ART.  But a few thoughts on the ethics:

  1. The initial work in mice does not appear to be unethical at all—certainly not in methods, and apparently not in intent—the researchers were trying to understand biology, and they say they are not trying to exploit it.
  2. Similarly, I would not condemn similar studies in primates, but I would ask, “why do we need to know?”  If the only answer is, “so we can do this in man,” then I would challenge the ethics of the aims of the research.
  3. iPSCs may be ethically-derived stem cells, but that does not mean that they do not raise ethical issues.  (I have seen this point raised by scientists in the general press—for example, in a Scientific American article a couple of years ago—but I don’t have the reference at hand.)
  4. We should recall that iPSCs are not a panacea.
  5. An obvious ethical objection to an eventual attempt to apply this work to humans is that the risks to the children to be born cannot be clearly estimated or fully understood, and therefore neither described in informed consent nor minimized.  A response to this would be to propose extensive studies in monkeys, with observation of multiple generations, and use of preimplantation diagnostic techniques (genetic and otherwise) to select only those human embryos from IVF that are determined to be normal or to have the best chance of being born healthy.   This line of objection mirrors the line taken by Paul Ramsey against IVF in the 1970’s—there was risk of unacceptable harm to the intended offspring—but the rejection of moral status to the unborn plus the birth of a healthy Louise Brown (“the first test tube baby”) in 1978 together were taken to refute the objection, and IVF is common today, with many live births that are entirely normal as far as we know.  In this case, I’d tend to argue for the moral status of the embryo, and against the notion that we could ever really have sufficient evidence of the safety of the procedure for the offspring or their descendants.   It may be an argument I get the opportunity to make in my lifetime.  Or not—we will see.
  6. Turning this line of research into a new human ART would be another method of turning children into manufactured products instead of begotten results of the union of two parents.  I would argue that this point would be sufficient to proscribe the approach even in the context of a faithful, monogamous, traditional, Christian marriage beset by infertility.
  7. Some of the permutations of the approach that may be envisioned raise the objections about confusion of parentage that have been raised against human cloning and some other approaches to ART.
  8. And finally, and of course, the ultimate argument against applying this approach to people is that we ought to take a more “essentialist” line of human nature, and the created human order, and recognize the natural order of begetting children as erecting boundaries that must not be tested, much less encroached or crossed.  But, also of course, you have to believe in God to think that; it won’t fly with a naturalist.

Again we are on ground where we ought to fear to tread, and which should prompt us to say, quickly and without reservation, “we shall not.”

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Susan Haack

Thanks for providing new and informative research–with reflection–information I would not have encountered for some time. As I ponder what you have said, I am reminded of how intricately interconnected all of life is. We cannot blithely alter one aspect of an entity without short- and long-term ramifications, many of which we are blindly unaware.