Stem Cell Advance and Cloning Debates

An important breakthrough in stem cell medical research is likely to re-ignite an ethical debate about human cloning. 

Researchers at the Oregon Health & Science University reported on May 15 that they have succeeded for the first time in human “somatic cell nuclear transfer” or SCNT, a process that the public often refers to simply as cloning.  Oregon researchers were able to transfer the nucleus from one human cell into a donated human egg from which the nucleus had been removed, essentially the same process that led to the creation of Dolly the sheep more than fifteen years ago. 

Caption: The first step during SCNT is enucleation or removal of nuclear genetic material (chromosomal) from a human egg. An egg is positioned with holding pipette (on the left) and egg's chromosomes are visualized under polarized microscope. A hole is made in the egg's shell (zone pellucida) using a laser and a smaller pipette (on the right) is inserted through the opening. The chromosomes then sucked in inside the pipette and slowly removed from the egg.  Credit: Cell, Tachibana et al. Usage Restrictions: Credit Required.

 

While other teams have achieved nuclear transfer with human cells, none has been able to produce an embryo that developed long enough to yield human embryonic stem cells.  The Oregon team, led by Shoukhrat Mitalipov, achieved this long-desired goal.

 

Even more remarkably, the Oregon team achieved SCNT repeatedly and with high efficiency, in one case producing a stem cell line for every two donated eggs. Along with other researchers around the world, Mitalipov’s team has discovered many ways to fine-tune the nuclear transfer process, making it far more demanding technically than when Ian Wilmut’s team first created Dolly.

But just as we learned from Dolly, any major technical advance in somatic cell nuclear transfer is likely to trigger public controversy about cloning and about the social impact of science.  While nearly everyone applauds the goal of the Oregon research—better understanding and treatment of disease—not everyone will like the way they went about their work.

For one thing, the result of successful nuclear transfer is a kind of embryo.  Mitalipov’s paper, published in the June 6, 2013 issue of the journal Cell (online on May 15), repeatedly refers to this new entity as the “SCNT embryo.”  Is a “SCNT embryo” a “real” embryo?  If an embryo is the result of fertilization, then of course a “SCNT embryo” is not a normal or real embryo.  But if an embryo is defined by its potential to develop, then a SCNT embryo probably is very close to a normal or real embryo, biologically at least.

Suppose we accept that a SCNT embryo is real enough to warrant the same protection as embryos created by IVF.  Is it legitimate to create such an embryo for the express purpose of research that will destroy this SCNT embryo?  Many people object to this, and major religious institutions such as the Catholic Church have been unambiguous in their denunciation of this research. 

On the other hand, a few religious groups have specifically endorsed this research.  One of the clearest statements of support is entitled “Cloning Research, Jewish Tradition and Public Policy.”  The statement, published in 2002, speaks for all major groups within American Judaism: 

Moreover, our tradition states that an embryo in vitro does not enjoy the full status of human-hood and its attendant protections.  Thus, if cloning technology research advances our ability to heal humans with greater success, it ought to be pursued since it does not require or encourage the destruction of life in the process.

Another statement in support comes from a study committee in the United Church of Christ, which released this statement in 1997: 

...we on the United Church of Christ Committee on Genetics do not object categorically to human pre-embryo research, including research that produces and studies cloned human pre-embryos through the 14th day of fetal development.”

For more religious statements on embryo research, check out God and the Embryo, especially the appendics. 

I personally agree with the statements quoted above.  So I support the research performed in Oregon.  But I have to admit that among people with religious commitments, I am in a minority.  As much as I wish it were otherwise, I expect that many will object to the idea that Mitalipov’s group has created and destroyed embryos for research.

Some will argue that the technology of induced pluripotent stem cells (iPSCs) makes the use of embryos unnecessary.  While it is true that iPSC technology is a remarkable and promising advance, so far the field has run into unexpected technical complications in its quest to produce pluripotent stem cells that function like cells from embryonic sources.  A great attraction of iPSCs—beyond the fact that no embryos are involved—is that they are a genetic match to the donor.  What the Oregon breakthrough provides is the best of both: embryonic quality in donor-specific cells. 

Others will object because they don’t like human cloning—understood now as the use of SCNT to produce a child.  They will see the Oregon breakthrough as ushering in the era human reproductive cloning, and they will see this as reason enough to ban any further advances in SCNT technology.

Far more sensible, I think, would be a moratorium on human reproductive cloning.  What the Oregon group has achieved does make it more likely that someone somewhere might try to offer cloning as a reproductive technology.  The problem is that using Mitalipov’s techniques, they might succeed in creating an embryo that survives but that is beset by many unforeseeable health problems.

If we have learned anything in the past fifteen years, it is that SCNT is a tricky and complex process.  Just because Mitalipov’s team learned how to create the SCNT embryo that is healthy and viable through the blastocyst stage does not mean that anyone knows how to create an SCNT child.  Too many things could go wrong, and only now are we beginning to get some idea of how these potential problems might arise.

Someday, many decades in the future, we may understand these problems so well that we can solve them technically.  If that day ever comes, then those who come after us will have to ask: is a cloned child a good idea.  Right now we do not even have to ask that question because an SCNT is an unsafe idea. 

The press release from The Oregon Health and Science University that announces this advance makes this claim:

One important distinction is that while the method might be considered a technique for cloning stem cells, commonly called therapeutic cloning, the same method would not likely be successful in producing human clones otherwise known as reproductive cloning. Several years of monkey studies that utilize somatic cell nuclear transfer have never successfully produced monkey clones. It is expected that this is also the case with humans. Furthermore, the comparative fragility of human cells as noted during this study, is a significant factor that would likely prevent the development of clones.

The Oregon release then quotes Mitalipov:

"Our research is directed toward generating stem cells for use in future treatments to combat disease," added Dr. Mitalipov. "While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning."

The article is entitled "Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer" and appears in the May 15 issue of the journal Cell. 

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.

Are Cybrids Even Possible?

A study published this morning by Robert Lanza's team at Advanced Cell Technology suggests that cybrids--a controversial attempt to create a cloned human/nonhuman embryo--may not even work.

What is a cybrid? The word is short for "cytoplasmic hybrid embryo." The idea is to use nuclear transfer or cloning to create a cloned embryo as a resource for stem cell research. But in the case of a cybrid, the human nucleus is transferred, not to an enucleated human egg, but to an egg from a cow or a rabbit.

Last year, the government of the United Kingdom, following a particularly nasty debate, passed legislation allowing researchers to create cybrids. No sooner had the legislation passed, however, that "induced pluripotency" became widely accepted as a technically easier way to achieve many of the goals that motivated scientists to want to create cybrids. Not just technically easier, of course, but morally easier, because induced pluripotency creates pluripotent stem cells without embryos--cybrid, cloned, or IVF.

Now comes the Lanza study, suggesting that the interplay between the human and nonhuman genes prevents the cybrid from developing at all, not even to the point of being useful for deriving pluripotent stem cells.

The whole cybrid question is intriguing theologically. Are they human, these strange entities that have human nuclear DNA but the mitochondrial DNA of a cow or a rabbit? For more on the religious and ethical questions, let me refer you to a statement that I helped to co-author, available through the International Society for Science and Religion. Sadly, the cybrid controversy marked a new low-point in the UK on the religion-science front, with the moral concerns of religious people often misconstrued as being anti-science. On the brighter side, the question of the cybrid challenges theology and ethics to engage research as it develops while asking the perennial questions, such as what does it mean to be human.