Consternation in Barad-dûr

One of the most memorable images in The Lord of the Rings is the eye of Sauron. From his fortress in Barad-dûr the evil overlord scans Middle Earth relentlessly for the ring, borne through endless travails by the hobbit Frodo Baggins. If he finds it, Sauron will hold the world in his thrall. But Frodo eludes him and on the brink of his triumph, Sauron finds that years of scheming are undone. As Frodo prepares to hurl the ring into Mount Doom, "The magnitude of his own folly was revealed to him in a blinding flash ... For he knew his deadly peril and the thread upon which his doom now hung".

Alan Trounson, the Australian head of the world’s biggest embryonic stem cell project, must have an inkling of Sauron’s fears. He is the boss of the California Institute for Regenerative Medicine, which was created after a controversial referendum in 2004. This authorised a US$3 billion bond issue to be spent on stem cell research, mainly of the embryonic kind.

At the time, voters were dazzled with claims that embryonic stem cell research was a kind of ring of power. According to the text of the referendum, it could lead to cures for "cancer, diabetes, heart disease, Alzheimer’s, Parkinson’s, spinal cord injuries, blindness, Lou Gehrig’s disease, HIV/AIDS, mental health disorders, multiple sclerosis, Huntington’s disease, and more than 70 other diseases and injuries". All people needed to do was to authorise scientists to clone human embryos and then to dice them up for their "pluripotent" stem cells - cells which can morph into any tissue in the body. A typical TV ad for the referendum featured identical twin brothers, one with cerebral palsy, who pleaded with voters to support the referendum.

Millions of dollars were poured into a campaign for a Yes vote. This money was needed to counter opponents’ claims that this massive and unprecedented expenditure was a waste of taxpayers’ money, that creating and destroying human life was unethical, and that women would be exploited for their eggs. All in vain. Proposition 71 coasted home by a 3 to 2 margin. The CIRM was established and scientists began to drift to California. In September the CIRM hired Alan Trounson, a pioneer in IVF research. Things were looking pretty good in Barad-dûr.

But only a few weeks into his new job, Trounson had a Frodo moment. A hitherto unknown Japanese scientist, Shinya Yamanaka, made an amazing announcement in November: he didn’t need to dice up embryos to obtain pluripotent cells. Instead he could reprogram skin cells into what he called induced pluripotent stem cells (iPS cells). This technique produced cells which seemed to have the same magical morphing ability and to Yamanaka it seemed more ethical. Recalling a moment when he looked at an IVF embryo under a microcope, he told the New York Times, "I suddenly realised there was such a small difference between it and my daughters. I thought, we can’t keep destroying embryos for our research. There must be another way."

Scientists around the world were electrified by Yamanaka’s discovery. For a range of technical reasons, progress with embryonic stem cells had been painfully slow. But here was a way forward without the ethical issues surrounding the destruction of human embryos and without the need to source millions of women’s eggs for cloning experiments. Almost immediately, leading figures in the field abandoned their work on embryonic stem cells. These included Ian Wilmut, the Scottish scientist who had cloned Dolly the sheep and James Thomson, the Wisconsin researcher who first isolated human embryonic stem cells.

Overnight, spending $3 billion on embryonic stem cell research looked remarkably like like Sauron’s folly. "If you can’t tell the difference between iPS cells and embryonic stem cells, the embryonic stem cells will turn out to be an historical anomaly," said James Thomson. Even Trounson says that journalists were asking him: "Isn't the California Institute of Regenerative Medicine (CIRM) out of business now that the Yamanaka and Thomson papers show human fibroblasts can be induced to pluripotency?"

Naturally, Trounson and his colleagues launched a public relations counter-attack. Writing in the journal Nature Reports Stem Cells he insisted that embryonic cells were the "gold standard" for research of this kind. A close ally, the Harvard-based president of the International Society for Stem Cell Research, George Daley, declared, "There will never be a time when we don’t need human embryo research." And Nature editorialised that "there is cause for concern as scientists hop on the iPS bandwagon". It warned of "over-hyped promises" and even of fraud.

And by coincidence, like the sinister Nazgûl, the chilling shadow of fraud passed over Yamanaka. It seems that in his haste to publish results in an online issue of Science on February 14 he had made some minor mistakes. Two weeks later, an anonymous email was sent to journal editors, science journalists and scientists from a ringwraith called "Reprogrammer Yamanaka". This pointed out "embarrassing inconsistencies" and insisted that Yamanaka’s team "either retract their paper or provide meticulous and thorough new analysis".

Had the Nazgûl wounded Frodo? It seems not, says Nature. "Happily, he has since given plausible explanations for the mistakes, and has effectively argued that they do not affect the article’s central conclusion - thus heading off worries (and one unsubstantiated accusation) that the errors signalled deeper problems with the article."

Unfortunately for Trounson, however, Frodo is far from the only problem facing the CIRM. Although it hasn’t been widely reported, he fears that his scientists’ research could grind to a halt unless he can buy women’s eggs, something which is banned in California. Without eggs, there can be no cloned embryos. And without clones, there will be no cures. According to a transcript of a recent CIRM meeting he lamented that he is spending "a lot of scientists' and people's energy on something that can't be done. That's not a very good return for what we want to do for the mission."

The backers of the CIRM seem to have assumed that women would happily donate their eggs. But they won’t. Harvard researcher Dr Kevin Eggan appeared to be on the verge of tears as he told the meeting:

I have spent countless hours stomping around to different disease advocacy groups, tea circles, knitting circles, trying to find anyone and everyone who would donate their oocytes [eggs] for our experiments ... We spent more than $100,000 in advertising in the Boston Globe, in the Boston Herald, in the Boston area papers, in the suburbs of Boston. We have literally pursued every option. We've pursued trying to recruit donors from other parts of the United States to come to Boston to donate their oocytes for research. This will not work.

One solution - which Trounson is mulling over - is to change the law. But this is sure to provoke impassioned opposition. As a patient advocate at the same meeting commented, "I can tell you that if we were going to go out and spend $3 billion buying eggs from women, I wouldn't have voted for it."

It is far too early to claim which type of cell, those derived from destroying embryos or those derived from a simple skin cell, will yield the magic cures. But as Trounson and his colleagues fight desperately to keep their $3 billion research plan intact, it is becoming evident that all the original objections are still valid, and perhaps insurmountable. Meanwhile Frodo, followed now by many others, plods on.