For some researchers in the United States, the number of human embryonic stem cell lines they can study with federal funding may fall from 21 to 16 after publication of an analysis revealing that embryos from which five of these lines were derived were not obtained with adequate informed consent, even by the standards of the time. Most news coverage of the analysis1, carried out by bioethicist Robert Streiffer at the University of Wisconsin-Madison, has focused on potential decisions by academic institutions that could further reduce the human embryonic stem (hES) cell lines available to federally funded researchers. There are, however, more ramifications of Streiffer's analysis than the loss of access to some lines. As the numbers of stem cell scientists and the links between them increase, the issue of who should take responsibility for deciding whether research materials were obtained under sufficiently informed consent becomes less clear, as does what to do when standards of informed consent change.

The University of Wisconsin-Madison is the institution at which James Thomson first derived hES cell lines. Streiffer says he got the idea of reviewing the informed consent forms for 'eligible' lines because he was familiar with the process that university went through then, some ten years before national guidelines for deriving hES lines were established. “Though I knew that was a good effort, I knew that there were problems, and there were a number of groups who were assuming that the lines had unproblematic consent,” he says.

Streiffer first evaluated the forms for the 21 cell lines according to standards for informed consent current at the time that the lines were derived. He found that forms erred in two broad categories: by making promises that would be hard to keep; and by failing to provide information that donors might consider important. He also compared the consent forms with a list of specific criteria issued by the US National Academy of Sciences in 2005 to define conditions under which researchers can obtain and use embryos and gametes in research.

“The human ES cell field is young in the overall scheme of things; views and approaches to the relevant ethical issues have evolved rapidly.” Peter Andrews

None of the 21 consent forms met every criterion of the 2005 guidelines, but that's to be expected. “The human ES cell field is young in the overall scheme of things; views and approaches to the relevant ethical issues have evolved rapidly,” says stem cell scientist Peter Andrews at Sheffield University, UK, who is chair of the scientific committee of the International Stem Cell Initiative, which funds projects to evaluate stem cell lines. “There is always a potential problem when we look back historically at what people did in the past and try to compare to what are the accepted norms today.”

Nevertheless, Streiffer found that forms used by two stem-cell companies to gain consent violated informed consent standards in place when the lines were derived. Both companies dispute this, saying they obtained the embryos with proper informed consent.

All this has left research-oversight committees at universities across the United States wondering whether they need to reassess what lines will be used for research, but hoping some other entity will make these difficult and time-consuming decisions for them.

Political warp

The organization that originally declared that the 21 lines were appropriate for use in government-funded research was the US National Institutes of Health (NIH), and that happened because of a political compromise. On 9 August 2001, President Bush declared that only hES cell lines already created at that time would be eligible for federal funding. He said destroying embryos for research was wrong and that his policy would allow scientists to “explore the promise and potential of stem cell research without crossing a fundamental moral line, by providing taxpayer funding that would sanction or encourage The NIH was charged with creating a registry of approved lines derived from human embryos that had been created for reproductive purposes and then donated for research without payment and with informed consent.

Since its inception, the NIH hES cell registry has been a political touchstone. The Bush administration initially said that 78 lines would be registered and that this would be sufficient to evaluate the promise of stem cell science. This number shrank to 21, mainly because many of the proposed lines were not stable. (These unviable lines are listed on the registry as eligible for funding but not available for shipping, and insiders report political pressures to boost the numbers of lines listed.) Last year, in a move widely decried as an effort to blunt political criticism of the restrictions. Bush issued an executive order to add embryonic-like stem cell lines derived without embryos to the registry even though these were already eligible for federal funding. (None of these lines has been added to the registry because there is no established way to assess their potential.) The executive order was entitled “Expanding Approved Stem Cell Lines in Ethically Responsible Ways.” Nor is Streiffer's article, which openly criticizes Bush's funding restrictions, politically neutral.

If US researchers have access to non-federal funds, however, ES cell research falls under a hodgepodge of state regulations; in some states, few restrictions apply. As research on non-NIH lines began to increase, the scientific community was hungry for guidance and eager to reassure the public that researchers were keeping their experiments within socially acceptable boundaries, recalled University of Wisconsin-Madison law professor Alta Charo at a meeting on cross-institutional collaborations in stem cell science earlier this year. Consequently, the National Academy of Sciences (NAS) formed an advisory committee to draft guidelines for ES cell research. This way, institutions could point to the advice of an overarching, respected body to fend off criticism that researchers were acting without sufficient oversight.

The NAS guidelines were issued in 2005 and advised institutions to set up ES cell research-oversight committees (ESCROs) that would function in a similar fashion to institutional review boards (IRBs), making sure that researchers' experiments fell within accepted norms of ethics and dignity. Setting policy well is not only time-consuming, according to members of research-oversight committees, but respected ethicists and policy-makers in different institutions can come to different conclusions, a disconcerting situation for all. Thus, ESCROs came to rely heavily on the NAS guidelines; the guidelines issued by the International Society for Stem Cell Research in 2006 also strongly resemble those from the NAS.

The NAS guidelines gave explicit instructions for what information should be provided to people donating embryos or gametes for the creation of stem cells, but ESCROs were still unsure how to treat lines derived before the guidelines were issued. In 2007, the NAS advisory committee told ESCROs explicitly that the NIH lines were derived under conditions sufficiently similar to its guidelines that research on those lines was acceptable. This was done, according to the text of the guidelines, to avoid further restricting available cell lines: “The intention of 'grandfathering' the NIH-approved cell lines is to avoid precluding hES cell research that would otherwise be rendered difficult or impossible for investigators using NIH funding who wish to follow the National Academies' guidelines.” After Streiffer's analysis was published, however, it became clear that members of the NAS advisory committee had relied on the NIH's assessment that the lines were appropriate for research.

Story Landis, director of the National Institute of Neurological Disorders and Stroke and chair of the NIH stem cell task force, says NIH staff were careful to consider the president's criteria set forth in 2001, including the requirement for informed consent. Although the main reason the number of lines shrank to 21 from 78 was because the lines themselves were not available or healthy, one line was withdrawn because the embryo had not been created for reproductive purposes, and another because the donor withdrew consent.

Asked why the NAS committee had not reviewed the consent forms themselves, Frances Sharples, study director for the advisory committee, said that it was already overworked and that a thorough review would have taken several months. Streiffer concurs that this time estimate is reasonable. NAS will reassess the grandfathering decision at a meeting later this year, but some institutions, including Stanford University in Palo Alto, California, and Johns Hopkins University in Baltimore, Maryland, plan to conduct their own analyses.

Decisions and revisions

Among the 21 approved by the NIH and NAS; for these five, the consent forms egregiously violated long-established standards of informed consent, says Streiffer, adding he'd be surprised if researchers would want to use such lines if they understood the lapses. (See Consent issues restrict stem cell use).

One company involved in obtaining the of the NIH lines in question was the Swedish biotech firm Cellartis. Originally, it explicitly told embryo donors that the purpose of the research was to develop techniques to culture eggs and that the experiments would last only a few days, after which all cells would be destroyed. But Mikael Englund of Cellartis says that those donors were re-contacted in accordance with changes in Swedish law and gave consent for their cells to be cultured permanently. Streiffer says that this information was not included in the material provided to him by the NIH, but the registry supports Englund's position: it lists three eligible derivations, but only two are listed as available for shipping; the third is described as unavailable because the donor withdrew consent.

Perhaps the worst consent form was that used by the biotech company Bresagen of Athens, Georgia. Bresagen's consent form was not for research at all but for infertility treatment. In the seven pages outlining the procedure and explaining the risks of in vitro fertilization (IVF), there was one sentence stating that multiply-fertilized eggs and embryos that were not developing would be donated for research. The Bresagen form did not tell patients that they could refuse to donate unused embryos without forgoing IVF treatment.

Allan Robins of Bresagen says that the company opted to use the IVF form because Bresagen's staff had no direct interaction with the donors, and so it seemed appropriate for the fertility clinic to follow its own procedures. The company wanted to use non-frozen embryos, and there wasn't time for back-and-forth, he says. Although the form clearly lacked key information, Bresagen was also following a practice that would later be strongly endorsed by the NAS: those who receive embryos for research should keep any interaction with donors and their care-givers to a minimum and take measures to avoid conflicts of interest. Robins believes that the forms should be considered good enough for the time. “It was ten years ago; we didn't have NAS guidelines,” he says. “Those IVF consent forms, we supplied them to NIH, and NIH said they were fine.” But both Streiffer and Henry Greely, a Stanford law professor and ESCRO member, believe that Cellartis's and Bresagen's the forms violated standards of informed consent at the time.

Murky past, clearer future

All of the consent forms Streiffer examined failed some of the NAS criteria. Only one (from the University of California, San Francisco, which supplied 2 of the 21 lines) explicitly described alternative options for the disposition or storage of embryos. None fully described the kinds of experiments the embryos might be used for or gave donors the option to participate in some forms of ES cell research, but not others.

Interpreting older consent forms is an issue many hope will just fade away as researchers turn to newer lines obtained with more up-to-date consent forms; ones that have a better shot at anticipating future concerns. Still, “this kind of thing will be an issue for everyone no matter how careful we are,” says Glyn Stacey, director of the UK Stem Cell Bank. “We proceed with care and try to future-proof our procedures.”

Generally, Streiffer feels that omissions in the forms arose not from a lack of candour but from inexperience. Nowadays, for example, people writing consent forms should know to watch out for words like 'embryo' that might have different meanings for scientific and lay audiences. Currently, some oversight committees find themselves facing a sort of ethical archaeology expedition, trying to suss out what a donor's understanding was at the time the consent form was signed.

In California, many researchers are looking to the California Institute of Regenerative Medicine (CIRM) to make these calls. CIRM official Geoff Lomax says he's circulated Streiffer's analysis to members of his standards working group, but that he's reluctant to start the labour-intensive analysis of consent forms without a clear mandate. “Right now, we're in listening mode,” he says.

As much as it can, CIRM is relying on international registries and cell banks to determine that cell lines meet state guidelines, but it will need to assess some lines itself. “The reasons they are ineligible are real technicalities,” says Lomax. “We do need to have a process for evaluating them.” Today, guidelines stipulate that gamete donors must receive specific information about ES cell research, but what if a particularly useful line was derived before the policy was in place? A typical problem case, Lomax says, would be when a properly consenting embryo donor obtained sperm or eggs from unrelated gamete donors who gave only general consent that an embryo could be used for research.

One task that's become markedly easier is predicting what kinds of studies scientists will want to perform using the ES cells. For example, Streiffer says, none of the older consent forms stated that cells might be genetically manipulated or put into animals, even though such experiments are now routine. Forms written today will probably have longer staying power than those devised when hES cells first appeared on the horizon, says Streiffer. “Now we're in a much better position to say what research will be done than we were when the NIH lines were derived.”

Kevin Eggan of the Harvard Stem Cell Institute recently reported that he has made embryonic-like stem cells from skin biopsies of patients with the fatal neurodegenerative disease amyotrophic lateral sclerosis. Donors for these recently derived lines would not be surprised to find out what kind of experiments scientists have planned, he says. “They consented specifically to have their cells turned into reprogrammed skin cells and were told specifically that their cells might be put into an animal.”

Streiffer thinks informed consent might actually get easier if more researchers start using reprogrammed cells for applications that could once only be addressed with ES cells. “People feel a special connection to their reproductive materials and their embryos; they might have a much greater interest in how those are handled than in a skin biopsy,” he says.

Stanford's Greely, who chairs the California Advisory Committee on Human Embryonic Stem Cell Research, agrees that current consent forms are stronger than those in the past. “You can never successfully predict what will come up as an issue, but they do a reasonable job of alerting donors to issues that we think they might be concerned about,” he says. “The trick is what to do about older lines that don't meet those requirements.”

That trick might be easier if funding policies had not made the older lines so important to research, says Streiffer. “Bush's restrictions don't let us capitalize on what we know now. They are not state-of-the-art in terms of the science or the ethics.”

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