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. 

Chimeric Monkeys? Where Do We Go From Here?

What is a “chimeric monkey”? Why would anyone want to create them? And why should anyone care?

In ancient myth, a chimera was an animal with a human head and, say, the body of a horse or a lion. That’s not what’s going on here.

In biology today, a chimera is an animal that comes from two or more embryos. This happens naturally, when twins are conceived but the two fertilized eggs fuse into one embryo, eventually producing one individual.

In research, scientists create chimeras in order to study how cells function. Mice chimeras are now commonplace in stem cell labs around the world. Researchers add stem cells to an early-stage mouse embryo (a blastocyst). If the experiment goes well, the developing mouse will have cells from two sources: the “host” embryo and the implanted cells. The implanted cells often integrate into the body and brain of the mouse pup. By this test, researchers know that the implanted cells are truly stem cells—or, more precisely, that they are pluripotent, capable of becoming any type of cell in the mouse body.

Caption: Chimero, a chimeric Rhesus monkey produced by aggregating six Rhesus blastocysts. Photo credit: OHSU.

Researchers also implant human stem cells into mice. If they multiply and are fully integrated into the body, it’s pretty clear that they are pluripotent and capable of functioning within a living biological system and not just in a dish in a lab. In that case, the mouse is an “inter-species” chimera. Two embryos, of course, but from two different species, human and mouse.

For all the ways in which mice resemble human beings, there are big differences, some of which are particularly noticeable at the earliest stages of life. So when researchers at the Oregon National Primate Research Center at Oregon Health & Science University tried to put pluripotent monkey stem cells into monkey blastocysts, they failed. At the blastocyst stage, Rhesus monkeys don’t behave like mice.

The Oregon team, led by Shoukhrat Mitalipov, kept trying other approaches, finally discovering a completely different technique. Instead of using embryonic or pluripotent stem cells and adding them to a blastocyst, they backed things up, at least in terms of embryonic development. How far back? All the way to the four-cell stage. When a Rhesus monkey egg is fertilized (in this case, in a lab dish), it divides into two cells, then four. What happens if two cells in one blastocyst were combined with two cells from another blastocyst? Success—but still only partly so.

So they tried another approach, one that seems complex and counterintuitive. Researchers “aggregated” three blastocysts—and “they” began to function as one embryo. Four blastocysts—same result. Five, even six blastocysts. They did this 29 times and produced 29 viable chimeric embryos. Or to quote the original paper: “Remarkably, all 29 aggregates developed to blastocysts…”

Just what will this mean for the field of stem cell research? At the very least, this research points to the complexity of living biological systems. It’s nice to think that researchers can extract pluripotent stem cells, keep them multiplying indefinitely, direct them to develop just the right way, and implant them into the human body to regenerate tissues. If only it were that simple. As the field advances, it is clear that what was once called “pluripotency”—the ability to become any cell type—is anything but clear or simple to define.

All the more reason, I believe, why the field needs to move forward as a whole. It’s morally and scientifically simplistic to say that the field can advance without cells from embryos.

But does the Oregon work suggest a step too far? For many, it may be morally permissible to work with cells derived from blastocysts, perhaps donated from IVF clinics and due to be discarded anyhow. But what the Oregon work seems to signal is that when it comes to primates—including human beings—the cells in the living blastocyst are significantly different from the cells derived from the blastocyst. The cells in the living blastocyst, though dynamic and changing, can be regarded as totipotent, capable of becoming any cell type including the placenta and umbilical cord. Cells derived from the blastocyst—human “embryonic” stem cells or pluripotent cells—have lost part of this potential.

Does this mean that research, in order to go forward, needs access to cells as they exist in living blastocysts? That would be a step clearly beyond federal funding guidelines (the “Dickey-Wicker Amendment”). Even with private funding, it would likely exceed what most Americans can support. In some states and many countries, it would be plainly illegal.

And yet this is exactly what lead Oregon researcher Shoukhrat Mitalipov seems to have in mind. "We need to study not just cultured embryonic stem cells but also stem cells in embryos,” Mitalipov said in a release from the journal Cell. “It's too soon to close the chapter on these cells." Is that OK as long as he sticks to non-human primates?

Mitalipov is clearly right: "We cannot model everything in the mouse." Rodents and primates are different in unexpected ways at the earliest stages. Stem cells inserted in mouse blastocysts form chimeras, but not in primate blastocysts.

Quoting Mitalipov once again: "The possibilities for science are enormous." All the more reason to think this through. As complex as the science might be, the moral and religious implications are even more complex.

I for one need time to think this through. I hope to be back here before long with some more thoughts. For now, let me recommend a statement that I helped prepare a few years ago on the question of chimeras.

The paper, "Generation of Chimeric Rhesus Monkeys," was released on January 5 and will appear in the January 20, 2012 issue of the journal, Cell.