26 May 2021
LONDON – New guidelines for stem cell research open the door to extending the legal limit on human embryo research beyond the current 14-day maximum set down 40 years ago.
In revised guidelines, the International Society for Stem Cell Research (ISSCR) has moved research on human embryos from category 3, which explicitly bans their study in culture post 14 days in any circumstances, to category 2B, in which research post 14 days would be permissible if there is a clear scientific rationale – and after a thorough specialized review.
The guidelines, published on May 26, are the first update for five years. They are designed to reflect advances in what has become scientifically possible during that time, including stem cell-derived embryo models, brain organoids, designer chimeras and human genome editing.
“The 2021 update presents practical advice for oversight of research posing unique scientific and ethical issues for research and the public,” said Robin Lovell-Badge, chair of the ISSCR guidelines taskforce, who is head of the division of stem cell biology and developmental genetics at the Francis Crick Institute in London.
“We think there are many valid reasons why you want to study human embryos in culture beyond the 14-day limit,” Lovell-Badge said.
Among those reasons are the need to investigate initial growth of the placenta, deficits in which are the main cause of miscarriage, and to study the earliest stages of the development of congenital abnormalities. There also is potential to improve in vitro fertilization techniques and conduct better safety studies of mitochondrial replacement in the treatment of inherited mitochondrial diseases.
Opponents of an extension say animal embryos can be used instead, but Lovell-Badge said there is increasing evidence that these do not accurately model early human development. In any case, extending the 14-day deadline would make it possible to validate – or not – animal models.
Kathy Niakan, professor of genetic regulation of early human development at Cambridge University, who was the first researcher in the U.K. to be given a license to use CRISPR/Cas9 genome editing for research in human embryos, said going beyond 14 days would require a “robust process of review” involving a two-way dialogue with the public, and with every experiment thoroughly assessed to ensure exceeding 14 days is justified.
There have been calls to extend the limit to 28 days, but ISSCR is not backing a specific extension, saying instead that any increase in the number of days in culture should be for a scientifically valid reason.
“Here’s what we want to underscore very clearly – this is not a green light to go ahead with extending human [embryo] culture beyond 14 days,” Niakan said.
The recommendation to end the 14-day limit on culturing human embryos is the most controversial move in a wide-ranging revision of stem cell research guidelines by ISSCR, the self-appointed nonprofit organization set up by stem cell researchers in 2002, to provide ethical overview while allowing their studies of human embryonic stem cells to proceed.
The updated guidelines will provide more flexibility to adapt to the regulations in each country, said Lovell-Badge. “The idea is to produce a set of guidelines that can be used widely, so specific stem cell research can go ahead, but will proceed responsibly, and be responsive to public and patient interests,” he said.
Categories of research
The previous guidelines had three categories: research that was exempt from review by stem cell committees; research that was permissible after specialized review; and research that was banned.
Those categories are now each divided into two. Category 1A is exempt from review, while category 1B also is exempt, but must be reported so there is awareness it is going on. An example of category 1B research would be putting human cells into animal embryos.
Stem cell-derived organoids are placed in category 1A, but ISSCR intends to keep that under review, in particular to monitor developments in brain organoids. At present, those are nowhere near consciousness or pain sensation, but the picture is changing rapidly, ISSCR said.
In category 1B, creating chimeras by implanting human stem cells into animals is exempt from specialized stem cell review, but would be reviewed under the usual standards for animal experiments and could require inputs from animal behavior specialists if the human cells are intended to integrate with the nervous system, for example.
Category 2 covers research that is permissible after specialized review. Human embryo research post 14 days is moving from category 3 to category 2B, in which there would be a specialized and stringent review process.
Also falling into category 2B is the recent creation of a blastocyst. These constructs are not subject to the 14-day rule because they are derived from stem cells rather than a fertilized egg, but the review process would set a minimum time for those models to be cultured to achieve the scientific objective. Any stem cell-derived embryo precursors are strictly models and cannot be transferred to human or animal uteruses, ISSCR said.
Also in category 2B is putting human cells into animal embryos in attempts to grow human transplantable organs.
Category 3, currently covering banned research, has been nuanced by dividing it into category 3A, covering research that should be prohibited even if there is a scientific rationale, because it is currently unsafe and viewed as unethical. An example here is heritable gene editing, which Lovell-Badge said, “is not safe yet, but there is hope [it] will become safe.”
Category 3B covers experiments for which there is no scientific rationale and which are unethical.
How quickly the new ISSCR guidelines might bring about a change in the 14-day rule on human embryo research will depend in part on the jurisdiction. In the U.K., it would require new legislation, while in the U.S., the 14-day rule is adhered to, but there is no legal ban.
The development of human embryos from two to four weeks, as organs begin to develop and the placenta to form is a “black box,” Lovell-Badge said. In his view, this provides the justification for lifting the 14-day limit. “Given the importance of this period of human development, it would be unethical not to do this research,” he said.Print
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