When California's US$3 billion Stem Cell Research and Cures Act, Proposition 71, was approved by voters in November 2004, the crucial paragraph did not mention embryonic stem cells (ES cells):

“There is hereby established a right to conduct stem cell research which includes research involving adult stem cells, cord blood stem cells, pluripotent stem cells, and/or progenitor cells. Pluripotent stem cells are cells that are capable of self-renewal, and have broad potential to differentiate into multiple adult cell types.”1

Had the drafters somehow foreseen the international effort that would be spurred by Shinya Yamanaka and colleagues' breakthrough 2006 paper2 in Cell? Did they know that Yamanaka's and James Thomson's reprogramming teams3,4 would announce in late 2007 that a quartet of transcription factors within the larger pool of embryo-specific genes was sufficient to reprogramme human skin cells to pluripotency? In 2004, the only known way to reset the genome of a cell from an adult animal was to transfer its nucleus to an egg and allow this to divide into an early embryo, and generating ES cells meant destroying the embryo. Unlike the original, differentiated cell, these ES cells would be pluripotent, capable of becoming any sort of cell in the body. Did the wording in Proposition 71 forecast or spur the innovation that patient-specific pluripotent stem cells might be possible without either embryo creation or embryo destruction?

Did Proposition 71 predict or spur embryo-free reprogramming?

No doubt some who helped draft the proposition had an inkling of the potential of nuclear reprogramming; certainly, by the time the California Institute for Regenerative Medicine (CIRM) announced funding for new types of pluripotent cells this year, research on induced pluripotent stem cells was well under way in many places, including California. But other evidence indicates that drafters of Proposition 71 did not foresee that the human embryo might soon be relegated to a naturally occurring site where cell nuclei happen to be doused with the transcription factors of pluripotency and no more necessary to pluripotency than hydrothermal vents are today to PCR. In fact, the paragraph quoted above goes on to say, “Pluripotent stem cells may be derived from somatic cell nuclear transfer or from surplus products of in vitro fertilization treatments” (my emphasis). In other words, in the text before the voters, the only options envisaged for pluripotent stem-cell research were either cloned embryos to be created using eggs extracted from women or embryos left over from in vitro fertilization (IVF).

One could plausibly argue that the wording of California's Proposition 71, when it named pluripotent but not embryonic stem-cell research, was part of an international collective spur to innovation.

More likely, the use of the word “pluripotent” was one of a number of rhetorically suspect — or rhetorically brilliant, depending on one's point of view — sleights of hand in the text of the proposition. Rather than foreshadowing future events, the word was used to avoid triggering pro-life opposition that the word “embryonic” would elicit, much as nuclear magnetic resonance imaging (NMR) shed the worrying word “nuclear” to become magnetic resonance imaging (MRI) in clinical settings. Proposition 71, after all, contained other notable examples of rhetorical 'flourish' (to use a euphemism myself): the absence of any mention of women, despite the need for women egg donors the proposition's passage created; the absence of the word cloning, except in a brief passage to outlaw “reproductive cloning”; the absence of a model of access to future publicly funded stem-cell therapies for all state residents; and the absence of any mention of the social model of disability, implying that 'We, the people of California' obviously all want 'cures' as opposed to cures balanced with accommodation.

It is clear that the word pluripotent did the work that euphemisms always do: it marked out socially unacceptable arenas. To avoid red-flagging the research, to maximize consensus at home and to promote California's leadership nationally and internationally, drafters avoided words like 'women', 'embryo', and 'cloning'. Their absence implicitly provided the parameters of the necessary 'invent around' zones. The raging of the embryo debate around stem-cell research, as well as the debate about the procurement of women's eggs that emerged subsequent to the passage of Proposition 71, were tangible presences in the text through their very absence.

Did opposition spur innovation?

If California's felicitous wording did not actually reflect a prediction of the recent dramatic breakthroughs, could it have helped spur this innovation with its implicit demarcation of unsavory aspects of the very technologies it was drafted to support?

The raging of the embryo debate around stem-cell research, as well as the debate about the procurement of women's eggs that emerged subsequent to the passage of Proposition 71, were tangible presences in the text through their very absence.

American pro-life commentators immediately credited conservative policies for propelling the breakthroughs. In their view, President George W. Bush's August 2001 moratorium on federal funding for work on new ES cell lines, and global efforts to save embryos from destruction, far from eroding scientific progress fostered instead the breakthrough needed to unleash the true potential of regenerative medicine, opening the door to an era of readily engineered patient-specific stem cells for transplantation, new kinds of disease modelling and diagnostics and a true scientific understanding of pluripotency itself. The new research is evidence that this science and this religion are in fact compatible. On this view, converting that which should be an end unto itself (one life, albeit that of an embryo) into a means (a stem cell line that might save other lives) must always be wrong. Indeed, the argument goes, morality, by creating the necessity of working around its restrictions, has been the mother of invention.

I am in general disposed to think that there is something to this 'morality as the mother of invention' account in explaining the recent international surge of innovation in induced pluripotency. But it is not the whole story; moral opposition did provide one spur to embryo-free reprogramming, but it did so in conjunction with other spurs and while simultaneously delaying some aspects of research. The causal take-home lesson should reflect this complexity. Both Thomson and Yamanaka have stated plainly that the breakthroughs in induced pluripotent stem cells would not have been possible without ES cells, and groups working to reprogramme cells without the involvement of embryos have lamented that innovation has been stalled both by restrictions on US federal funding and Japanese ethical guidelines. And, although these breakthroughs are proof of principle, they are still very far from being ready for clinical application. Likewise, there are many things for which human ES cell research probably remains the best scientific — and possibly also moral — option, such as modelling disease progression using stem-cell lines derived from embryos deselected after pre-implantation diagnosis because they carry a fatal disease.

What factors, then, might be said to have characterized the recent innovation environment around pluripotent research that we could aim to replicate elsewhere? Evidence seems clear for at least the following contributing factors:

  • moral pro-life opposition in an environment, especially the upcoming US elections, where it is politically costly to be seen to be against science and opposed to cures

  • an intrinsically important and fascinating scientific and clinical problem area — regenerative medicine itself

  • rapidly changing and hotly contested mores for human tissue and egg donation like those about provenance, procurement, compensation, intellectual and other kinds of property and disposition

  • new academy-industry-clinical-public alliances in biomedical science in the US and globally, tying research to economic to health issues

  • genuine international competition, evident in both brain drains as scientists move physically or topically to more permissive research environments and patients engage in medical tourism, and in the increasing bureaucratization of ethical standards to achieve international harmonization and standardization for research

  • preexisting national expertise and ethical constraints in the innovating scientists' working environments. For example, embryos are deemed worthy of special consideration and embryo procurement faces hurdles in the US, even among many of those who do not think that embryos are persons, so being able to do research without embryos has appeal. In addition, embryo procurement poses many ethical and practical hurdles. For its part, Japan prohibits many kinds of third-party reproduction, not because of pro-life views but because of qualms over parentage, and so although its 2001 guidelines for stem-cell research permitted human research cloning, preexisting expertise and infrastructure was in animal cloning rather than third-party reproductive techniques, and this is where its scientists have continued to out-perform others.

Restrictions often play negative roles in innovation, but sustained passions can spur progress

With so many contributing factors, what role can opposition to research and research restrictions play in scientific breakthroughs? Innovating around restrictions on research only sometimes leads to a reframing or overcoming of the obstacles themselves, and only sometimes leads to better science. At other times, obstacles to research remain just that: obstacles. Common examples of this include intellectual property barriers, undue regulatory burdens such as national restrictions on the movement of scientific materials, difficulties in getting permission to work in a particular place or with a particular group of human subjects and lack of public or private funding for the research in question. As far as I know, this is as likely to happen for laudatory as for ethically problematic research. It is also common to think (especially in post-World War II liberal democracies) that research thrives where there is robust balance between what would otherwise be a contradictory state of affairs — freedom to pursue science for science's sake with minimal interference, and the need for financial and public support of targeted lines of research. We know that both public and private research entities can create and maintain versions of this balance productively, and that either can get the balance wrong.

What is unique about the stem-cell debate is that it has ranged over a sufficiently wide stage with a sufficiently large, attentive audience for these scientific, clinical, ethical and economic factors to be articulated as interconnected, and for their competitive potential to be seen and pursued. In California, it is of particular note that the landslide passage of Proposition 71 and subsequent establishment of the CIRM was followed immediately by a moratorium on funding pending the resolution of lawsuits filed by pro-life detractors. This created a local forum for discussion, an agora, where scholars from many disciplines lent their minds and their time to devising ways to work around opposition; this resulted in medical and ethical standards and intellectual property policies, for example, that are more forward looking than comparable policies outside stem-cell research. The public mandate, the promise of not-yet-flowing funds, and the political stakes combined to provoke sustained public scrutiny, and the conversation was carried out with an atypical degree of public participation. The religious and conservative oppositions were part of the discussion, but so were progressive critics and others.

If we desire the most innovative scientific research for the global public good, it seems that we should seek to promote the unusual degree of international scientific competitiveness that characterizes stem-cell research. Restrictions on research in this case helped a wide-ranging scientific discussion to become a reality. This internationalization is in line with common beliefs about the intrinsically international nature of science, even if it is not quite in keeping with its frequently nationalist, not to say imperialist, realities.

Should we also pursue an implication for the US implicit in the causal factors listed above? Are there benefits when the innovative impulse (rapid scientific advance) is decoupled from market uptake and translational development of research, and from the government's role as the guarantor of the balance between freedom of research and the need for funding? Key texts such as the Bayh–Dole Act of 1980 tell us that basic research, R&D and diffusion to the market can be synergistic and together define modern life-science innovation. In the case of blockages in funding for human ES cell research, however, the public participation and international competitiveness that took over where these connections failed proved themselves to be tremendous spurs to innovation.

While it might be impractical to have all, or even most, innovation proceed in this manner, I suggest that this kind of public scrutiny promotes innovation in science and in the relations between science and society, and should happen when we are faced with scientific work that genuinely challenges common public perceptions of what is acceptable.

It is time now, perhaps, to begin to move away from talking about ES cells and towards talking about pluripotent stem cells, of which ES cells are but a subset. We need to turn our attention to the fact that the ability to induce pluripotency raises its own troubling technical and ethical issues that have nothing to do with the moral status of the embryo. Perhaps most obvious is the potential to use one person's cells to produce viable sperm and egg in a dish.

The recent breakthroughs are a non-partisan victory. But we should also take home a fundamental lesson — ingenuity and innovation are never so well served as when there is the kind of attention, and, dare I say it, confrontation, that has marked the past few years of human pluripotent stem-cell research. This is a far cry from relying solely on patient advocates to stand in for the entire public, as favoured in the United States or, as favoured in Europe, soliciting opinion from lay people in various exercises of civic engagement in science. Real scientific breakthroughs and robust scientific democracy both emerge when many people pay attention for sustained periods of time, each identifying the goals of the research with their own well-being and commitments. Every administrator, scientific researcher, ethicist, pundit or member of the public tempted to brook no opposition to his or her own particular opinion should bear in mind that this kind of agora, borne not just of opposition, but of passion, is the very scaffolding of democracy and supports rather than undermines individual scientific achievement. Our challenge now is to begin to learn how to produce just such an innovation environment for issues that do not already map onto deep political fissures; to bring many and new aspects of scientific and technical innovation into a space where they get the kind of attention and are worked on by, and not just consumed or assumed by, our collective minds, hands and hearts.