CORRESPONDENCE Open Access

Is belief larger than fact expectations optimismand reality for translational stem cell researchTania Bubela1 Matthew D Li1 Mohamed Hafez2 Mark Bieber1 and Harold Atkins2

Abstract

Background Stem cell (SC) therapies holdremarkable promise for many diseases but there is asignificant gulf between public expectations and thereality of progress toward clinical application Publicexpectations are fueled by stakeholder arguments forresearch and public funding coupled with intensemedia coverage in an ethically charged arena Weexamine media representations in light of theexpanding global landscape of SC clinical trials askingwhat patients may realistically expect by way oftimelines for the therapeutic and curative potential ofregenerative medicine

Methods We built 2 international datasets (1) 3404clinical trials (CT) containing lsquostem cellrsquo fromClinicalTrialsgov and the World Health OrganizationrsquosInternational Clinical Trials Registry Search Portal and(2) 13249 newspaper articles on SC therapies usingFactivacom We compared word frequencies betweenthe CT descriptions and full-text newspaper articlesfor the number containing terms for SC type anddiseasesconditions We also developed inclusion andexclusion criteria to identify novel SC CTs mainlyregenerative medicine applications

Results Newspaper articles focused on humanembryonic SCs and neurological conditions withsignificant coverage as well of cardiovascular diseaseand diabetes In contrast CTs used primarilyhematopoietic SCs with an increase in CTs usingmesenchymal SCs since 2007 The latter dominatedour novel classification for CTs most of which are inphases I and II From the perspective of the publicexpecting therapies for neurological conditions thereis limited activity in what may be considered novelapplications of SC therapies

Conclusions Given the research regulatory andcommercialization hurdles to the clinical translation ofSC research it seems likely that patients and politicalsupporters will become disappointed anddisillusioned In this environment proponents need tomake a concerted effort to temper claims Eventhough the field is highly promising it lackssignificant private investment and is largely reliant onpublic support requiring a more honestacknowledgement of the expected therapeuticbenefits and the timelines to achieving them

Keywords stem cell therapy clinical trials publicexpectations newspaper coverage commercializationethics

IntroductionStem cell (SC) therapies hold remarkable promise parti-cularly in the management of diseases and conditionsfor which there are currently limited or no treatmentoptions [1] As with all emerging technologies creatingnovel applications from an evolving knowledge base is aslow process Often development commences in nicheareas and only after initial success does the technologyexpand to broader use Many SC investigators thereforefeel that there is a significant gulf between public expec-tations and the reality of progress toward clinical SCapplication a phenomenon observed for other novelbiotechnologies [2] In this paper we examine this gulfby comparing public expectations as represented inmedia coverage with translation of SC research towardsthe clinic as represented in registers of clinical trials(CT)This paper examines media coverage in an era of

expanding SC clinical activity around the globe Mediacoverage both shapes and reflects public expectations forSC research [3] The media record provides a generaltimeline of translational SC research and spikes in atten-tion that reflect specific events [4] As media reports area major source of health and science information for the

Correspondence tbubelaualbertaca1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta CanadaFull list of author information is available at the end of the article

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

copy 2012 Bubela et al licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (httpcreativecommonsorglicensesby20) which permits unrestricted use distribution and reproduction inany medium provided the original work is properly cited

public [3] they also represent the public face of SCresearch and thus the messages on which public expecta-tions are based Likewise examining the current clinicaltrial landscape reveals the reality and direction ofongoing improvements to established SC applicationsand the development of new applications based uponinnovative research While SC transplants are the stan-dard of care for hematopoietic cancers and are gainingacceptance in the treatment of burns and corneal disor-ders pioneering SC therapies directed at the regenerationof other tissues and organs (that is the promise of regen-erative medicine) are few in number use adult ratherthan embryonic stem cells and are in the early stages ofclinical investigationIn this paper we characterize the gap between public

expectations represented in media coverage and the spec-trum of ongoing SC clinical trials We first describe theinfluences that can alter expectations for SC research Wethen describe our methods and results which focus on thesubset of trials that comprise novel regenerative medicineapplications and representations of the types of SCs usedand diseases to be treated or cured Our discussion con-textualizes the gap between current realities and expecta-tions concentrating on the scientific regulatory ethicaland commercial challenges facing SC research as it pro-gresses through clinical development to clinical applica-tion Our goal is to uncover the nature of the biases in thepublic discourse on stem cell research that separates factfrom fiction This is the first step to creating better com-munication strategies among the clinical research commu-nity and the public patients and policy makers The latterstakeholders need to understand what realistically toexpect by way of timelines for the therapeutic and curativepotential of regenerative medicine

BackgroundThere are many potential reasons for the publicrsquos highexpectations for SC based therapy [5] however advancesin the stem cell arena reported to the public may beskewed by media coverage that focuses preferentiallyupon ethically charged topics [4] This could fuel overlyoptimistic speculation by investigators and patient advo-cates looking to counter ethical opposition to humanembryonic (hESCs) and fetal SC research even thoughethical objections have been tempered with the discoveryof induced pluripotent SCs (iPSCs) [6] Further inflationof expectations occurs through direct advertising to des-perate patients by clinics offering unproven SC therapieswhich have sprung up in jurisdictions with lax regulatoryoversight [7] and by dramatic situations portrayed inpopular culture [18] such as the growth of multipleorgans from SCs on Greyrsquos AnatomyInflation of expectations may also result from societal

pressures such as the potential for economic returns on

research investment job creation in a new industry andthe fear that commercial benefits will flow elsewhere inthe absence of a supportive funding and regulatory envir-onment [5] The notion of research largely from aca-demic centers as an economic engine has been gainingmomentum since the 1960s when policymakers beganlinking innovation with productivity and economicgrowth [9] This argument has fueled support for publicfunds for biomedical research but in the case of SCresearch Vannevar Bushrsquos observation may hold that lsquoabelief may be larger than a factrsquo [8] Policy reports claimSC therapies will in the foreseeable future not onlyregenerate damaged tissues and organs but enable thegrowth of transplantable organs and combat risinghealthcare costs [10] Policy-based estimates of economicreturn range over orders of magnitude from tens of mil-lions to billions of dollars [5] while predicted employ-ment gains vary from tens of thousands to hundreds ofthousands of jobs Jurisdictions as disparate as IndiaChina Japan Singapore the UK Australia and Canadaall signal intense international competition for economicadvantage each declaring a bid for pre-eminence Forexample in his parting speech to the Labour Party for-mer British Prime Minister Tony Blair declared lsquoHow tobe the worldrsquos number one place of choice for bioscienceif America does not want stem-cell research we dorsquo [11]Yet contrary to the hype large-scale corporate invest-ment in the field has been slow to materialize because ofthe lack of proven business and investment modelsNevertheless many researchers attempt to temper

expectations and timelines acknowledging the complexityof cellular processes and the need for a better understand-ing of developmental biology [112] Based on the historyof advances in biotechnology George Daley has recentlystated that lsquoit takes some two decades for a new biotech-nology advance to translate into widely successful clinicaltherapiesrsquo [12] Given that hESCs were first described in1998 and iPSCs in 2007 lsquowe might anticipate some 10 to15 years before effective products are developed therebylaunching the era of regenerative medicinersquo [12] Else-where however Daley has stated lsquoWe should be humbleand appreciate it may take us the better part of this cen-tury to truly harness the power of cells as medicinesrsquo [13]Regulators are similarly taking a cautionary approach to

emerging applications [1415] despite building pressuresto accelerate the development of SC therapies Regulatorsshare the concerns of many investigators that exaggerationand hype have real-world consequences currently mani-fested by the rise in SC tourism [16] to SC clinics [7]Services are offered most commonly for neurologicaldiseases including multiple sclerosis stroke Parkinsonrsquosdisease spinal cord injury and Alzheimerrsquos disease andcardiovascular diseases [7] SC tourism has necessitated aresponse by the International Society for Stem Cell

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Page 2 of 10

Research (ISSCR) because lsquoadministering unproven SCinterventions outside a carefully regulated clinical trialputs individual patients at risk and also jeopardizes thelegitimate progress of translational SC researchrsquo [14]These scientific regulatory and commercial challenges areat odds with public expectations which seek to increasethe pace of clinical development and have healthcare sys-tems fund what will likely be personalized and costlytherapies

MethodsNewspaper articlesWe built a dataset of newspaper articles using Factivacom (Dow Jones amp Co) a comprehensive database ofmajor newspapers from the USA and UK which alsoincludes all major newspapers in Canada We searchedwithout date restrictions for (lsquostem cellrsquo or lsquostem cellsrsquo)AND (therapy or therapies or therapeutic or therapeu-tics or treatment or treatments) Factiva identified andremoved duplicates We then analyzed both our CTdataset described below (title brief summary anddetailed description for each CT) and the full-text news-paper dataset using a custom word frequency analysisprogram that enabled a set of documents to be searchedusing multiple words or phrases separated by andorThe result of each search query was not the number oftimes that a search term occurred rather it was thenumber of documents containing the term(s) We com-pared word frequencies using c2 analyses in two timeblocks 1990 to 2000 and 2001 to 2010 While the broadsearch strategy may have captured newspaper articlesthat were only tangentially related to translational SCresearch our keyword analysis extracted newspaper arti-cles from this set that specifically referred to SC typesand disease categories

Clinical trialsWe searched the term lsquostem cellrsquo in the worldrsquos largest andmost comprehensive database for CTs ClinicalTrialsgovand a second portal that captures international trials notregistered with the US National Institutes of Health (NIH)the World Health Organizationrsquos International ClinicalTrials Registry Search Portal [17] The latter included trialsfrom Australia and New Zealand UK Brazil China IndiaSouth Korea Cuba Germany Iran Japan Africa SriLanka and The Netherlands We removed non-SC-relatedtrials that were nevertheless captured by the search andduplicates (trials registered in more than one database)We constructed a database of CT information usingall fields limiting our analysis to CTs registered before1 January 2011We coded all CTs in the dataset for the principle dis-

easecondition addressed and CTs could fall within morethan one category We then developed inclusion and

exclusion criteria to identify groundbreaking or novel SCtherapies and coded the trials based on their descriptionsupplemented by related publications and websites Thelatter was necessary for example to characterize a thera-peutic agent identified only by its proprietary name in thetrial descriptionOur definition of novel SC therapies was CTs that

involved (1) the use of stem or precursor cells to stimulatenon-hematopoietic organ regeneration (for example lim-bal SCs for corneal regeneration or hematopoietic SCs forcardiac repair) (2) the use of agents to stimulate stem orprecursor cell action for regenerative or therapeutic pur-poses (3) the use of established hematopoietic SC trans-plantation procedures for novel indications (for exampleautoimmune or congenital diseases) (4) the use of novelagents or processes for stem or precursor cell collectionpurification or expansion and (5) the use of geneticallymodified stem or precursor cells These categories fall pre-dominantly within Mason et alrsquos definition of regenerativemedicine [18]We excluded CTs from our lsquonovelrsquo category that were

observational in nature for example some CTs measuredcirculating endothelial precursor cells without a therapeu-tic goal involved an established SC therapy for an estab-lished indication most commonly hematopoietic SCtransplantation for hematological malignancies or investi-gated supportive measures surrounding an SC therapy forexample antibiotics to prevent infection in hematopoieticSC transplant recipients

ResultsThe analysis was based on the total of 13249 newspaperarticles collected using our broad search strategy and3404 CTs from 1978 to 2011 The apparent decline inCTs from 2009 to 2010 may reflect economic declinefrom 2008 but is more likely due to a lag in the registra-tion of trials It is worth noting that there was a slight risein CTs after 2000 which may be the result of the institu-tion of stricter registration requirements for acceptance ofCTs for publication [19]

Newspaper articlesNewspaper articles focused mainly on human embryonicSCs and neurological conditions with significant coverageof cardiovascular disease and diabetes as well Newspapercoverage peaked in 2001 and again in 2005 coincidingwith US President George Bushrsquos 2001 Directive limitingthe use of federal funds for derivation of new hESC linesand similar discourse following his re-election at the endof 2004 (Figure 1A) [4] Notably a similar spike in cover-age did not accompany US President Barack ObamarsquosExecutive Order signed 9 March 2009 reversing PresidentBushrsquos Directive We discussed the framing of the issues innewspaper coverage around hESC research in a previous

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Page 3 of 10

paper [4] The key result here is that hESCs dominatednewspaper coverage of SC research with slight coverageof the discovery of iPSCs in November 2007 mainlyfocused on their being an lsquoethicalrsquo alternative to hESCs(Figure 1A) [6] This leaves hESCs front and center in thepublic mind with respect to the type of stem cell in clinical

development In contrast while newspapers referred toadult SCs and occasionally their tissue of origin theyrarely referenced terms such as hematopoietic andmesenchymal or synonyms for these such as blood SCsIn addition newspaper articles focused disproportionatelyon neurological conditions primarily multiple sclerosis

a)

b)

Figure 1 Stem cell types in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage of newspaperarticles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to 2000 and2001 to 2010 (P lt0001)

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stroke Parkinsonrsquos disease spinal cord injury and Alzhei-merrsquos disease with significant coverage also of cardiovascu-lar disease and diabetes (Figure 2A) Neurological diseaseswere significantly linked to coverage of hESC research andtherapies Promising research in therapies for ocular con-ditions such as corneal repair and macular degenerationreceived a small but steady amount of coverage from 2000onwards

Clinical trialsIn contrast all CTs (n = 3404) were dominated by useof adult SCs primarily hematopoietic SCs with sometrials using umbilical cord blood derived SCs Therewere an increasing number of trials using mesenchymalstem cells (MSCs) from 2007 (Figure 1B) The latterdominated our novel classification for CTs most ofwhich were in phases I and II (Figure 3) Figure 4 showsthe global landscape for innovative CTs with higherproportions using MSCs in Asia and the Middle EastAs of 2011 iPSCs had not entered CTs and the best-

known trial using hESCs started in October 2010 byGeron for spinal cord injury was halted in November2011 after use in only four trial subjects Three additionaltrials by Advanced Cell Technology (Santa Monica CAUSA) began in July 2011 two using retinal pigmentepithelial cells derived from hESCs for Stargardtrsquos maculardystrophy and one for dry age-related macular degenera-tion [20] CTs for cancers and graft-versus-host disease(GVHD) which composed most of the lsquoother diseasesrsquocategory dominated the SC CT landscape (Figure 2B)Nevertheless there was a steady increase in CTs for cardi-ovascular disease beginning in 2001 and a small numberof trials for neurological ocular conditions and diabetes(note that the key word analysis for diabetes also capturedCTs for associated morbidities such as diabetic foot) Ourdetailed examination of novel CTs was dominated by trialsusing MSCs and for conditions other than hematologicalcancersOur criteria for novel SC CTs resulted in the selection of

639 (19) CTs that if successful would become the nextgeneration of regenerative treatments A total of 512 ofthese CTs clearly indicated study phase and of these themajority were safety trials in phases I or II (Figure 4) Only54 novel CTs were in phases IIIII or III and 17 were inphases IIIIV or IV (Table 1) The majority of clinical trialsin phase IIIIV (n = 11) used drug treatments to activateendothelial progenitor cells for therapeutic purposes incardiovascular diseases (which may be associated withother diseases such as diabetes and ankylosing spondylitis)A further three advanced stage trials used stents to facili-tate vascular repair by capturing endothelial progenitorcells in the stent and three trials addressed metabolicsyndrome critical limb ischemia and breast deformitiesfollowing a lumpectomy

While the public and policymakers expect therapies forneurological conditions there was limited activity inwhat may be considered novel application of SC thera-pies Among the novel CTs only 69 trials addressed neu-rological conditions (Table 2) and only 1 in our datasetthe Geron (Menlo Park CA USA) trial used hESCs Themajority of trials used hematopoietic stem cells or MSCsFor example clinical trials for multiple sclerosis usedautologous transplantation of MSCs or hematopoieticSCs following chemotherapy to achieve immunomodula-tion and facilitate regeneration of the central nervous sys-tem Two trials being conducted in India for Parkinsonrsquosdisease used MSCsThe majority of novel trials were publicly funded how-

ever some industry involvement was evident Industrytrials targeted both orphan and common diseases Threephase I trials by StemCells Inc (Newark CA USA)employed cultured allogeneic neural SCs (HuCNS-SC) totreat Pelizaeus-Merzbacher disease and neuronal ceroidlipfuscinosis Ischemic stroke was the focus of significantindustry involvement with 6 of 18 CTs sponsored byStem Cell Therapeutics (Toronto Canada) ReNeuron(Guildford UK) and Stempeutics Research (BangaloreIndia) The phase I trial by ReNeuron used a manufac-tured neural SC line (CTX cells) while the four Stem CellTherapeutics trials attempted to use a proprietary drug(NTx-265) to promote neural regeneration Howevernews reports indicated the lack of demonstrable effect inthe latter CTs [21]Of all the other diseases highlighted in the media 208

CTs were for cardiovascular disease 75 targeted theheart and 25 the peripheral vascular system Almost allof these trials involved MSCs mobilization of hemato-poietic SCs other purified bone marrow-derived SCs orendothelial progenitor cells for regenerative and suppor-tive purposes There were 27 novel trials for diabetesmellitus and these CTs attempted to treat both Type Iand Type II diabetes using hematopoietic and MSCsfrom adipose tissue umbilical cord blood and bone mar-row Private sector companies were involved as colla-borators or sponsors in eight of the trials includingOsiris Therapeutics (Columbia MD USA) Adistem(Hong Kong China) Transition Therapeutics (TorontoCanada) Cellonis Biotechnology (Beijing China) andGenzyme (Cambridge MA USA)

DiscussionInnovative biomedical technologies are prone to lsquosocialbubblesrsquo where categories of lsquoenthusiastic supportersweave a network of reinforcing feedbacks that lead towidespread endorsement and extraordinary commitmentby those involved in the projectrsquo [22] The enthusiasm ofstakeholders such as researchers the public politiciansand funders in promoting optimistic timelines often

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Page 5 of 10

masks the slow uptake of clinical applications and tech-nologies within health systems whether in biotechnology[2324] in general or more specifically in genomics [25]

or SC research Our results show that there is a large gapbetween public expectations and clinical realities withpublic representations focused on hESCs and on cures

a)

b)

Figure 2 Categories of diseases in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage ofnewspaper articles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to2000 and 2001 to 2010 (P lt 0001)

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Page 6 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

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dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

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long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

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Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

Research (ISSCR) because lsquoadministering unproven SCinterventions outside a carefully regulated clinical trialputs individual patients at risk and also jeopardizes thelegitimate progress of translational SC researchrsquo [14]These scientific regulatory and commercial challenges areat odds with public expectations which seek to increasethe pace of clinical development and have healthcare sys-tems fund what will likely be personalized and costlytherapies

MethodsNewspaper articlesWe built a dataset of newspaper articles using Factivacom (Dow Jones amp Co) a comprehensive database ofmajor newspapers from the USA and UK which alsoincludes all major newspapers in Canada We searchedwithout date restrictions for (lsquostem cellrsquo or lsquostem cellsrsquo)AND (therapy or therapies or therapeutic or therapeu-tics or treatment or treatments) Factiva identified andremoved duplicates We then analyzed both our CTdataset described below (title brief summary anddetailed description for each CT) and the full-text news-paper dataset using a custom word frequency analysisprogram that enabled a set of documents to be searchedusing multiple words or phrases separated by andorThe result of each search query was not the number oftimes that a search term occurred rather it was thenumber of documents containing the term(s) We com-pared word frequencies using c2 analyses in two timeblocks 1990 to 2000 and 2001 to 2010 While the broadsearch strategy may have captured newspaper articlesthat were only tangentially related to translational SCresearch our keyword analysis extracted newspaper arti-cles from this set that specifically referred to SC typesand disease categories

Clinical trialsWe searched the term lsquostem cellrsquo in the worldrsquos largest andmost comprehensive database for CTs ClinicalTrialsgovand a second portal that captures international trials notregistered with the US National Institutes of Health (NIH)the World Health Organizationrsquos International ClinicalTrials Registry Search Portal [17] The latter included trialsfrom Australia and New Zealand UK Brazil China IndiaSouth Korea Cuba Germany Iran Japan Africa SriLanka and The Netherlands We removed non-SC-relatedtrials that were nevertheless captured by the search andduplicates (trials registered in more than one database)We constructed a database of CT information usingall fields limiting our analysis to CTs registered before1 January 2011We coded all CTs in the dataset for the principle dis-

easecondition addressed and CTs could fall within morethan one category We then developed inclusion and

exclusion criteria to identify groundbreaking or novel SCtherapies and coded the trials based on their descriptionsupplemented by related publications and websites Thelatter was necessary for example to characterize a thera-peutic agent identified only by its proprietary name in thetrial descriptionOur definition of novel SC therapies was CTs that

involved (1) the use of stem or precursor cells to stimulatenon-hematopoietic organ regeneration (for example lim-bal SCs for corneal regeneration or hematopoietic SCs forcardiac repair) (2) the use of agents to stimulate stem orprecursor cell action for regenerative or therapeutic pur-poses (3) the use of established hematopoietic SC trans-plantation procedures for novel indications (for exampleautoimmune or congenital diseases) (4) the use of novelagents or processes for stem or precursor cell collectionpurification or expansion and (5) the use of geneticallymodified stem or precursor cells These categories fall pre-dominantly within Mason et alrsquos definition of regenerativemedicine [18]We excluded CTs from our lsquonovelrsquo category that were

observational in nature for example some CTs measuredcirculating endothelial precursor cells without a therapeu-tic goal involved an established SC therapy for an estab-lished indication most commonly hematopoietic SCtransplantation for hematological malignancies or investi-gated supportive measures surrounding an SC therapy forexample antibiotics to prevent infection in hematopoieticSC transplant recipients

ResultsThe analysis was based on the total of 13249 newspaperarticles collected using our broad search strategy and3404 CTs from 1978 to 2011 The apparent decline inCTs from 2009 to 2010 may reflect economic declinefrom 2008 but is more likely due to a lag in the registra-tion of trials It is worth noting that there was a slight risein CTs after 2000 which may be the result of the institu-tion of stricter registration requirements for acceptance ofCTs for publication [19]

Newspaper articlesNewspaper articles focused mainly on human embryonicSCs and neurological conditions with significant coverageof cardiovascular disease and diabetes as well Newspapercoverage peaked in 2001 and again in 2005 coincidingwith US President George Bushrsquos 2001 Directive limitingthe use of federal funds for derivation of new hESC linesand similar discourse following his re-election at the endof 2004 (Figure 1A) [4] Notably a similar spike in cover-age did not accompany US President Barack ObamarsquosExecutive Order signed 9 March 2009 reversing PresidentBushrsquos Directive We discussed the framing of the issues innewspaper coverage around hESC research in a previous

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 3 of 10

paper [4] The key result here is that hESCs dominatednewspaper coverage of SC research with slight coverageof the discovery of iPSCs in November 2007 mainlyfocused on their being an lsquoethicalrsquo alternative to hESCs(Figure 1A) [6] This leaves hESCs front and center in thepublic mind with respect to the type of stem cell in clinical

development In contrast while newspapers referred toadult SCs and occasionally their tissue of origin theyrarely referenced terms such as hematopoietic andmesenchymal or synonyms for these such as blood SCsIn addition newspaper articles focused disproportionatelyon neurological conditions primarily multiple sclerosis

a)

b)

Figure 1 Stem cell types in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage of newspaperarticles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to 2000 and2001 to 2010 (P lt0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 4 of 10

stroke Parkinsonrsquos disease spinal cord injury and Alzhei-merrsquos disease with significant coverage also of cardiovascu-lar disease and diabetes (Figure 2A) Neurological diseaseswere significantly linked to coverage of hESC research andtherapies Promising research in therapies for ocular con-ditions such as corneal repair and macular degenerationreceived a small but steady amount of coverage from 2000onwards

Clinical trialsIn contrast all CTs (n = 3404) were dominated by useof adult SCs primarily hematopoietic SCs with sometrials using umbilical cord blood derived SCs Therewere an increasing number of trials using mesenchymalstem cells (MSCs) from 2007 (Figure 1B) The latterdominated our novel classification for CTs most ofwhich were in phases I and II (Figure 3) Figure 4 showsthe global landscape for innovative CTs with higherproportions using MSCs in Asia and the Middle EastAs of 2011 iPSCs had not entered CTs and the best-

known trial using hESCs started in October 2010 byGeron for spinal cord injury was halted in November2011 after use in only four trial subjects Three additionaltrials by Advanced Cell Technology (Santa Monica CAUSA) began in July 2011 two using retinal pigmentepithelial cells derived from hESCs for Stargardtrsquos maculardystrophy and one for dry age-related macular degenera-tion [20] CTs for cancers and graft-versus-host disease(GVHD) which composed most of the lsquoother diseasesrsquocategory dominated the SC CT landscape (Figure 2B)Nevertheless there was a steady increase in CTs for cardi-ovascular disease beginning in 2001 and a small numberof trials for neurological ocular conditions and diabetes(note that the key word analysis for diabetes also capturedCTs for associated morbidities such as diabetic foot) Ourdetailed examination of novel CTs was dominated by trialsusing MSCs and for conditions other than hematologicalcancersOur criteria for novel SC CTs resulted in the selection of

639 (19) CTs that if successful would become the nextgeneration of regenerative treatments A total of 512 ofthese CTs clearly indicated study phase and of these themajority were safety trials in phases I or II (Figure 4) Only54 novel CTs were in phases IIIII or III and 17 were inphases IIIIV or IV (Table 1) The majority of clinical trialsin phase IIIIV (n = 11) used drug treatments to activateendothelial progenitor cells for therapeutic purposes incardiovascular diseases (which may be associated withother diseases such as diabetes and ankylosing spondylitis)A further three advanced stage trials used stents to facili-tate vascular repair by capturing endothelial progenitorcells in the stent and three trials addressed metabolicsyndrome critical limb ischemia and breast deformitiesfollowing a lumpectomy

While the public and policymakers expect therapies forneurological conditions there was limited activity inwhat may be considered novel application of SC thera-pies Among the novel CTs only 69 trials addressed neu-rological conditions (Table 2) and only 1 in our datasetthe Geron (Menlo Park CA USA) trial used hESCs Themajority of trials used hematopoietic stem cells or MSCsFor example clinical trials for multiple sclerosis usedautologous transplantation of MSCs or hematopoieticSCs following chemotherapy to achieve immunomodula-tion and facilitate regeneration of the central nervous sys-tem Two trials being conducted in India for Parkinsonrsquosdisease used MSCsThe majority of novel trials were publicly funded how-

ever some industry involvement was evident Industrytrials targeted both orphan and common diseases Threephase I trials by StemCells Inc (Newark CA USA)employed cultured allogeneic neural SCs (HuCNS-SC) totreat Pelizaeus-Merzbacher disease and neuronal ceroidlipfuscinosis Ischemic stroke was the focus of significantindustry involvement with 6 of 18 CTs sponsored byStem Cell Therapeutics (Toronto Canada) ReNeuron(Guildford UK) and Stempeutics Research (BangaloreIndia) The phase I trial by ReNeuron used a manufac-tured neural SC line (CTX cells) while the four Stem CellTherapeutics trials attempted to use a proprietary drug(NTx-265) to promote neural regeneration Howevernews reports indicated the lack of demonstrable effect inthe latter CTs [21]Of all the other diseases highlighted in the media 208

CTs were for cardiovascular disease 75 targeted theheart and 25 the peripheral vascular system Almost allof these trials involved MSCs mobilization of hemato-poietic SCs other purified bone marrow-derived SCs orendothelial progenitor cells for regenerative and suppor-tive purposes There were 27 novel trials for diabetesmellitus and these CTs attempted to treat both Type Iand Type II diabetes using hematopoietic and MSCsfrom adipose tissue umbilical cord blood and bone mar-row Private sector companies were involved as colla-borators or sponsors in eight of the trials includingOsiris Therapeutics (Columbia MD USA) Adistem(Hong Kong China) Transition Therapeutics (TorontoCanada) Cellonis Biotechnology (Beijing China) andGenzyme (Cambridge MA USA)

DiscussionInnovative biomedical technologies are prone to lsquosocialbubblesrsquo where categories of lsquoenthusiastic supportersweave a network of reinforcing feedbacks that lead towidespread endorsement and extraordinary commitmentby those involved in the projectrsquo [22] The enthusiasm ofstakeholders such as researchers the public politiciansand funders in promoting optimistic timelines often

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 5 of 10

masks the slow uptake of clinical applications and tech-nologies within health systems whether in biotechnology[2324] in general or more specifically in genomics [25]

or SC research Our results show that there is a large gapbetween public expectations and clinical realities withpublic representations focused on hESCs and on cures

a)

b)

Figure 2 Categories of diseases in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage ofnewspaper articles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to2000 and 2001 to 2010 (P lt 0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 6 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 7 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

paper [4] The key result here is that hESCs dominatednewspaper coverage of SC research with slight coverageof the discovery of iPSCs in November 2007 mainlyfocused on their being an lsquoethicalrsquo alternative to hESCs(Figure 1A) [6] This leaves hESCs front and center in thepublic mind with respect to the type of stem cell in clinical

development In contrast while newspapers referred toadult SCs and occasionally their tissue of origin theyrarely referenced terms such as hematopoietic andmesenchymal or synonyms for these such as blood SCsIn addition newspaper articles focused disproportionatelyon neurological conditions primarily multiple sclerosis

a)

b)

Figure 1 Stem cell types in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage of newspaperarticles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to 2000 and2001 to 2010 (P lt0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 4 of 10

stroke Parkinsonrsquos disease spinal cord injury and Alzhei-merrsquos disease with significant coverage also of cardiovascu-lar disease and diabetes (Figure 2A) Neurological diseaseswere significantly linked to coverage of hESC research andtherapies Promising research in therapies for ocular con-ditions such as corneal repair and macular degenerationreceived a small but steady amount of coverage from 2000onwards

Clinical trialsIn contrast all CTs (n = 3404) were dominated by useof adult SCs primarily hematopoietic SCs with sometrials using umbilical cord blood derived SCs Therewere an increasing number of trials using mesenchymalstem cells (MSCs) from 2007 (Figure 1B) The latterdominated our novel classification for CTs most ofwhich were in phases I and II (Figure 3) Figure 4 showsthe global landscape for innovative CTs with higherproportions using MSCs in Asia and the Middle EastAs of 2011 iPSCs had not entered CTs and the best-

known trial using hESCs started in October 2010 byGeron for spinal cord injury was halted in November2011 after use in only four trial subjects Three additionaltrials by Advanced Cell Technology (Santa Monica CAUSA) began in July 2011 two using retinal pigmentepithelial cells derived from hESCs for Stargardtrsquos maculardystrophy and one for dry age-related macular degenera-tion [20] CTs for cancers and graft-versus-host disease(GVHD) which composed most of the lsquoother diseasesrsquocategory dominated the SC CT landscape (Figure 2B)Nevertheless there was a steady increase in CTs for cardi-ovascular disease beginning in 2001 and a small numberof trials for neurological ocular conditions and diabetes(note that the key word analysis for diabetes also capturedCTs for associated morbidities such as diabetic foot) Ourdetailed examination of novel CTs was dominated by trialsusing MSCs and for conditions other than hematologicalcancersOur criteria for novel SC CTs resulted in the selection of

639 (19) CTs that if successful would become the nextgeneration of regenerative treatments A total of 512 ofthese CTs clearly indicated study phase and of these themajority were safety trials in phases I or II (Figure 4) Only54 novel CTs were in phases IIIII or III and 17 were inphases IIIIV or IV (Table 1) The majority of clinical trialsin phase IIIIV (n = 11) used drug treatments to activateendothelial progenitor cells for therapeutic purposes incardiovascular diseases (which may be associated withother diseases such as diabetes and ankylosing spondylitis)A further three advanced stage trials used stents to facili-tate vascular repair by capturing endothelial progenitorcells in the stent and three trials addressed metabolicsyndrome critical limb ischemia and breast deformitiesfollowing a lumpectomy

While the public and policymakers expect therapies forneurological conditions there was limited activity inwhat may be considered novel application of SC thera-pies Among the novel CTs only 69 trials addressed neu-rological conditions (Table 2) and only 1 in our datasetthe Geron (Menlo Park CA USA) trial used hESCs Themajority of trials used hematopoietic stem cells or MSCsFor example clinical trials for multiple sclerosis usedautologous transplantation of MSCs or hematopoieticSCs following chemotherapy to achieve immunomodula-tion and facilitate regeneration of the central nervous sys-tem Two trials being conducted in India for Parkinsonrsquosdisease used MSCsThe majority of novel trials were publicly funded how-

ever some industry involvement was evident Industrytrials targeted both orphan and common diseases Threephase I trials by StemCells Inc (Newark CA USA)employed cultured allogeneic neural SCs (HuCNS-SC) totreat Pelizaeus-Merzbacher disease and neuronal ceroidlipfuscinosis Ischemic stroke was the focus of significantindustry involvement with 6 of 18 CTs sponsored byStem Cell Therapeutics (Toronto Canada) ReNeuron(Guildford UK) and Stempeutics Research (BangaloreIndia) The phase I trial by ReNeuron used a manufac-tured neural SC line (CTX cells) while the four Stem CellTherapeutics trials attempted to use a proprietary drug(NTx-265) to promote neural regeneration Howevernews reports indicated the lack of demonstrable effect inthe latter CTs [21]Of all the other diseases highlighted in the media 208

CTs were for cardiovascular disease 75 targeted theheart and 25 the peripheral vascular system Almost allof these trials involved MSCs mobilization of hemato-poietic SCs other purified bone marrow-derived SCs orendothelial progenitor cells for regenerative and suppor-tive purposes There were 27 novel trials for diabetesmellitus and these CTs attempted to treat both Type Iand Type II diabetes using hematopoietic and MSCsfrom adipose tissue umbilical cord blood and bone mar-row Private sector companies were involved as colla-borators or sponsors in eight of the trials includingOsiris Therapeutics (Columbia MD USA) Adistem(Hong Kong China) Transition Therapeutics (TorontoCanada) Cellonis Biotechnology (Beijing China) andGenzyme (Cambridge MA USA)

DiscussionInnovative biomedical technologies are prone to lsquosocialbubblesrsquo where categories of lsquoenthusiastic supportersweave a network of reinforcing feedbacks that lead towidespread endorsement and extraordinary commitmentby those involved in the projectrsquo [22] The enthusiasm ofstakeholders such as researchers the public politiciansand funders in promoting optimistic timelines often

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 5 of 10

masks the slow uptake of clinical applications and tech-nologies within health systems whether in biotechnology[2324] in general or more specifically in genomics [25]

or SC research Our results show that there is a large gapbetween public expectations and clinical realities withpublic representations focused on hESCs and on cures

a)

b)

Figure 2 Categories of diseases in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage ofnewspaper articles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to2000 and 2001 to 2010 (P lt 0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 6 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 7 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

stroke Parkinsonrsquos disease spinal cord injury and Alzhei-merrsquos disease with significant coverage also of cardiovascu-lar disease and diabetes (Figure 2A) Neurological diseaseswere significantly linked to coverage of hESC research andtherapies Promising research in therapies for ocular con-ditions such as corneal repair and macular degenerationreceived a small but steady amount of coverage from 2000onwards

Clinical trialsIn contrast all CTs (n = 3404) were dominated by useof adult SCs primarily hematopoietic SCs with sometrials using umbilical cord blood derived SCs Therewere an increasing number of trials using mesenchymalstem cells (MSCs) from 2007 (Figure 1B) The latterdominated our novel classification for CTs most ofwhich were in phases I and II (Figure 3) Figure 4 showsthe global landscape for innovative CTs with higherproportions using MSCs in Asia and the Middle EastAs of 2011 iPSCs had not entered CTs and the best-

known trial using hESCs started in October 2010 byGeron for spinal cord injury was halted in November2011 after use in only four trial subjects Three additionaltrials by Advanced Cell Technology (Santa Monica CAUSA) began in July 2011 two using retinal pigmentepithelial cells derived from hESCs for Stargardtrsquos maculardystrophy and one for dry age-related macular degenera-tion [20] CTs for cancers and graft-versus-host disease(GVHD) which composed most of the lsquoother diseasesrsquocategory dominated the SC CT landscape (Figure 2B)Nevertheless there was a steady increase in CTs for cardi-ovascular disease beginning in 2001 and a small numberof trials for neurological ocular conditions and diabetes(note that the key word analysis for diabetes also capturedCTs for associated morbidities such as diabetic foot) Ourdetailed examination of novel CTs was dominated by trialsusing MSCs and for conditions other than hematologicalcancersOur criteria for novel SC CTs resulted in the selection of

639 (19) CTs that if successful would become the nextgeneration of regenerative treatments A total of 512 ofthese CTs clearly indicated study phase and of these themajority were safety trials in phases I or II (Figure 4) Only54 novel CTs were in phases IIIII or III and 17 were inphases IIIIV or IV (Table 1) The majority of clinical trialsin phase IIIIV (n = 11) used drug treatments to activateendothelial progenitor cells for therapeutic purposes incardiovascular diseases (which may be associated withother diseases such as diabetes and ankylosing spondylitis)A further three advanced stage trials used stents to facili-tate vascular repair by capturing endothelial progenitorcells in the stent and three trials addressed metabolicsyndrome critical limb ischemia and breast deformitiesfollowing a lumpectomy

While the public and policymakers expect therapies forneurological conditions there was limited activity inwhat may be considered novel application of SC thera-pies Among the novel CTs only 69 trials addressed neu-rological conditions (Table 2) and only 1 in our datasetthe Geron (Menlo Park CA USA) trial used hESCs Themajority of trials used hematopoietic stem cells or MSCsFor example clinical trials for multiple sclerosis usedautologous transplantation of MSCs or hematopoieticSCs following chemotherapy to achieve immunomodula-tion and facilitate regeneration of the central nervous sys-tem Two trials being conducted in India for Parkinsonrsquosdisease used MSCsThe majority of novel trials were publicly funded how-

ever some industry involvement was evident Industrytrials targeted both orphan and common diseases Threephase I trials by StemCells Inc (Newark CA USA)employed cultured allogeneic neural SCs (HuCNS-SC) totreat Pelizaeus-Merzbacher disease and neuronal ceroidlipfuscinosis Ischemic stroke was the focus of significantindustry involvement with 6 of 18 CTs sponsored byStem Cell Therapeutics (Toronto Canada) ReNeuron(Guildford UK) and Stempeutics Research (BangaloreIndia) The phase I trial by ReNeuron used a manufac-tured neural SC line (CTX cells) while the four Stem CellTherapeutics trials attempted to use a proprietary drug(NTx-265) to promote neural regeneration Howevernews reports indicated the lack of demonstrable effect inthe latter CTs [21]Of all the other diseases highlighted in the media 208

CTs were for cardiovascular disease 75 targeted theheart and 25 the peripheral vascular system Almost allof these trials involved MSCs mobilization of hemato-poietic SCs other purified bone marrow-derived SCs orendothelial progenitor cells for regenerative and suppor-tive purposes There were 27 novel trials for diabetesmellitus and these CTs attempted to treat both Type Iand Type II diabetes using hematopoietic and MSCsfrom adipose tissue umbilical cord blood and bone mar-row Private sector companies were involved as colla-borators or sponsors in eight of the trials includingOsiris Therapeutics (Columbia MD USA) Adistem(Hong Kong China) Transition Therapeutics (TorontoCanada) Cellonis Biotechnology (Beijing China) andGenzyme (Cambridge MA USA)

DiscussionInnovative biomedical technologies are prone to lsquosocialbubblesrsquo where categories of lsquoenthusiastic supportersweave a network of reinforcing feedbacks that lead towidespread endorsement and extraordinary commitmentby those involved in the projectrsquo [22] The enthusiasm ofstakeholders such as researchers the public politiciansand funders in promoting optimistic timelines often

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 5 of 10

masks the slow uptake of clinical applications and tech-nologies within health systems whether in biotechnology[2324] in general or more specifically in genomics [25]

or SC research Our results show that there is a large gapbetween public expectations and clinical realities withpublic representations focused on hESCs and on cures

a)

b)

Figure 2 Categories of diseases in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage ofnewspaper articles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to2000 and 2001 to 2010 (P lt 0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 6 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 7 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

masks the slow uptake of clinical applications and tech-nologies within health systems whether in biotechnology[2324] in general or more specifically in genomics [25]

or SC research Our results show that there is a large gapbetween public expectations and clinical realities withpublic representations focused on hESCs and on cures

a)

b)

Figure 2 Categories of diseases in newspapers (A) and clinical trials (B) from 1991 to 2010 The difference in the percentage ofnewspaper articles versus clinical trials using keyword synonyms for stem cell types is significant overall as well as between the decades 1991 to2000 and 2001 to 2010 (P lt 0001)

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 6 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 7 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

for neurological conditions There is little awareness ofthe dominant clinical applications that use hematopoieticSCs and increasingly use MSCs This leaves patients des-perately hoping for life-altering therapies vulnerable to

unscrupulous providers of unproven and expensive treat-ments Indeed there is a direct correlation between thenumerous therapies for neurological conditions adver-tised by SC tourism clinic providers and media coverage

Figure 3 Study phases of novel clinical trials Note that only 512 out of 639 clinical trials clearly indicated study phase The drop in clinicaltrials in 2010 may be due to a lag in registration of clinical trials in databases by investigators

Figure 4 Global map of innovative clinical trials representative of the future of regenerative medicine indicating the proportion usingmesenchymal stem cells (MSCs in red) Numbers denote the total number of novel clinical trials in the region small circles denote regionswith one to three novel clinical trials

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 7 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

dominated by neurological diseases as described in thestudy by Lau et al [7]

Why do therapies take so long to reach patientsStem cell biology is highly complex and variable usingcells as therapeutic agents bears few parallels to the use ofsmall molecule drugs This creates significant challengesfor regulators developing the testing necessary to assurethe quality of novel technologies and therapies for busi-nesses that require reproducible large scale productioncapacity and for the health systems that need to find thefunds for what will likely be personalized and expensivetherapies As an example there are valid concerns aboutmanufacturing consistency of cell cultures and the geneticstability of cell lines Both hESCs and iPSCs have beenshown to experience genetic and phenotypic drift in long-term in vitro culture There are further concerns about

iPSCs due to the degree to which differentiated adult cellsmust be manipulated to become pluripotent [2627]Given that there is a potential for late tumor formationresulting from inadvertent mutagenesis in the creation ofSC products prolonged monitoring of animals used inpreclinical studies and long-term monitoring of CT parti-cipants will be required SCs that are manipulated or man-ufactured or used in a non-homologous manner [28]require more stringent oversight to ensure the safety ofthe recipientRegulators are still developing systems specifically for

complex cell therapies The conventional preclinical reg-ulatory studies for absorption distribution metabolismexcretion and toxicity of drugs cannot be applied to cell-based therapies in part because of an inability to trackdifferentiation and migration of transplanted cells [15]In contrast to drugs SC based therapies may result in

Table 1 Novel clinical trials (CTs) in phase IIIII phase III phase IIIV or phase IV (n = 71) (note that phase IIIV andphase IV trials all fell in the drug treatments stents or other categories (n = 17))

Clinical trial subject No ofCTs

Country

Bone conditions 3 Iran USA

Cardiovascular disease 29 Brazil Canada China Finland Germany India Iran Italy Mexico The Netherlands Russia SouthKorea UK USA

Cartilage damage 2 Egypt South Korea

Crohnrsquos Disease 4 UK USA

Diabetes 2 India China

Multiple sclerosis 1 USA

Ocular surface disease 2 Malaysia Thailand

Scleroderma 3 USA

Spinal cord injury 1 India

Drug treatments for stem cellmobilization

11 China Germany Italy South Korea Turkey USA

Stents for capturing endothelialprogenitor cells

3 China The Netherlands Poland

Other (mainly graft-versus-host disease) 3 India Germany UK

Table 2 Novel clinical trials (CTs) for neurological conditions (n = 69)

Clinical trial subject No of CTs Country

Amyotrophic lateral sclerosis 7 China Israel Spain USA

Cerebral palsy 3 Mexico South Korea USA

Cerebral palsy using MSCs 3 China India

Diabetic neuropathy 3 Germany Mexico USA

Ischemic Stroke 18 Brazil Canada France India Malaysia Russia Spain Taiwan UK USA Russia

Multiple sclerosis 12 Canada Israel Spain UK USA

Neuronal ceroid lipfuscinosis 2 USA

Parkinsonrsquos Disease 2 India

Pelizaeus-Merzbacher Disease 1 USA

Spinal cord injury (non-hESC) 5 Egypt India USA

Spinal cord injury (hESC) 1 USA

Traumatic brain injury 3 Canada India USA

Other 10 Brazil China The Netherlands South Korea Thailand USA

hESCs = human embryonic stem cells MSCs = mesenchymal stem cells

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 8 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

long-term engraftment with amplification of the admi-nistered dose of SC and further growth and differentia-tion of the SC progeny Regulators in consultation withthe SC research community are attempting to develop aproportionate response which will balance patient safetyyet will not stifle innovation in this fieldDeveloping or modifying regulatory pathways takes time

trust and communication between regulators and theresearch community all of which are undermined by hype[1528] or public representations of SC research that donot reflect its current state and the realistic developmentaltimelines for specific diseases or conditions as documen-ted by this study Even with cooperation between SCresearchers and regulators oversight may prove difficult ina translational environment that has gone global asdemonstrated in Figure 3 Significantly our results showthat CTs testing novel SC approaches are occurringbeyond the borders of North America and Europe Indeedwhile there are SC trials for novel application increasinglybeing registered from sites in India China and Iran andto a lesser extent in Brazil Mexico and Malaysia thesemay use SC with only rudimentary characterization or forsituations with as yet poorly understood biological ratio-nale the very types of trials concerning to the ISSCR Ethi-cal issues and conflicts of interests are more likely to arisewhere inadequately developed regulatory and consent fra-meworks exist This will be of special concern in an arenasuch as the complex regulatory environment for cell thera-pies that necessitate long-term monitoring and follow-upfor participantsMedia reporting of therapeutic benefits especially for

neurological conditions may exacerbate the lsquotherapeuticmisconceptionrsquo in all countries [29] While our analysisdemonstrates that most SC CTs are in phases I or II parti-cipants may conflate such early stage safety trials withtherapeutic benefit This mistaken therapeutic beliefwhich undermines informed consent may arise frompoorly structured consent forms or from the descriptionsof CTs in trial registries [30] In reality most therapies failin phase I and II and those that are proven both safe andeffective take between US$200 million and US$1 billion ininvestment over a span of 10 to 15 years before they areapproved and adopted by the medical community [31]A further challenge highlighted in our results of public

versus private support of trials is that commercial enter-prise has been slow to move into the cell therapy arenaprimarily because of the lack of easily defined businessmodels [32] Cell therapies are not drugs and require thedevelopment of new manufacturing and distribution sys-tems While a few allogeneic products with central manu-facturing have been developed most notably Carticel fromGenzyme and Apligraf from Organogenesis the closestmodel to many of the current CTs is hematopoietic SCtransplantation (HSCT) HSCT is a high-cost highly

specialized treatment requiring significant infrastructureand an interdisciplinary network of healthcare profes-sionals [3334] Its global use is highly correlated withgross national income healthcare expenditure and theavailability of transplant teams Given these system coststhe bar for therapeutic value which compares the benefitsof SC therapies with existing treatments will be high Themodel also belies the anticipated health system savingspromised by proponents of SC research These financialpressures such as the scientific and regulatory issues areabsent from media reports and are hidden from public dis-course contributing to the disconnected state of currentexpectations

ConclusionsGiven the research regulatory commercialization andhealth system hurdles involved in the clinical translationof SC research it seems likely that patients and politicalsupporters will become disappointed and disillusionedIn this environment proponents need to make a con-certed effort to temper claims It is simply lsquounfair toraise peoplersquos hopes to unrealistic levels when they andtheir families are desperate for treatments that willrelieve their suffering and improve their healthrsquo [35]Even though the field is highly promising the road tothe clinic is long and hard and the technology may yetdevelop in unanticipated ways For a field that lackingsignificant private investment is largely reliant on publicsupport there needs to be a more honest acknowledge-ment of the expected therapeutic benefits and the time-lines to achieving them

AcknowledgementsWe thank the organizer Timothy Caulfield for inviting to present this studyat the Using and Abusing Evidence in Science and Health Policy workshopheld in Banff Alberta Canada on 31 July to 1 August 2012 and theconference participants for their insightful comments We thank ProfessorGian Jhangri for his help with statistical analysis and Professor David Hik andMs Rosario Isasi for comments on the manuscript This study was funded bythe Stem Cell Network Strategic Core Grant (TB HA) and a Stem CellNetwork Strategic Core Grant Public Policy amp ELSI (TB HA) MDL wasawarded an Alberta Innovates Health Solutions Summer Studentship and aStem Cell Network Social Sciences Summer Studentship

Author details1Department of Public Health Sciences School of Public Health EdmontonClinic Health Academy University of Alberta Edmonton Alberta Canada2The Ottawa Hospital Research Institute The Ottawa Hospital GeneralCampus Ottawa Ontario Canada

Authorsrsquo contributionsTB and AH conceptualized the research question AH MH MDL and MBobtained and analyzed data AH and MH designed the CT codingmethodology TB MDL and AH drafted the paper AH and MH designed theCT coding methodology All authors were involved in editing the paper andapproved the final text

Authorsrsquo informationDr Tania Bubela has a PhD from the University of Sydney in biology and aJD from the University of Alberta She researches in the field of health law

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 9 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10

and policy as an Associate Professor School of Public Health University ofAlberta Dr Harry Atkins is a stem cell transplant physician at the OttawaHospital Research Institute and is currently the principal investigator of aclinical trial using hematopoietic stem cell transplantation for multiplesclerosis Mark Bieber is a computer and data management specialist at theUniversity of Alberta Dr Hafez has an MB and a BCh from Cairo Universityand an MHA from the University of Ottawa At the time of this study hewas working as a research assistant with Dr Atkins but is currently MedicalEducation Manager with Janssen Inc Matthew D Li is a research assistantwith Dr Bubela and from 2012 a medical student at Stanford University

Competing interestsThe authors declare that they have no competing interests

Received 15 June 2012 Accepted 6 November 2012Published 6 November 2012

References1 Weissman IL Translating stem and progenitor cell biology to the clinic

barriers and opportunities Science 2000 2871442-14462 Sung JJ Hopkins MM Towards a method for evaluating technological

expectations revealing uncertainty in gene silencing technologydiscourse Technol Anal Strateg 2006 18345-359

3 Bubela T Nisbet MC Borchelt R Brunger F Critchley C Einsiedel E Geller GGupta A Hampel J Hyde-Lay R Jandciu EW Jones SA Kolopack P Lane SLougheed T Nerlich B Ogbogu U OrsquoRiordan K Ouellette C Spear MStrauss S Thavaratnam T Willemse L Caulfield T Science communicationreconsidered challenges prospects and recommendations NatBiotechnol 2010 27514-518

4 Rachul C Zarzeczny A Bubela T Caulfield T Stem cell research in thenews more than a moral status debate Script-ed 2010 7311-323

5 Caulfield T Stem cell research and economic promises J Law Med Ethics2010 38303-313

6 Caulfield T Rachul C Science spin iPS cell research in the news ClinPharmacol Ther 2011 89644-646

7 Lau D Ogbogu U Taylor B Stafinski T Menon D Caulfield T Stem cellclinics online the direct-to-consumer portrayal of stem cell medicineCell Stem Cell 2008 3591-594

8 Ellison B Communicating hope the bridge between science and thefuture it creates Cell Stem Cell 2011 8616-617

9 Berman EP Creating the Market University How Academic Science Became anEconomic Engine Princeton NJ Princeton University Press 2012

10 US Department of Health amp Human Services A New Vision - A Future forRegenerative Medicine [httphttpwwwhhsgovreferencenewfutureshtml]

11 BBC News In full Tony Blairrsquos speech [httpnewsbbccoukgoprfr-2hiuk_newspolitics5382590stm]

12 Daley GQ Stem cells roadmap to the clinic J Clin Invest 2010 1208-1013 Associated Press Stem cell payoff could take decades not days [http

wwwmsnbcmsncomid29719086nshealth-cloning_and_stem_cellststem-cell-payoff-could-take-decades-not-days]

14 Hyun I Lindvall O Ahrlund-Richter L Cattaneo E Cavazzana-Calvo MCossu G De Luca M Fox IJ Gerstle C Goldstein RA Hermereacuten G High KAKim HO Lee HP Levy-Lahad E Li L Lo B Marshak DR McNab A Munsie MNakauchi H Rao M Rooke HM Valles CS Srivastava A Sugarman JTaylor PL Veiga A Wong AL Zoloth L Daley GQ New ISSCR guidelinesunderscore major principles for responsible translational stem cellresearch Cell Stem Cell 2008 3607-609

15 Goldring CE Duffy PA Benvenisty N Andrews PW Ben-David U Eakins RFrench N Hanley NA Kelly L Kitteringham NR Kurth J Ladenheim DLaverty H McBlane J Narayanan G Patel S Reinhardt J Rossi A Sharpe MPark BK Assessing the safety of stem cell therapeutics Cell Stem Cell2011 8618-628

16 Barclay E Stem-cell experts raise concerns about medical tourism Lancet2009 373883-884

17 World Health Organization International Clinical Trials Registry PlatformSearch Portal [httpappswhointtrialsearch]

18 Mason C Brindley DA Culme-Seymour E Davie NL Cell therapy industrybillion dollar global business with unlimited potential Regen Med 20116265-272

19 Krleza-Jerić K Chan AW Dickersin K Sim I Grimshaw J Gluud C Principlesfor international registration of protocol information and results fromhuman trials of health related interventions Ottawa statement (part 1)BMJ 2005 330956-958

20 Atala A Human embryonic stem cells early hints on safety and efficacyLancet 2012 379689-690

21 Marketwire Stem Cell Therapeutics (SSV) Stroke Drug NTx-265 FailsPhase 2 Trial [httpwwwbiospacecomnews_storyaspxStoryID =181731ampfull = 1]

22 Gisler M Sornette D Woodard R Innovation as a social bubble theexample of the Human Genome Project Res Policy 2011 401412-1425

23 Hopkins MM Martin PA Nightingale P Kraft A Mahdi S The myth of thebiotech revolution as assessment of technological clinical andorganizational change Res Policy 2007 36566-589

24 Glassman RH Sun AY Biotechnology identifying advances from thehype Nature Rev Drug Disc 2004 3177-183

25 Evans JP Meslin EM Marteau TM Caulfield T Genomics Deflating thegenomic bubble Science 2011 331861-862

26 Zwaka TP Troublesome memories Nature 2010 467280-28127 Pera MF The dark side of induced pluripotency Nature 2011 47146-4728 von Tigerstrom BJ The challenges of regulating stem cell-based

products Trends Biotechnol 2008 26653-65829 Kimmelman J Gene Transfer and the Ethics of First-in-Human Experiments

Lost in Translation New York NY Cambridge University Press 200930 Scott CT DeRouen MC Crawley LM The language of hope therapeutic

intent in stem-cell clinical trials AJOB Prim Res 2010 14-1131 Paul SM Mytelka DS Dunwiddie CT Persinger CC Munos BH Lindborg SR

Schacht AL How to improve RampD productivity the pharmaceuticalindustryrsquos grand challenge Nat Rev Drug Disc 2010 9203-214

32 Rao MS Funding translational work in cell-based therapy Cell Stem Cell2011 97-10

33 Gratwohl A Baldomero H Frauendorfer K Niederweiser D Why are thereregional differences in stem cell transplantation activity An EBMTanalysis Bone Marrow Transpl 2008 42S7-S10

34 Gratwohl A Baldomero H Aljurf M Pasquini MC Bouzas LF Yoshimi ASzer J Lipton J Schwendener A Gratwohl M Frauendorfer KNiederwieser D Horowitz M Kodera Y Hematopoietic stem celltransplantation a global perspective JAMA 2010 3031617-1624

35 Petersen A The ethics of expectations biobanks and the promise ofpersonalised medicine Monash Bioethics Rev 2009 28(05)1-12

Pre-publication historyThe pre-publication history for this paper can be accessed herehttpwwwbiomedcentralcom1741-701510133prepub

doi1011861741-7015-10-133Cite this article as Bubela et al Is belief larger than fact expectationsoptimism and reality for translational stem cell research BMC Medicine2012 10133

Submit your next manuscript to BioMed Centraland take full advantage of

bull Convenient online submission

bull Thorough peer review

bull No space constraints or color figure charges

bull Immediate publication on acceptance

bull Inclusion in PubMed CAS Scopus and Google Scholar

bull Research which is freely available for redistribution

Submit your manuscript at wwwbiomedcentralcomsubmit

Bubela et al BMC Medicine 2012 10133httpwwwbiomedcentralcom1741-701510133

Page 10 of 10