On May 4, 2011, the California Institute for Regenerative Medicine (CIRM) awarded $25-million to Geron Corp. to support the first ever FDA approved clinical trial based on cells derived from human embryonic stem cells. The occasion represents a milestone for CIRM, which has shifted its focus from funding basic science research in the early years to funding translational (“bench to bedside”) research.

As the largest source of funding for stem cell research outside the NIH, CIRM was established through the passage of Proposition 71 to invest $3-billion in stem cell research over ten years. It is no coincidence that the consortium is based in San Diego. With our extraordinarily high density of academic and commercial biotech interests, San Diego is one of the leading centers of stem cell research in California and perhaps the country.

Regardless of how San Diegans feel about stem cell research, our city is helping to blaze the trail for creating new therapies for disabling diseases such as Parkinson’s, Alzheimer’s, diabetes, Lou Gherig’s and now, with the Geron study, spinal cord injuries.

“By funding this trial, CIRM is taking a major step toward making that hope a reality,” CIRM chairman, Robert Klein, said in a statement.

The Geron spinal cord treatment is derived from the human embryonic stem cell (hESC) line H1, which (along with two other early WiCell lines, H7 and H9) is one of the most extensively studied lines among researchers worldwide prompting many to call them the “gold standard” for stem cell research.

However, in March 2009 when President Obama repealed Bush’s 2001 hESC directive, these widely used WiCell lines, along with 18 other stem cell lines approved during the Bush administration, were not grandfathered in to the new NIH registry.

That’s because the NIH’s April 2009 draft guidelines explicitly required specific types of informed consent in their consent documents: first, embryos left over from IVF treatments must be freely donated to scientific research in general; and second, they must be donated for stem cell research specifically. Thus, research utilizing these lines was no longer eligible for federal funding until proof of meeting these criteria could be established.

For scientists using H7 and H9, this meant delaying research for over a year as researchers scrambled to gather the consent forms needed for the NIH approval application. Because the embryos for these lines were donated over ten years ago through a clinic in Israel, locating the decade-old consent forms and translating them from Hebrew to English took significant time and effort.

While awaiting approval, scientists were forced to consider scrapping a decade worth of research and starting from scratch-or possibly beginning the equally frustrating, time-consuming, and extremely expensive scenario of switching to another line.

Although H7 and H9 were eventually approved on April 28, 2010, the delay illustrates the tension between the desire to create potentially life-improving therapies using stem cells as quickly as possible and the need to ensure that patients making these donations are truly informed.

“The standards for consent evolve over time,” said Sean Morrison, a cell biologist at the University of Michigan, “it would make no sense to take out lines that, 10 years ago, everyone agreed were ethically derived, just because they don’t meet the letter of the new requirements.”

Although this statement sums up the ethical quagmire surrounding hESC lines and informed consent for the most part, the picture is even more complicated than that.

Fueling the debate further are the 2008 findings of University of Wisconsin-Madison bioethicist, Robert Streiffer, who, using the Freedom of Information Act, discovered that consent documents for 5 of the 21 hESC lines eligible for federal funding during the Bush administration were marred by ethical concerns even by the consent standards of their time. The lines in question were created by Athens, Ga.-based BresaGen and Cellartis of Sweden.

The problems were broadly categorized in to two groups: 1) consent documents were not for research but for patients to begin fertility treatments with only a vague mention of research at the end of the form; and, 2) consent forms mentioned a specific research study and stated that the embryos would be destroyed at the end of the experiment.

In response to this study, other research institutions across the U.S., irrespective of federal funding eligibility, began to wonder whether they should reassess the ethical validity of their stem cell lines, including Stanford University, which determined that the five hESC lines derived by Cellartis and BresaGen did not meet ethical standards-theirs or the NIH’s.

Why should it matter whether donors consent to general research instead of stem cell specific research? Why the fuss over exact wording?

Some ethicists hold that when donors give blanket consent to future research purposes, the contemplation that their cells might live indefinitely in stem cell lines is unlikely to be a consideration. Even more so if the cells were donated before stem cell research entered mainstream consciousness. (For example, a patient who donated an embryo in 1998.) Under these conditions, is the patient’s consent truly informed? Or how about adequately informed?

“My biggest fear about what will happen is that someone downstream who donated an embryo … comes forward and says, ‘I wouldn’t have consented, I wouldn’t have agreed to that type of research if I had only known that was what they were going to do,’” said Bernard Lo, director of the medical ethics program at the University of California, San Francisco.

However, now that human embryonic stem cell research has shifted from endless tinkering in the lab to being on the cusp of developing real-life therapies, are there circumstances under which research should be allowed even when donors have not given stem cell or study specific consent? For example, should the possibility of curing spinal cord injuries and paralysis for millions override individual autonomy?

In an April 2011 donor-privacy study, CIRM-grantees at Stanford University discovered that participants were just as likely to donate unused embryos to stem cell research as they were to the study of human development. Highest on their list of concerns? That their donation “not be used to make a baby for another person.” Does this generalized information about human nature in any way mitigate the need for research specificity in consent documents?

With or without federal funding, scientists at research institutions and biotech firms “must make ongoing decisions about whether it is ethically appropriate to use stem cell lines given shifting standards of informed consent,” says Michael Kalichman, director of the Research Ethics Program at the UCSD School of Medicine. “A mistaken decision could mean that months, or even years of research effort, could be wasted if it is later concluded that research based on those lines cannot be used for the purpose of publication, commercialization, or future grant funding.”

Although the final NIH guidelines contain a provision for pre-July 9, 2009, stem cell lines that do not meet the letter of the law, scientists must continue to do their best to anticipate future ethical concerns and “administration-proof” their research. For all the breakthroughs and setbacks that occur in the lab, perhaps none is more frustrating than the human-derived obstacles that shift to accommodate the concerns of the time.

Kim Faulkner lives in San Diego and writes as a member of the San Diego Center for Ethics in Science and Technology.

The Reuben H. Fleet Science Center and the San Diego Center for Ethics in Science and Technology will be hosting a free public forum to discuss issues of informed consent. Come join the conversation on June 1 at 5:30 p.m.

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