In response to the technological advances of recent years, the International Society for Stem Cell Research today (May 26) released an updated version of its guidelines for basic and clinical research involving human stem cells and embryos. The ISSCR’s changes include recommendations for using human embryo models, lab-derived gametes, and human-animal chimeras as well as an end to the widely accepted two-week maximum for growing human embryos in culture.
“What has happened in the past . . . four years is that this area of research advanced really, really quickly and there have been multiple discoveries that put us in a position where we have no guidelines [for] the kind of things we are doing in the lab,” says developmental biologist Marta Shahbazi of the Medical Research Council’s Laboratory of Molecular Biology in the UK who was not involved with the development of the document. “[So] it’s nice to see these guidelines. . . . They were really needed,” she says.
The ISSCR, founded in 2002, produced its original standards for human embryonic stem cell research in 2006, followed closely in 2008 with guidelines for the use of such cells in clinical settings. In 2016, these two documents were combined and updated to form the ISSCR’s Guidelines for Stem Cell Research and Clinical Translation. And now, five years on, the document has been updated again—the result of two years of work and deliberation by an international team of close to 50 scientists, bioethicists, and policy experts, with peer review by a separate team of independent researchers and ethicists from around the world, explains ISSCR president Christine Mummery of Leiden University Medical Center in the Netherlands.
Human embryonic stem cell research “sits at the intersection of several areas where the stakes are fairly high in terms of public trust,” says bioethicist Josephine Johnston of the Hastings Center who was not involved with crafting the new guidelines. “It’s human material, it’s embryos, it’s sometimes fetal cells . . . and they also use animals.”
[If] what has been followed up until now is ISSCR guidelines, [then] I predict that we will see US institutions permitting research beyond fourteen days now, because they will have ISSCR behind them.—Josephine Johnston, Hastings Center
Formal guidelines for this type of research are helpful, says Mummery, because it “makes it very clear on paper what is and what is not allowed.” The guidelines exist “to make scientists feel comfortable with what they’re doing and to make regulators and the public feel comfortable [too].”
Although the guidelines themselves are not law, institutions, funding bodies, and journals can and do use them to set standards for the work they allow, fund, and publish, explains Johnston. “A lot rides on these.”
Since the 2016 guide, stem cell researchers have made a number of significant technical advances. It is now possible, for example, to grow in culture embryonic stem cell–derived models of human embryos as well as chimeric human-monkey embryos. Aside from these breakthroughs, the last five years have seen improvements in organoid culture, germ cell culture and transplantation, gene editing, and other areas for which updates to the ISSCR guidelines were needed, says bioethicist Insoo Hyun of Harvard Medical School and Case Western Reserve University who is a member of the ISSCR guidelines update steering committee.
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The updates include the categorization of organoid research as an area not requiring specialized oversight. That’s because “brain organoids are not sophisticated enough at this stage, we think, that in the next five years there are going to be any real concerns about consciousness. They’re too small, too rudimentary, and they’re not hooked up to any external stimuli,” says Hyun.
In the ISSCR’s new three-tier system of research categorization, the culturing of organoids is placed firmly in level one—least concern—as are the culturing of chimeric human-animal embryos, stem cell–derived gametes, and human embryo models that do not contain all components necessary for normal development.
The transfer of human-animal chimeric embryos to a nonhuman uterus (not including that of an ape) is considered a level two procedure requiring specialized oversight, as are the culturing or manipulation of any actual human embryos and the culturing of embryo models with all component parts (such as blastoids).
Furthermore, the use of stem cell–derived gametes for human reproduction, the transfer of chimeric or model human embryos to human or ape uteruses, and the editing of germline genomes are prohibited and therefore placed on level 3.
Relaxed limitations for stem cell research
In addition to these changes, the ISSCR has removed the 14-day limit for culturing a human embryo—a restriction that has been widely accepted, or even enacted into law, in countries performing human stem cell research for the last 40 years.
“We have removed it from the category of prohibited activities,” says Hyun, “and encourage different jurisdictions to have their own discussions with their publics about the permissibility of going a little past day fourteen.”
Although human embryos have never been cultured that long, “we know that it is potentially doable,” says Shahbazi, “because there are a couple of publications showing the culture of monkey embryos past day fourteen in vitro.” In 2019, for instance, researchers reported growing monkey embryos for 20 days. It would definitely be interesting to go beyond two weeks with human embryos, she adds, “because this is the point at which gastrulation starts so this is really when cells start to decide their fate. . . . It’s a really critical stage.”
Johnston is concerned that now, with no recommended limit, public trust in embryonic research may be eroded. The 14-day rule “did a lot of political work for embryo research,” she argues, “because it said to policy makers and the public, ‘We are not without restrictions. We have lines that we will not cross.’”
Rather than removing the limit, she says, it may have been better to set a new one—either a longer time limit, or a biological one. Assuming that going beyond 14 days is scientifically justified, she says, keeping some sort of limit would be a signal of accountability, restraint, and respect for this early form of human life.
For many countries, the fact that the ISSCR no longer views human embryo culture beyond 14 days as impermissible will not change rules on research. In the UK, for example, the Human Fertilization and Embryology Act has written the 14-day rule into law.
But in countries without such laws, such as the US, where laws on human stem cell research apply only to that funded by the National Institutes of Health, this alteration to the guidelines may be “much, much more impactful,” says Johnston. “[If] what has been followed up until now is ISSCR guidelines,” she says, then, “I predict that we will see US institutions permitting research beyond fourteen days now, because they will have ISSCR behind them.”
R. Lovell-Badge et al., “ISSCR guidelines for stem cell research and clinical translation: The 2021 update,” Stem Cell Reports, doi:10.1016/j.stemcr.2021.05.012, 2021.
A.T Clark et al., “Human embryo research, stem cell-derived embryo models and in vitro gametogenesis: considerations leading to the revised ISSCR guidelines,” Stem Cell Reports, doi:10.1016/j.stemcr.2021.05.008, 2021.
I. Hyun et al., “ISSCR guidelines for the transfer of human pluripotent stem cells and their direct derivatives into animal hosts,” Stem Cell Reports, doi:10.1016/j.stemcr.2021.05.005, 2021.
L. Turner, “ISSCR’s guidelines for stem cell research and clinical translation: supporting the development of safe and efficacious stem cell-based interventions,” Stem Cell Reports, doi:10.1016/j.stemcr.2021.05.011, 2021.