Pluripotency: the third option?
Posted by Elie Dolgin
[Entry posted at 16th June 2009
The excitement surrounding cellular reprogramming and the possibility of federal funding for human embryonic stem cell (ESC) research in the US could be overshadowing another promising therapeutic source of stem cells: those derived via parthenogenesis, some researchers say. But later-developed techniques such as induced pluripotent stem cells (iPSCs) could make this approach obsolete, and the final draft of the stem cell guidelines, due out by July 7, might put the nail in the parthenote coffin.
"Parthenotes will probably be as good as the two other alternatives" -- ESCs and iPSCs -- for cell replacement therapies, Shoukhrat Mitalipov, a developmental biologist at the Oregon National Primate Research Center, told The Scientist. "The advantages are much more attractive than the limitations of these cell lines."
So what are the advantages? First, parthenogenetic embryonic stem cells (pESCs) are derived from unfertilized eggs and can never form viable embryos, which means they circumvent the ethical issues that have dogged ESCs. They also have broader immunological matching potential than any other type of stem cell because some pESCs harbor a duplicated haploid genome. This leads to high rates of homozygosity, including at major histocompatibility genes, so these cells might pose less risk of tissue rejection.
But the published literature on pESCs is "rather scanty," noted John Gearhart, director of the University of Pennsylvania's Institute for Regenerative Medicine. The hundreds of well-characterized ESC lines created from fertilized embryos and the promise of iPSCs render parthenote-derived stem cells "less significant," he said. What's more, the utility of pESCs is hampered by potential safety concerns associated with incorrect imprinting, a shortage of eggs, and a lack of federal funding, many stem cell scientists point out.
In 2007, two Chinese research groups and a third team in the US and Russia independently reported the first fully characterized human pESCs (papers here, here, and here). All three groups created embryos by activating unfertilized eggs with chemicals rather than fertilizing them with sperm. (Ironically, parthenotes were actually first created earlier than that: Harvard University's George Daley showed that Hwang Woo-Suk's allegedly cloned cell lines were in fact the world's first pESCs, although Hwang didn't know it at the time.)
The findings marked "the beginning of a new era in [human embryonic stem] cell research," Linzhao Cheng, a stem cell biologist at Johns Hopkins University School of Medicine, wrote in a 2008 commentary. The stem cell field was abuzz with the potential for making customized stem cells, and after the myriad attempts at deriving patient-specific ESCs from nuclear cloning had either failed or been notoriously fabricated, parthenotes seemed to provide a way forward. Both cloned and parthenogenetic ESCs share a common limitation -- they require unfertilized eggs -- yet whereas thousands of eggs are needed for nuclear cloning, and it's never been shown to work, only a handful of eggs are sufficient to make a viable pESC line. "Parthenotes are much more efficient and require very little expertise," said Mitalipov.
But cellular reprogramming, which arrived on the scene later that year in the form of embryonic-like iPSCs, promised the ability to create perfectly matched stem cells for any donor, not just reproductive-age women, and with normal, biparental imprinting patterns. The advent of iPSCs means it's "harder now to justify" pursuing pESCs for therapeutic applications, said Jose Cibelli, a stem cell researcher at Michigan State University in East Lansing.
That doesn't mean we should abandon pESCs altogether, though, Cibelli stressed. "We should produce more [pESC] cell lines for some of the basic scientific questions," he said. Tiziana Brevini, an embryologist at the University of Milan, Italy, noted that parthenotes can be used to study the effects of asymmetric imprinting, genetic homozygosity, and drug toxicity on early embryonic development, but "I would be extremely cautious to suggest their use in therapy," she said.
International Stem Cell Corporation (ISCO) feels otherwise. The publicly-traded southern California-based biotech company has been on the stump for parthenotes, arguing that only pESCs have broad immune matching potential. iPSCs do provide a perfect immunological match for the patient from which they are derived, but for use in different patients, ISCO says, they will share the same problems of tissue rejection as other cell types. "Parthenogenetic stem cells really provide the only viable method for creating a true stem cell bank from which any patient who needs a cell based transplant can get cells that match his immune system," said ISCO chairman and CEO Kenneth Aldrich. The company has one cell line that matches more than 300 million people, Aldrich said. A strategically selected portfolio of 100 cell lines would be sufficient to cover the vast majority of the world's population, he noted, but trying to do the same with ESCs or iPSCs would require at least 10 times more cell lines.
UPenn's Gearhart remains skeptical. "We need a heck of a lot more work to really establish that [pESCs] are the same thing [as ESCs]," he said. "Number one, it's a safety issue, and number two, you'd want to know how well these things are going" to form the specialized cell types that clinicians would like to transplant for cellular therapies.
ISCO, which claims to have filed the first patents for deriving human pESCs in 2006, is currently testing pESC-derived retinal cells and liver cells in animal models. "Every indication we have is that they definitely are [safe]," said Aldrich. "We have found thus far no evidence whatsoever that there is an imprinting issue that adversely affects the cells." Mitalipov noted that many experiments show that pESCs can differentiate into any cell type in the body, just like ESCs. "There is no deficiency found, at least in vitro," he said. "These cells are actually functional."
ISCO also plans to supply its cells to researchers investigating potential cell therapies. But there's a hitch. Under the 1995 Dickey-Wicker amendment, taxpayer-backed grants cannot be used to create any embryos, including parthenogenetic ones. What's more, even existing pESC lines would not be eligible for federal funding under the National Institutes of Health's proposed guidelines, which are currently being weighed against a flood of some 49,000 comments that the agency received last month. "It will be a tragedy for the country" if the NIH doesn't amend its draft guidelines, Aldrich said. "It would force us to do a lot of things overseas that we'd rather be doing domestically."
Ronald M. Green, a bioethicist at Dartmouth College in New Hampshire, said that banning funding for pESCs is based on "uninformed apprehensions" that parthenotes might form viable embryos. "Ethically, it's unobjectionable in a deep sense" to fund pESCs, he said. "Sex cells are routinely destroyed and [creating parthenotes from unfertilized eggs] raises no ethical problems."
The jury's still out on whether pESCs will ultimately be used for transplantation or if the cells will remain confined to the culture dish. Either way, most researchers agree that the cells' full potential -- whatever it is -- will only be realized with sufficient government-backed funding for basic research.
Posted by Elie Dolgin
[Entry posted at 16th June 2009
The excitement surrounding cellular reprogramming and the possibility of federal funding for human embryonic stem cell (ESC) research in the US could be overshadowing another promising therapeutic source of stem cells: those derived via parthenogenesis, some researchers say. But later-developed techniques such as induced pluripotent stem cells (iPSCs) could make this approach obsolete, and the final draft of the stem cell guidelines, due out by July 7, might put the nail in the parthenote coffin.
"Parthenotes will probably be as good as the two other alternatives" -- ESCs and iPSCs -- for cell replacement therapies, Shoukhrat Mitalipov, a developmental biologist at the Oregon National Primate Research Center, told The Scientist. "The advantages are much more attractive than the limitations of these cell lines."
So what are the advantages? First, parthenogenetic embryonic stem cells (pESCs) are derived from unfertilized eggs and can never form viable embryos, which means they circumvent the ethical issues that have dogged ESCs. They also have broader immunological matching potential than any other type of stem cell because some pESCs harbor a duplicated haploid genome. This leads to high rates of homozygosity, including at major histocompatibility genes, so these cells might pose less risk of tissue rejection.
But the published literature on pESCs is "rather scanty," noted John Gearhart, director of the University of Pennsylvania's Institute for Regenerative Medicine. The hundreds of well-characterized ESC lines created from fertilized embryos and the promise of iPSCs render parthenote-derived stem cells "less significant," he said. What's more, the utility of pESCs is hampered by potential safety concerns associated with incorrect imprinting, a shortage of eggs, and a lack of federal funding, many stem cell scientists point out.
In 2007, two Chinese research groups and a third team in the US and Russia independently reported the first fully characterized human pESCs (papers here, here, and here). All three groups created embryos by activating unfertilized eggs with chemicals rather than fertilizing them with sperm. (Ironically, parthenotes were actually first created earlier than that: Harvard University's George Daley showed that Hwang Woo-Suk's allegedly cloned cell lines were in fact the world's first pESCs, although Hwang didn't know it at the time.)
The findings marked "the beginning of a new era in [human embryonic stem] cell research," Linzhao Cheng, a stem cell biologist at Johns Hopkins University School of Medicine, wrote in a 2008 commentary. The stem cell field was abuzz with the potential for making customized stem cells, and after the myriad attempts at deriving patient-specific ESCs from nuclear cloning had either failed or been notoriously fabricated, parthenotes seemed to provide a way forward. Both cloned and parthenogenetic ESCs share a common limitation -- they require unfertilized eggs -- yet whereas thousands of eggs are needed for nuclear cloning, and it's never been shown to work, only a handful of eggs are sufficient to make a viable pESC line. "Parthenotes are much more efficient and require very little expertise," said Mitalipov.
But cellular reprogramming, which arrived on the scene later that year in the form of embryonic-like iPSCs, promised the ability to create perfectly matched stem cells for any donor, not just reproductive-age women, and with normal, biparental imprinting patterns. The advent of iPSCs means it's "harder now to justify" pursuing pESCs for therapeutic applications, said Jose Cibelli, a stem cell researcher at Michigan State University in East Lansing.
That doesn't mean we should abandon pESCs altogether, though, Cibelli stressed. "We should produce more [pESC] cell lines for some of the basic scientific questions," he said. Tiziana Brevini, an embryologist at the University of Milan, Italy, noted that parthenotes can be used to study the effects of asymmetric imprinting, genetic homozygosity, and drug toxicity on early embryonic development, but "I would be extremely cautious to suggest their use in therapy," she said.
International Stem Cell Corporation (ISCO) feels otherwise. The publicly-traded southern California-based biotech company has been on the stump for parthenotes, arguing that only pESCs have broad immune matching potential. iPSCs do provide a perfect immunological match for the patient from which they are derived, but for use in different patients, ISCO says, they will share the same problems of tissue rejection as other cell types. "Parthenogenetic stem cells really provide the only viable method for creating a true stem cell bank from which any patient who needs a cell based transplant can get cells that match his immune system," said ISCO chairman and CEO Kenneth Aldrich. The company has one cell line that matches more than 300 million people, Aldrich said. A strategically selected portfolio of 100 cell lines would be sufficient to cover the vast majority of the world's population, he noted, but trying to do the same with ESCs or iPSCs would require at least 10 times more cell lines.
UPenn's Gearhart remains skeptical. "We need a heck of a lot more work to really establish that [pESCs] are the same thing [as ESCs]," he said. "Number one, it's a safety issue, and number two, you'd want to know how well these things are going" to form the specialized cell types that clinicians would like to transplant for cellular therapies.
ISCO, which claims to have filed the first patents for deriving human pESCs in 2006, is currently testing pESC-derived retinal cells and liver cells in animal models. "Every indication we have is that they definitely are [safe]," said Aldrich. "We have found thus far no evidence whatsoever that there is an imprinting issue that adversely affects the cells." Mitalipov noted that many experiments show that pESCs can differentiate into any cell type in the body, just like ESCs. "There is no deficiency found, at least in vitro," he said. "These cells are actually functional."
ISCO also plans to supply its cells to researchers investigating potential cell therapies. But there's a hitch. Under the 1995 Dickey-Wicker amendment, taxpayer-backed grants cannot be used to create any embryos, including parthenogenetic ones. What's more, even existing pESC lines would not be eligible for federal funding under the National Institutes of Health's proposed guidelines, which are currently being weighed against a flood of some 49,000 comments that the agency received last month. "It will be a tragedy for the country" if the NIH doesn't amend its draft guidelines, Aldrich said. "It would force us to do a lot of things overseas that we'd rather be doing domestically."
Ronald M. Green, a bioethicist at Dartmouth College in New Hampshire, said that banning funding for pESCs is based on "uninformed apprehensions" that parthenotes might form viable embryos. "Ethically, it's unobjectionable in a deep sense" to fund pESCs, he said. "Sex cells are routinely destroyed and [creating parthenotes from unfertilized eggs] raises no ethical problems."
The jury's still out on whether pESCs will ultimately be used for transplantation or if the cells will remain confined to the culture dish. Either way, most researchers agree that the cells' full potential -- whatever it is -- will only be realized with sufficient government-backed funding for basic research.