In a study published today in the journal Cell Stem Cell, a team of Harvard researchers reveals that the dubious stem cells created by Korean scientist Woo Suk Hwang were indeed historic, just not for the reason that he originally claimed.
In 2004, the world heralded Hwang, who reported that he had created the world's first human embryonic stem cells using a delicate cloning technique called somatic cell nuclear transfer (SCNT). If Hwang had actually done what he had claimed, he would certainly have brought stem-cell-based therapies closer to reality, by making it possible to develop patient-specific cells to treat diseases from diabetes to Parkinson's. Two years after his announcement, however, allegations of fraud led to an investigation by an independent committee of scientists, which failed to verify his findings, and Hwang and his feat were discredited; last year he and his principal researchers were fired from their posts at Seoul National University.
But the new study, led by Dr. George Daley at the Children's Hospital in Boston, shows that Hwang's stem cell line contains the first human cells to be generated not through SCNT, but through a process called parthenogenesis, sometimes referred to as virgin birth, since development is sparked spontaneously from the egg alone, rather than from the union of egg and sperm. Parthenogenesis is always a risk during nuclear transfer, since the process involves extensive manipulation of the egg and its nucleus. At the time that Hwang's original paper was published in Science, stem cell researchers raised the possibility that the cells had been generated by the egg alone, but the limited genetic analysis that Hwang provided appeared to rule it out. But, says Daley, "the data they presented was either wrong or fabricated."
Daley's subsequent detailed genetic analysis of Hwang's stem cells have clearly established that they come from a single egg, putting to rest nagging questions about what, if anything, Hwang and his team had actually accomplished. It may not have been Hwang's original goal, but successful parthenogenesis is no small feat. If he had reported it in 2004, says Daley, stem cell research might be much further along today and enjoying a better reputation. "If we had known three years ago that it was possible to generate stem cells through parthenogenesis, then we almost certainly would already have patient-specific embryonic stem cells by parthenogenesis by now," says Daley. "We might now have a means of generating stem cell lines from women who could donate eggs."
Dr. Renee Reijo Pera, director of the center for human embryonic stem cell research and education at Stanford University, agrees. "Hwang's actions were a great setback mentally for the nuclear transfer community," she says. "He really would have been far ahead of the rest of the field by just reporting these lines as parthenogenetic; they could have reported these legitimate results and been scientific heroes."
So, did Hwang know what he had accomplished and purposefully suppress that knowledge? Or did he stumble into the parthenogenetic breakthrough by accident, oblivious to the biological milestone? While Hwang has not commented on his work apart from apologizing for his actions in 2006, most experts believe that he and his team were unaware of their achievement.
In nuclear transfer, stem cells are created by inserting the nucleus from a donor's cell, usually a skin cell, into an egg cell, whose DNA-containing nucleus has been removed. The new cell then starts to divide and produce stem cells. In some cases, however, through mistakes in the nuclear-transfer process, eggs may begin dividing on their own. And Hwang may have increased his chances of parthenogenesis by using the gentler, squeezing technique he pioneered to remove the egg's nucleus; the process may have actually left behind enough genetic material for the egg to spontaneously divide. "As the egg starts to mature, [these elements] migrate and after about an hour, you can remove 30% of a primate's egg cytoplasm, for example, and not successfully remove the entire nucleus," says James Byrne, a stem cell postdoctoral fellow at Stanford University who studies parthenogenesis in primates.
To find out whether Hwang's stem cells came from a single egg, Daley's team, which included leading researchers from England, Japan and Canada, conducted a whole-genome analysis of the DNA from Hwang's stem cell line. By analyzing tens of thousands of gene snippets on the cells' genomes, and comparing these signatures to those of the egg donor and of the skin cell donor, they were able to determine that the DNA fingerprint of the stem cells was consistent with that of the egg. "The genetic signature of a parthenote is very very obvious," says Daley. Because the genetic material in parthenotes comes only from the egg, they are missing key genes for development that normally come from the sperm, and therefore their genetic profiles are very distinctive.
Now that parthenogenetic stem cells have been discovered, will we finally begin to see the kind of individualized treatments for diabetes, Parkinson's, Alzheimer's and spinal cord injuries that science has promised? Probably not. Although parthenogenesis is easier to achieve than nuclear transfer about 20% of the time, eggs can be stimulated to divide on their own, compared to a 3%-5% development rate for nuclear transfer embryos parthenogenesis still requires a steady supply of good quality human eggs. These are notoriously difficult to obtain, so the technique won't likely revolutionize medicine yet. But, suggests Daley, it could be used to help alleviate the organ-donation shortage in the U.S.: parthenogenetically created transplant tissues and organs can be banked and later matched on major immune markers to many different patients. It's not quite patient-specific medicine, but it is one step closer.