Human Stem Cells From Cloning, Finally
Damien Marsic
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Source: http://www.sciencemag.org/content/340/6134/795.full
Vol. 340 no. 6134 p. 795
DOI: 10.1126/science.340.6134.795
Human Stem Cells From Cloning, Finally
This time it looks like it's for real: Researchers have made personalized human embryonic stem (ES) cells with a method similar to how Dolly the sheep was cloned—though with an added jolt of caffeine.
The success, which produced stem cells carrying DNA belonging to a baby with an inherited disorder, comes 9 years after South Korean researchers claimed in a famously faked paper that they had achieved a similar feat. After their story unraveled, a handful of researchers continued trying, but human eggs, or oocytes, responded poorly to the techniques that have worked in sheep, mice, cows, pigs, and other animals.
Now, thanks to years of work in monkey cells, a group led by Shoukhrat Mitalipov of the Oregon National Primate Research Center in Beaverton reports a recipe that works for human cells. In a paper published online by Cell on 16 May, the scientists describe removing the DNA-containing nucleus from human oocytes and then fusing them with either fetal skin cells or skin cells from an 8-month-old baby, producing embryos that carried DNA from the skin cells. They were then able to use those embryos to derive ES cells, which in theory can form any of the body's cell types. "It's a fantastic paper," says Dieter Egli, who studies somatic cell nuclear transfer (SCNT)—the technical term for the cloning technique—at the New York Stem Cell Foundation. "We are looking forward to replicating their results." The result is "a hard-won triumph after many years of diligent research," adds George Daley, a stem cell researcher at Children's Hospital Boston.
While welcomed by many researchers, who envision creating personalized stem cells for therapies or research, the achievement is also likely to stir up old ethical debates about human SCNT, including whether it should be regulated to prevent attempts at reproductive human cloning. In the short term, that shouldn't be a worry, Mitalipov says. Despite more than 100 tries, he and his colleagues have not managed to get any SCNT-derived monkey embryos to implant in a surrogate mother and trigger pregnancy. The cells that give rise to the placenta are underdeveloped in the cloned monkey embryos, he says, and the human SCNT embryos have similar abnormalities.
Those issues don't seem to interfere with deriving stem cells from the embryos. In some experiments, half of the human SCNT embryos that developed to the blastocyst stage (when the embryo forms a hollow ball of cells) gave rise to stable ES cell lines, Mitalipov and his colleagues report.
Given the years of unsuccessful tries, the team had surprisingly good success generating embryos. Fragile human oocytes are easily damaged by the manipulations necessary for nuclear transfer, so the researchers made several tweaks to the process based upon their monkey work. Instead of using an electric pulse to fuse the enucleated oocyte and the nuclear donor cell, they exposed the cells to surface proteins from an inactivated virus, an old technique that had fallen out of favor after Dolly was born. They also added caffeine to the medium that bathed oocytes during the nucleus removal and cell fusion. The caffeine stabilizes key molecules in the oocyte cytoplasm that help reprogram the fused cells into an embryonic state, Mitalipov says. Without caffeine, only 11% of the SCNT embryos developed to the blastocyst stage, and none of them produced ES cells. With caffeine, 23% of the SCNT embryos formed blastocysts, and half of them produced ES cells.
This high efficiency could mean that SCNT is not as impractical for creating personalized human stem cells as many observers had expected. But it faces stiff competition from the current method of making genetically matched pluripotent cells, called induced pluripotent stem (iPS) cells. By adding extra copies of several genes to skin or other cells, scientists can reprogram them to behave like ES cells. That technique is much easier than SCNT, and it doesn't require a supply of human oocytes. (The oocytes used in Mitalipov's experiments were donated by healthy volunteers for research purposes; donors were paid $5000 for their time and trouble, the local rate paid to egg donors for fertility treatments.)
Some researchers have found evidence, however, that there may be subtle but potentially significant differences between the genes expressed in iPS cells and ES cells derived from embryos. The chance to compare SCNT-derived human ES cells with iPS counterparts is one of the most important aspects of the new advance, Daley says. "There may be advantages to SCNT-ES cells, but this must be rigorously proven," he says. In practice, he says, making iPS cells "remains considerably easier."
Rudolf Jaenisch, who studies cellular reprogramming at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, says he doubts that human SCNT will be widely used. "For practical reasons, I don't think it will play a major role." Egli and Mitalipov see things differently. "We don't know whether one or another technology has an advantage," Egli says. "I see them as both very useful."
The use of the baby's DNA offers a
therapeutic proof of principle, but the researchers have not yet shown
that the technique
works with adult cells as nucleus donor cells. In
previous experiments, it has been easier to clone fetal cells or those
from
young animals than those from adults. "It needs to
be shown that it works with more cells of various ages," Egli says. "But
I expect it does."