Stemming Our Irrational Exuberance
Authors: Malcolm K Brenner
Journal: Molecular Therapy (2011)

As every cynic knows, the five stages of almost any project are (1) euphoria and excitement, (2) disenchantment, (3) search for the guilty, (4) punishment of the innocent, and (5) reward for the uninvolved. Those of us who have been involved with clinical gene transfer will recognize how closely these stages were followed in our own field. Stem cell therapy with human embryonic stem cells (hESCs) and now inducible pluripotent stem cells (iPSCs) may be in danger of following the same well-worn route.1Wilson JM Medicine. A history lesson for stem cells.Science. 2009; 324: 727-728Crossref PubMed Scopus (92) Google Scholar Techniques that could generate hESCs and iPSCs were landmark scientific discoveries, but the application of these cells to human disease was unquestionably promoted with unusual hype and chutzpah. For example, one argument used to gain public support for the bond issue of the Californian stem cell initiative (to establish the California Institute for Regenerative Medicine) was that it would probably pay for itself within five years by virtue of the more effective treatments that would be developed and implemented during that time. Predictably, a host of private ventures were set up around the world to exploit this publicity, and they delivered uncharacterized “stem cell therapies” of questionable provenance to individuals suffering from almost every human disorder, both real and imagined. Equally predictable were the resulting problems and adverse publicity.2Amariglio N Hirshberg A Scheithauer BW Cohen Y Loewenthal R Trakhtenbrot L et al.Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient.PLoS Med. 2009; 6: e1000029Crossref PubMed Scopus (747) Google Scholar Moreover, as research in the field progressed, the difficulties of actual clinical implementation became apparent. For example, hESCs, essentially by definition, are tumorigenic, and iPSCs are not as truly pluripotent as they once seemed3Polo JM Liu S Figueroa ME Kulalert W Eminli S Tan KY et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (949) Google Scholar,4Kim K Doi A Wen B Ng K Zhao R Cahan P et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1730) Google Scholar—and may, in fact, be “damaged goods” at both the genetic and epigenetic levels.5Gore A Li Z Fung HL Young JE Agarwal S Antosiewicz-Bourget J et al.Somatic coding mutations in human induced pluripotent stem cells.Nature. 2011; 471: 63-67Crossref PubMed Scopus (1003) Google Scholar,6Lister R Pelizzola M Kida YS Hawkins RD Nery JR Hon G et al.Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells.Nature. 2011; 471: 68-73Crossref PubMed Scopus (1220) Google Scholar,7Hussein SM Batada NN Vuoristo S Ching RW Autio R Narva E et al.Copy number variation and selection during reprogramming to pluripotency.Nature. 2011; 471: 58-62Crossref PubMed Scopus (758) Google Scholar They may also be immunogenic, even when they are apparently genetically identical to the recipient.8Zhao T Zhang ZN Rong Z Xu Y Immunogenicity of induced pluripotent stem cells.Nature. 2011; 474: 212-215Crossref PubMed Scopus (1125) Google Scholar Irrespective of their current problems, it is all but certain that (genetically modified) hESCs and iPSCs will ultimately come to be of major benefit for almost every disease, even degenerative conditions that are poorly amenable to conventional drugs. If these benefits are to be swiftly realized, however, it will be essential for the field to avoid progression to project stage 4—the punishment of the innocent—and return instead to stage 1, albeit with more measured enthusiasm and excitement. This may not happen if serious investigators in the field and their associated societies decide to react to maverick usage of stem cells inside and outside the United States by developing extensive self-policing. Although this is a commendable idea in principle, the danger is that such policing would become yet another barrier to implementation. The argument that “If we don't do it, the government will” is appealing but almost always spurious. Long experience with related approaches shows us that government agencies will—and indeed already do—regulate the field, regardless of the policing efforts of scientists. Investigators may thus be subjected to the dual encumbrance of distinct sets of regulations, self-imposed and externally mandated. This will certainly serve to punish the innocent and impede progress to no one's benefit, least of all our patients. A more constructive focus is for societies to educate investigators about preexisting regulations and help them maintain the highest (and well-established) standards of good clinical practice in the conduct of their hESC and iPSC studies. There should also be greater emphasis on research to increase the intrinsic safety of approaches using these cells. Every effective drug in existence has significant, sometimes fatal, adverse effects; these represent part of the risk–benefit assessment that clinicians consider before administering any new agent. Although stem cell therapies will ultimately be able to receive the same type of assessment, at present the field suffers from the same two burdens as those with the initial studies of gene transfer: there are no firm efficacy data for stem cell therapeutics and, if things go wrong, the adverse events may persist and progress as the cells survive and expand. We already know that unwanted proliferation, inappropriate differentiation, and immune recognition of stem cells are likely to occur in vivo; we need to urgently devote resources to tackling these issues. Until recently, it has been difficult to excite pivotal figures in the stem cell field about the need to address these concerns expeditiously, in part because many remained locked in project stage 1. But as more and more high-profile descriptions of these problems have appeared in the scientific and lay press, their crucial importance has become increasingly evident, and energy and resources can now be devoted to their solution. Every new field of scientific study has to mature, experimentally and emotionally. Human stem cells are no different, but if we rapidly develop a realistic acceptance of the inevitable problems and sustain a determined optimism about their solution, we can prove the project cynics wrong, avoid gloomy disavowal, and accelerate our exploitation of these extraordinary cells.