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Global Challenges in Stem Cell Researchand the Many Roads AheadDouglas Sipp 1 ,*1 RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047 Japan*Correspondence: sipp@cdb.riken.jpDOI 10.1016/j.neuron.2011.05.008

The eld of stem cell research has grown to include a vibrant international community of scientists and clini-cians whocome from both academia and industry and who strive to shed light on the biology of these remark-able cells and nd applications in drug discovery, disease modeling, and regenerative medicine.

IntroductionThe study of stem cell biology as a scien-tic discipline distinct from its roots in he-

matology, cancer biology, immunology,developmental biology, and neurosciencetraces back to landmark ndings in thelate 1990s. Such ndings include thecloning of Dolly the sheep ( Campbellet al., 1996 ) and the rst successful deri-vation of human embryonic stem (ES)cells ( Thomson et al., 1998 ). In a remark-ably short time-span, the eld has at-tracted an extraordinary level of publicexpectation and government support forits potential applications in regenerativemedicine, but it has also attracted signi-cant political and ethical controversy overthe use and manipulation of human bio-logic materials in some studies. Researchand policy approaches to stem cell bio-logy have coevolved, and the eld hasbecome a truly global enterprise.

One striking aspect of the internationalstem cell research community is the di-versity and depth ithas achieved ina shortspan. A number of smaller nations, suchas Israel, Sweden, and Singapore, havepunched well above their weight by iden-tifying and concentrating their efforts inspecic niches within the eld, whereas

many other countries with comparativelyscant prior experience in advanced bio-medical research and development, no-tably China andKorea, have built compet-itive research facilities and programs fromthe ground up. Meanwhile, religious andpolitical debates over issues such as theuse of human embryos for research,somatic cell nuclear transfer (therapeuticcloning), and the generation of human-animal hybrids have created problemsfor, and in some cases prevented, workin this eld in major research nations,

including the United States, Germany,and Australia. Indeed, the funding res-trictions on human ES cell research in

the USA might have inspired countries,many of them in Asia, that had not histor-ically conducted leading biomedical re-search to promote such research throughspecic regulatory and funding initiatives.

Despite the limitations imposed on fed-eral funding, however, the United Stateshas showed great robustness and inge-nuity in developing alternative fundingsources for stem cell research, for ex-ample through industry and philanthropicinvestment, patient activism, and fundinginitiatives by individual states. This de-federalization of stem cell research fund-ing is exemplied by the CaliforniaInstitute of Regenerative Medicine, whichhas led a $3 billion commitment over 10years ( CIRM, 2011 ). Other factors,including the countrys powerful researchuniversities, a tradition of scientic entre-preneurialism, regulatory clarity, and thesheer size of its life sciences and biotech-nology communities have ensured thateven in the face of numerous nonscientichurdles and intense international compe-tition, the United States remains theleader in most important metrics of

productivity, including publications,patents, and funding.

European UnityThis is not, however, to minimize thecontributions of other regions of theworld. In Europe, multiple countries haveshown consistently strong support forand high levels of achievement in stemcell research. The United Kingdom wasinstrumental in leading efforts to developtransparent, reasoned policies over theuse of human embryos for research,

nuclear transfer, and the creation of human admixed embryos. With strongconcentrations of talent and facilities

in London, Cambridge, and Edinburgh,among others, UK stem cell biologistshave made advances in fundamentalbiology and are leading the developmentof stem-cell-based treatments for strokeand macular degeneration. Sweden hasdeveloped dozens of human ES cell linesand has conducted pioneering clinicalstudies of fetal cell transplantation in thetreatment of Parkinson disease; thesestudies have helped to spur interest inthe use of stem cells in treating neuro-degenerative disorders. Germany, ham-pered by longstanding legal barriers tohuman ES cell research, has establishedcenters of excellence for the study of somatic stem cells and their potentialuse in regenerative medicine in Berlin,Munich, and the North Rhine/Westphaliaregion. In Barcelona, a joint investmentby the Spanish national and Catalonianstate governmentshas createda researchpark that is home to institutes such as theCenter for Genomic Regulation and theCenter for Regenerative Medicine withsuperior faculties and facilities support.

Intraregional cooperation and outreach

has also been a successful feature of stem cell science within the EU. In onefamousexample, a collaboration betweenscientistsand clinicians in Spain,Italy, andthe UK achieved a breakthrough proof-of-concept demonstration of the decellulari-zation-recellularization approach to tissuereplacement in 2009 when they useda patients own stem cells to repopulatea transplantable allogeneic tracheal seg-ment that had been denuded of thedonors cells ( Macchiarini et al., 2008 ). TheEuropean Science Foundation launched

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the EuroStells program to support basicresearch and comparative analyses of stem cells from various sources, and theFP6 program supported the development

of a much-needed online database of human embryonic stem cell lines, knownas hESCreg ( hESCreg, 2009 ). The Euro-StemCell project established under theFP7 program in 2010 brings togetherscientists and communicators fromaround 90 stem cell laboratories to en-gage with the public about their work( EuroStemCells, 2011 ).

The unifying structure of the EUhas not,however, entirely eliminated policy differ-ences betweencountries, and it has failedto bridge the considerable gap betweenmember states in areas such as human

ES cell research regulations. Recently,EU stem cell scientists have expressedgrowing concern over the possibility thatpatents based on human ES cell technol-ogies will be disallowed on the groundsthat they would offend public morality. A coalition of prominent scientists haveargued that such a decision would doirreparable harm to the ability of EU scien-tists and companies to compete in thisarea.

Asia Comes of AgeThe governments of many nations in Asiaand Oceania have shown extraordinarysupport for the development of stem cellresearch and application within theirborders. China, Korea, Singapore, India,and Taiwan have all invested unprece-dented amounts in stem cell researchsince 2001, and Japan and Australiahave built on their historical strengths inbasic biology and clinical developmentto create leading stem cell institutesin Kyoto, Kobe, and Melbourne ( Sipp,2009 ). Progress has not always beensmooththe scandal surrounding Woo-

Suk Hwangs fraudulent claimsof somaticcell nuclear transfer highlighted weak-nesses in the funding and oversightsystems that Korea, to its credit, wasquick to rectifyand, with the exceptionof Japan and more recently China,productivity has been incommensuratewith funding levels.

The Asia-Pacic region lacks a govern-ing organization equivalent to that of theEU, and this defecit continues to makethe establishment of region-wide stemcell research programs and collabora-

tions difcult. In 2007, Stem Cell Network: Asia-Pacic (SNAP) was launched byscientists from eight countries in theregion, but the organization has failed to

attract sustained funding or activity levelsin recent years. At the national level, many Asian countries have organized strongnational stem cell societies; some, suchas those in Singapore,Taiwan, andKorea,have hundreds of members representingdozens of labs. Japan lacks a stem cellsociety per se, but the Japanese Societyfor Regenerative Medicine has well over2,000 members. Unfortunately, the lackof a regional entity to coordinate stemcell research and development has led insome cases to redundancy and needlesscompetition in the building of stem cell

banks and the scheduling of internationalsymposia.

Although regulations of the use of human embryos for research have tendedtobe quite favorablein much of theregion,several countries have been caught off guard by a lack of preparedness for theclinical translation of stem cell research,andnumerous clinics advertisingspuriousstem cell injections for the treatment of a wide range of medical conditions haveput patients in harms way and damagedthe reputations of legitimate scientistsworking in the same country. Effortshave been made to address such unregu-lated uses of stem cells and have resultedin new regulations in Thailand and China,and the national prosecutors ofce in Ko-rea investigated one company that hadbeen recruiting patients to receive stemcell injections overseas.

Stem Cells on the Global Stage A number of organizations bring togetherscientists and stakeholders from aroundtheworld to promote the eld. Preeminentamong these is the International Society

for Stem Cell Research (ISSCR), withmore than 3600 members from morethan 40 countries representing academia,industry, government, and philanthropicorganizations ( ISSCR, 2011 ). The ISSCRworks to promote global discussion onthe latest advances in stem cell researchin its annual meetings, which are held ona rotating basis in North America, Europe,and the Asia-Oceania region, as well as toconduct educational and public-engage-ment activities around the world. It hasproducedconsensusguidelineson human

ES cell research and the clinical transla-tion of stem cell technologies, as well asinformation for patients considering stemcell treatments.

Other, more clinically oriented interna-tional groups focusing on stem cells andregenerativemedicine include the Interna-tional Society of Cellular Therapy (ISCT)and TERMIS, both of which gather re-searchers and clinicians from academiaand industry to discuss the developmentof human cell- and tissue-based medicalproducts and procedures. Support forinternational research efforts, with a par-ticular focus on human ES cell character-ization, banking, and cultural standards,has been provided for nearly ten yearsby the International Stem Cell Forum,

which comprises nearly 20 national andother funding agencies. The Interna-tional Consortium of Stem Cell Networksbrings together support and promotionorganizations from many countries, mostnotably Canada, Australia, and Germany.Industry meetings, research institutes,and national societies all also regularlyhold international conferences and work-shops on the full spectrum of stem cellresearch, ensuring that scientists in theeld are confronted by an embarrassmentof choices when making their conferenceschedules.

New Discoveries, New DirectionsMuch of the rst half of the rst decade of the 21 st century saw the eld dominatedby controversy and uncertainty over ques-tions such as the moral status of humanblastocysts, the comparative advantagesof ES and somatic stem cells, and therushto developstemcell-based transplan-tation procedures for use in regenerativemedicine. Therstreportof inducedplurip-otent stem (iPS) cells in 2006 ( TakahashiandYamanaka,2006 ) had a transformative

effecton theeldbecause itpavedthe wayto an alternative source for human pluripo-tent stem cells; this new source was muchless encumbered than human ES cellresearch by ethical concerns. Althoughthe initial discovery was made by a Japa-nese laboratory, it paradoxically strength-ened the hand of US-based researcherswho were freed from the funding restric-tions and legal and political disputes thathad dogged human ES cell research, andat present it is the US rather than Japanthat dominate iPS cell research. The

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Japanese government has, however, in-vested heavily in the eld and hascreated a Center for iPS Cell Researchand Application led by Shinya Yamanaka

at Kyoto University; China has alsoramped up its stem cell investment,including its investment in many iPS celllabs, in its most recent national 5 yrspending plan.

Technological developments have alsoled to a number of industry-funded clinicaltrials of stem cell-based treatments forconditions such as heart failure, spinalcord injury, cerebrovascular accident,and amyotrophic lateral sclerosis. In allcases, however, these studies are at theearliest stages of safety testing, and theroad to regulatory approval will doubtless

be long and fraught with challenges. Afterthe excitement of the rst days of inten-sive stem cell research, the reality of theunique challenges of cell-based productshas set in. Scientists, physicians, andregulators alike have recognized the risksand limitations imposed by the ability of stem cells of various types to proliferate,differentiate, home to wound and tumorsites, and secrete multiple molecularfactors; indeed, nearly every property of potential clinical benet also representsa potential risk. Whether stem cells ortheir derivatives will be able to integrateinto target tissues, particularly dynamicor complex environments such as cardiacmuscle or the nervous system, and lead tothe restoration of physiological functionremains very much an open question,and concerns have also been raised thatsome degenerative diseases might beassociated with pathogenic tissue envi-ronments capable of damaging or trans-forming stem cells, which might furthercomplicate their use in the treatment of such conditions. Furthermore, the long-term genetic and karyotypic stability of

stem cells in vivo outside the hematopoi-etic system is largely unknown, and anytreatment protocol that calls for cells tofunctionally integrate and survive for thelife of the patient will need to includeprovisions for follow-up and surveillanceover the long term. It will be importantfor scientists, policymakers, and fundingbodies to remain focused and alert foropportunities in the development of truestem cell-based treatments while main-taining realistic and responsible oversightto ensure patient safety and public trust.

At the same time, a number of potentialstem cell applications that do not followthe cell therapy paradigm have gainedprominence in recent years. The advent

of human iPS cells has opened up pos-sibilities for the generation of large, purepopulations of differentiated cells, suchas cardiomyocytes, hepatocytes, andneurons of various types, which couldprove invaluable as test beds for use indrug discovery, toxicology testing, anddisease modeling. These have the addedadvantage of serving as a potential re-placement for some types of animalstudies, provided that human cells in vitrocan be shown to differentiate into phys-iological tissue and mimic disease stateswith sufcient accuracy. Stem Cells for

Safer Medicine ( SC4SM, 2010 ), a coalitionthat includes three major drug companies,has already been formed with the aim of exploring the possibilities of stem cells inpharmaceutical development.

Results from some clinical studies usingmesenchymal stem cells (MSCs) haveshown transient benets but poor cellsurvival, leading to speculation that theeffectsmight be due to paracrine secretionof cytokines andother factors,which mighttrigger wound healing or angiogenesis ormodulate the immune response. Bio-pro-specting research into such stem cellsmight reveal the specic cocktails of factors able to elicit such healing res-ponses, and if isolated and tested, suchfactors might one day lead to the develop-ment of cell therapy without cells. Simi-larly, there have been proposals to useMSCs, which have been shown to hometo sites of tissue damage and tumorigen-esis, asvehicles forthe deliveryof bioactivemolecules or nanomaterials. Finally, thediscovery that cell fates can be reprog-rammed, as evidenced by the transforma-tionof broblasts into pluripotentstemcells

in the iPS cell process, might lead tonew advances in direct reprogrammingbetween differentiated cells types; suchreprogramming has already been demon-strated in the conversion of exocrine intoendocrine cells in the pancreas ( Zhouet al., 2008 ) and in the conversion of B cellsinto macrophages in the blood system( Bussmann et al., 2009 ). Although thesealternative uses of stem cells might haveless charismatic appeal than the classicconcept of cell transplantation, they couldallow important successes in the near

term while studies on more challengingclinical applications move forward.

The unregulated use of stem cells inmedicine, often referred to as stem cell

tourism, remains one of the greatestthreats to patients and to the eld itself ( Taylor et al., 2010 ). Hundreds of compa-nies market untested stem cell productsand injections for an extremely broadrange of diseases, many of which, suchas spinal cord injury, ALS, autism, Parkin-son disease, and multiple sclerosis, affectthe nervous system. Strides have beenmade in reining in such unscrupulousbehavior after multiple incidents of tumor-igenesis anddeath as the resultof compli-cations following injections of cells intothe brainstem or carotid artery, but com-

panies have shown great resourcefulnessin their ability to evade oversight and lurepatients. The international stem cell com-munity has been extremely active incombatting the premature commerciali-zation of stem cell treatments and willneed to continue to work with authorities,patient groups, and media organizationsto inform and protect patients from suchpractices.

Stem cell research continues to be oneof themost exciting andhighlyanticipatedelds of biological research, and it enjoysexceptional support from funding agen-cies and the general public in countriesaround the world. The road to applica-tions will be a long one, and numeroushurdles lie ahead. The success of the eldwill continue to rely heavily on funda-mental research to provide a solid basisof understanding for clinical studies, andscientists in all countries will need tocontinue to collaborate, share, compete,and strive together if the extraordinarypromise of stem cell research is to berealized.

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