Engineered Eggs

Researchers in Japan have reported success in generating mouse eggs or oocytes from pluripotent stem cells. When fertilized, these induced eggs grew into live, healthy pups capable of producing their own offspring. The work is reported in the October 5 issue of the journal Science.

The research team used two different types of pluripotent cells, embryonic and induced. In both cases, they were able to produce cells that are the precursor of the cells of the ovaries, which form eggs. Once they produced these cells and grew them in clusters, they implanted them into the bodies of female mice, where they developed into cell structures that functioned like ovaries. From these reconstituted ovaries, researchers harvested mature oocytes, much as they would for in vitro fertilization (IVF).

The next step, predictably, was to fertilize these eggs and implant them in surrogate mother mice. Once born, the pups developed and were allowed to breed, producing viable offspring.

Pups from ES-oocyte. Female offspring from primordial germ cell-like cell-derived oocytes were fully fertile. Courtesy of Katsuhiko Hayashi.

The most immediate impact of this research will be to advance our understanding of the fundamentals of reproductive biology, especially the development of egg cells. If similar strategies will work with human pluripotent stem cells—especially induced cells—this research may open new approaches for reproductive medicine in the years ahead.

What other possibilities might there be? Again, if the work can be replicated in human beings, two things might happen. Somewhat more remote is the possibility that this strategy will be used for the purposes of human germline modification or so-called “designer babies.” For example, pluripotent stem cells might be genetically modified before they are induced to become the source of oocytes. The modification could be to avoid a disease or for the purposes of enhancement.

More likely, of course, is that this strategy will be used to create human oocytes for research purposes. For example, human induced ovary-like cells could be implanted into a mouse or other nonhuman animal, grown to the right stage of development, then “harvested” in order to collect a significant number of oocytes.

Today, research in certain areas is hampered because of limited supplies of human oocytes. One area that comes to mind is nuclear transfer or cloning. While “Dolly” the sheep is now only a distant memory, this advance brings closer the possibility that with an ample supply of human oocytes for experimentation, researchers will learn how to create human clones reliably.

So the big question is whether this research can be replicated in humans. On that point, here's how the article concludes: "our system serves as a robust foundatin to investige and further reconstitution femaile germline development in vitro, not only in mice, but also in other mammals, including humans."

The article, entitled "Offspring from Oocytes Derived from in vitro Primordial Germ Cell-like Cells in Mice," appears in the 5 October 2012 issue of the journal, Science.

Designer Babies Revisited

“Designer Babies” are back in the news. Scientists and medical experts in Australia have asked the government to allow the use of a controversial technique to allow couples to conceive without passing on a genetic disease.

The technique is controversial, at least in the media accounts, because the child that is conceived would have three parents.

The truth is a little more complicated but a lot less dramatic. Most of the genes in our cells are located in chromosomes, which we get from both our parents. A very few genes are located outside the chromosomes in small structures called mitochondria. These genes—our “mitochondrial DNA”—are necessary for energy production in the cell. If they are defective, the result can be a number of diseases.

We get our mitochondria only from our mothers. That means that if a woman has a defect in her mitochondrial DNA, she will inevitably pass it on to all her children, who may be more or less ill than she has been during her lifetime.

But what if a couple could conceive a child using their own chromosomal DNA while using a donor’s mitochondria? That would give the couple the best opportunity to have a child that is almost entirely “their own” genetically while avoiding diseases associated with mitochondrial irregularities. That’s the hope that doctors in Australia are holding out.

In 2001, word leaked out that a fertility clinic in New Jersey was quietly offering this technique. The report triggered a bit of a flap, mostly over issues of safety and the utter lack of government oversight or public moral reflection. The best account of that episode is found in an essay by Erik Parens and Eric Juengst, “Inadvertently Crossing the Germ Line,” appearing in the journal Science in April of 2001.

Is the strategy safe? Should it be permitted? Is it moral? Is “germline” modification in general ethically defensible? Is it religiously objectionable?

I try to address some of these questions in my 2008 collection of essays, Design and Destiny: Jewish and Christian Perspectives on Human Germline Modification. Among other findings: Catholic teachings may object to specific techniques but not so much to the core idea. As long is “in vitro” techniques are not used, what could be wrong with helping a couple conceive a healthy child? (See my earlier post.) But for all religious people, is there a line to be drawn between germline modification aimed at avoiding disease and the very same technique that might be used to produce a “better” child—one that is smarter or healthier than normal?

To be clear, the Australian scientists are proposing no such thing. But as they know, these techniques will likely advance along a common front. The minimal modification to avoid mitochondrial disorders will help pave the way to germline modification to avoid other diseases. And those techniques will almost certainly lead in time to the possibility of enhancing our offspring.

A New Approach to Enhancement?

Some people object to human germline modification because they do not like the idea of one generation messing with the DNA of future generations. Even worse, they say, is modifying the genes for the sake of…gasp!...enhancement!

But now comes a tantalizing study in tomorrow’s issue of Nature hinting at the possibility that what we do to live longer may change the lifespan of our grandchildren. It’s only a hint—the research reported here involves the faithful nematode, Caenorhabditis elegans. By exposing one generation of these tiny worms to just three proteins, researchers in Anne Brunet’s lab at Stanford produced worms that live up to 30% longer. The surprising thing is that the enhanced lifespan was passed to the next 2-3 generations. The really surprising thing is that the lifespan of the C. elegans great-grandchildren was enhanced even though no DNA sequences were modified. In other words: germline enhancement without genetic modification.

How is that possible? Epigenetics. The three proteins changed the way the DNA is structured or packed without changing the DNA code itself. Such epigenetic changes can change the way genes are expressed. The effect can be dramatic—in this case, a 30% longer lifespan. What’s more, the epigenetic change can be passed to future generations. Most often, epigenetic changes are reset during reproduction. But in some cases, epigenetic modifications are passed to the next 2-3 generations. When that happens, the structure and the expression of DNA are changed even though the DNA sequence remains unchanged. Over time, however, the effect washes out so that the great-great-grandchildren are back to the starting point.

Will this epigenetics-to-lifespan relationship be found in human beings? Who knows. Again, it must be repeated: this research involves flatworms. Humans are just a bit more complicated. Already, however, Brunet’s lab is looking for something similar in mice and in African killfish.

Whether anything similar will be found in human beings, this research already suggests a truly interesting thought experiment. Suppose this leads someday to a human-application technology. Would it be opposed by those who object to human germline modification? Sure, future human beings would be changed without their consent. But no genes are changed, and the changes are not permanent.

Perhaps the more sobering thought is this. Maybe this research will lead to a startling discovery. Never mind some new technology. Might it turn out that what health-minded human beings normally do—eat their green vegetables, get their exercise—has the effect of enhancing their offspring by modifying the expression of their genes by means of generating inheritable epigenetic changes? Could be. If just three proteins make C. elegans progeny live 30% longer, just imagine how your dinner might change your grandchildren (assuming, of course, that you’re in your reproductive years or younger).

The article, “Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans,” appears in the October 20 issue of Nature.