PERSPECTIVES

about whether but also about how graftsexert their functional effects, it becomesapparent that effective therapies can only bedeveloped hand-in-hand with acquiring arational understanding of the neurobiologi-cal principles that underlie the integrationand function of grafted cells in the damagednervous system.

Successful transplantation of cate-cholamine-secreting cells in the nervous sys-tem was first achieved by Olson and col-leagues in the early 1970s by grafting adrenalchromaffin cells or embryonic dopamineneurons into the rat anterior eye chamber4,5.These studies established that survival, neu-rite outgrowth and formation of contactswith the host nervous system are best achievedusing developing embryonic neurons. Thedopaminergic fate of the implanted cells isdetermined before implantation and dependson accurate dissection of the relevant ventralmesencephalic cell groups from embryosharvested during a critical stage of develop-ment6. Initial attempts to transplant embry-onic neurons into the adult brain provedmore difficult and required rather complextechnical protocols to provide adequatenutrient support for newly grafted tissuepieces7. However, these limitations werelargely overcome with the development oftechniques for preparation of dissociated cellsuspensions, allowing stereotactic implanta-tion of embryonic dopamine neurons directlyinto deep brain sites8.

The first reports of functional recovery insimple tests of motor asymmetry in hemi-

parkinsonian rats were based on solid graftimplants into the lateral ventricles9 or corti-cal cavities10,11. However, this was soon repli-cated using the then new cell-suspensiontechnology, revealing the importance oftopographic placement and terminal rein-nervation in determining functional efficacyof the grafted cells12,13. At the technical level,subsequent experimental studies have identi-fied treatments for cool storage (‘hiberna-tion’) of donor tissues14, refinements in themethods of cell preparation and implanta-tion15, and improved trophic/neuroprotec-tive support of grafted tissues16. Furtherbehavioural analysis has demonstratedrecovery in a range of more complex motorfunctions17 and extended functional valida-tion to primates18,19. In parallel, a combina-tion of electrophysiological, in vivo neuro-chemistry and behavioural analyses haveprovided a clearer understanding of themechanisms of graft function20. It is not sim-ply sufficient for the grafted cells to secretedopamine at physiological levels into thehost neuropil; rather, full functional activityis dependent on a synaptic integration of thegrafted cells into the host neural circuitry.

Open-label clinical trialsThe first clinical trials of cell transplantationin PD used adrenal autografts21. In this proce-dure, one adrenal medulla of the person withPD is removed for dissection of the relevantcells, and implanted back into the brain,either as solid pieces into a ventricular cavityor by stereotaxic injections of cell suspensionsinto the striatal neuropil. Following a singlereport of an apparently profound effect22, sev-eral hundred patients received this operationin the late 1980s in a series of rather poorlycontrolled trials worldwide. However, it soonbecame apparent that the grafts did not sur-vive long-term and that, at best, modest clini-cal effects were accompanied by significantside effects and an unacceptable level of mor-bidity and mortality23. This procedure, there-fore, is generally not considered to offer anacceptable option.

The results of the first double-blind placebo-controlled trial using grafts of embryonictissue to treat Parkinson’s disease havearoused widespread interest and debateabout the future of cell replacementtherapies. What are the key issues that needto be resolved and the directions in whichthis technology is likely to develop?

The recent publication in The New EnglandJournal of Medicine of the first double-blindplacebo-controlled trial of embryonic tissuetransplantation in Parkinson’s disease (PD)1

has stimulated widespread media interestand scientific debate about the whole futureof cell replacement therapies2. Whereas someof the concerns might have been overplayed3,it is appropriate to review the current statusof clinical trials of cell-based therapies for PDin the context of the historical developmentof the field. We consider here the key issuesstill to be resolved and the directions inwhich this technology is likely to develop inthe near future.

Cell-based therapies for PD have beendeveloped over the past three decades(TIMELINE) within a relatively simple concep-tual framework: if the human disease isattributable to a primary degeneration of thedopamine neurons of the substantia nigraand a corresponding loss of dopamineinnervation of the neostriatum (caudatenucleus and putamen), then replacement ofthe lost dopamine neurons by transplanta-tion should yield recovery of the associatedmotor symptoms. As we learn more, not just

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Cell therapy in Parkinson’s disease –stop or go?

Stephen B. Dunnett, Anders Björklund and Olle Lindvall

O P I N I O N

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survival after embryonic tissue transplanta-tion (TABLE 1). This can be illustrated from theseries of 18 patients studied in Lund, with col-laborators in London and Munich/Marburg29.These patients have been followed longitudi-nally for up to ten years; the substantialmajority show significant increases in the pro-portion of time spent in the ‘on’ phase (that is,with few or no motor symptoms), improve-ments in the speed and accuracy of move-ments (as observed, for example, in timedseries of pronation/supination) in defined‘off ’ (that is, after drug withdrawal), andmaintenance of the improvement with pro-gressive reduction (or complete cessation inseveral cases) of concurrent L-DOPA (3,4-dihydroxyphenylalanine) treatment30–35. Inparallel with the neurological testing, thepatients have received regular [18F]-DOPApositron-emission tomography (PET) scansin which [18F]-DOPA uptake, as measured bythe K

iuptake constant, is seen to return

towards normal levels30–37. However, in thisand other patient series operated with the cur-rent transplantation procedure, [18F]-DOPAuptake in the putamen has reached only48–68% of that measured in healthy volun-teers (TABLE 1), with the exception of onepatient with a unilateral graft where restitu-tion was seen to reach 100% (REF. 37), indicat-ing that there is room for considerableimprovement. The step-by-step approachadopted in these studies has made it possibleto introduce, for example, modifications inthe surgical technique38, and improvements instorage and preparation of the tissue34.We areconfident that this stepwise approach hasbeen successful in yielding significant refine-ments in methodology without the risk ofaffecting large numbers of patients with apoor or ill-conceived technique.

longitudinal analysis of individual cases underdefined conditions of drug administration. Aconsortium of European and US centres hasdeveloped a standardized Core AssessmentProtocol for Intracerebral Transplantations(CAPIT), which defines regular neurologicaland imaging assessments at defined timeintervals to provide an extended baseline overa minimum of three months pre-operationand one to two years post-operation27,28.Adoption of the CAPIT protocol provides twodistinct advantages: it allows data to be pooledfrom several centres to provide large samplesizes even when each contributing centremight study only a few cases, and it allowsdirect comparison between different tissuepreparations and surgical methods used in dif-ferent centres according to a common set ofbaseline and outcome assessments28.

On the basis of such open-label longitudi-nal analysis of small numbers of cases usingdefined assessment protocols, there is nowclear evidence of both clinical benefit and graft

The alternative was to pursue a clinicalstrategy based on that which works best inexperimental model systems, namely humanembryonic tissue allografts. The complex eth-ical and legal issues associated with the use ofhuman embryonic tissues from elective abor-tions have now been considered in detail inmost western countries, resulting in approvedguidelines that permit use of embryonic tis-sues subject to stringent conditions for selec-tion, consent, collection, handling and appli-cation24. The first patients to receive humanembryonic nigral grafts, in Sweden andMexico, had only very limited benefit25,26.However, subsequent improvements in tech-nique have resulted in clear-cut and long-last-ing symptomatic improvement (in the orderof 30–50% on the the motor examinationpart of the unified Parkinson’s disease ratingscale) as reported in open-label trials fromseveral centres around the world (TABLE 1).

The issue of how to determine whether anovel surgical treatment in PD is having sig-nificant benefit is not straightforward. PD is aslowly progressive disorder and symptomscan fluctuate markedly depending on time ofday and position in the drug cycle, as well asbeing sensitive to mood and motivation.Placebo effects are well known. Moreover,transplanted cells require many months todevelop and integrate into the host nervoussystem and the grafts cannot easily beremoved (other than as a result of graft failureor rejection), so an experimental design fortesting patients reversibly on and off treat-ment is not feasible. Finally, at this stage oftheir development, we consider that grafttechnologies are not yet optimized and soneed to be refined and developed on a case-by-case basis. Consequently, most centres haveadopted the strategy of undertaking detailed

Successfultransplantation ofadrenal medulla andfetal nigral cells inthe anterior eyechamber4,5.

First publishedreport of functionalnigral grafts inhemiparkinsonianrats9,10.

Successfultransplantation offetal nigral cells inthe rat brain7.

Introduction of thecell-suspensiontransplantationmethod in rats8.

Functional recoveryby nigral grafts in arange of behaviouraltests (dependent onplacement and extentof reinnervation)54–56.

First published report offetal nigral grafts inpatients with Parkinson’sdisease (operations in1987)25,26,57.

First published reportof adrenal medullagrafts in patients withParkinson’s disease(operations in 1982)21.

First post-mortemevidence of nigral graftsurvival in patients withParkinson’s disease42.

Positron-emission tomography(PET) evidence of regulateddopamine release from nigralgrafts in a patient withParkinson’s disease37.

First report of survivingnigral xenografts in apatient withParkinson’s disease(operations in 1994)46.

PET evidence of graft-induced restoration ofmovement-related corticalactivation in patients withParkinson’s disease48.

First evidence of nigralgraft survival andfunctional recovery inpatients withParkinson’s disease30.

1970–1972 1976 1979 1980 1981 1985 1988 1990 1995 1997 1999 2000

Timeline | A brief history of cell therapies for Parkinson’s disease

“It is only through the studyof a progressively modifiedtechnology in smallnumbers of patients usingstandardized, well-validatedassessment protocols thatwe can determine whetherthe refinements identifiedexperimentally translateinto clinical benefit.”

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the most successfully treated person report-ed so far, in whom the grafts had restoreddopamine storage and release in the stria-tum to normal levels37, has not developedany significant dyskinesias.

What do we still need to know?With the development of new effective treat-ments for patients with advanced PD, in par-ticular deep-brain stimulation, it is necessaryto ask whether it is justified to make any fur-ther efforts to develop cell-based therapiesfor this disorder. We would argue that celltherapy, if successful, offers several uniquefeatures and distinctive advantages overother treatment strategies. Cell therapy aimsto restore dopamine transmission in thestriatum, that is, in the precise area that haslost its intrinsic dopamine afferent innerva-tion. In successful cases, this has given majorclinical improvements and allowed thepatient to stop L-DOPA medication, withoutmajor side effects. The grafted neurons arenot destroyed by the disease process up to atleast ten years after surgery, indicating thatthe symptomatic relief can be maintained formany years31–33,37.

The further development of the cellreplacement approach, however, is severelyhampered by the lack of well-characterized,standardized and quality-controlled cellmaterial. As long as neural transplantationhas to rely on the access to embryonic donortissue, widespread application will always belimited. For this reason, the past decade hasseen an active search for alternative sourcesof cells for therapeutic application44. Themain alternatives under active investigationare xenografts, stem cells and other geneticallymanipulated or immortalized cells and celllines. Each has significant advantages over

Denver/New York trialThe recent Denver/New York surgical trial1 isdistinctive for providing the first publisheddouble-blind placebo-controlled trial ofneural transplantation in PD. Although sucha design is considered necessary by some toprovide unequivocal scientific evidence ofefficacy of any treatment modality39, there aresignificant ethical problems associated withusing sham procedures in surgical trials40.Three other surprising features of the designof this trial were: clinical assessment was notconducted according to established CAPITprotocols (which would have allowed compa-rability with other studies); assessments wereonly undertaken up to one year after grafting(which would maximize placebo effects butwhich is likely to be too early to assess thelevel of slowly developing graft-induced ther-apeutic benefit); and the selection of patients’retrospective global self-assessment as theprimary outcome measure (which showedconsiderable variation but no differencebetween placebo and control groups).Moreover , the technique for cell transplanta-tion in this trial differed from most otherstudies in the number of embryonic donors,methods of cell preparation and long-termstorage, absence of immunosuppression andthe use of an unconventional surgicalapproach, so that it was unclear from the out-set whether this controlled trial would in factbe informative41. Nevertheless, even at theearly one-year time point, modest but signifi-cant improvement was obtained in two neu-rological rating scales, in particular in youngpatients. There was no improvement in thesham-operated group. This was accompaniedby a 40% increase in [18F]-DOPA uptake, andsurvival of 7,000–40,000 tyrosine-hydroxy-lase-positive (presumed dopamine) cells per

side in two post-mortem cases (comparedwith 80,000–135,000 cells per side using con-ventional methods in other post-mortemanalyses42). As such, the outcome using thisdistinctive surgical approach follows that seenin the open label trials, with a level of func-tional benefit commensurate with the modestsurvival of the grafts obtained (TABLE 1).

However, what has attracted widespreadattention about this trial has been the reportsof severe and uncontrollable dyskinetic sideeffects after 1–3 years in 5 of 33 patients in thetrial. This has been taken in various mediareports as a serious blow to the acceptabilityof dopamine neuron transplantation per se2.However, it should be noted that side effectsof the dramatic severity reported from theDenver/New York trial have not been evidentin the open-label trials, and ameliorationrather than induction of dyskinesias has beenobserved after dopamine neuron transplanta-tion in animal models of PD43. We believethat once the reported dyskinesias are proper-ly characterized, they might be found to beattributable to one or several features of theparticular protocol used in this trial — in par-ticular, the use of tissue stored in culture forup to four weeks before grafting and theunconventional surgical approach using nee-dle trajectories passing through the frontallobes, and perhaps also the lack of anyimmunosuppressive treatment — rather thanbeing a general feature of dopamine-cellreplacement using experimentally validatedmethods. Freed et al.1 have suggested that thelate-appearing dyskinesias observed in theDenver/New York trial might be due to adopamine overdose effect in their graftedpatients. However, the low dopamine neu-ronal survival observed in their study clearlyargues against this possibility. Furthermore,

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Table 1 | Functional outcome after bilateral intrastriatal nigral grafts in clinical trials*

Surgical Trial No. of No. of ventral Graft [18F]-DOPA uptake UPDRS Time L-DOPA Referencescentre design cases mesencephalon placement (%increase/ motor score in ‘off’ doses

per putamen %normal) (% change) (% change#)(% change#)

Lund‡ OL 4 4.9 Put 60/52 –30 –59 –37 33OL 2 2.5 C + Put 87/68 –50 (total) –50, NR 0, –70 35 OL 5 2.8 (+L) C + Put 55/48 –40 –43 –45 34,48

Tampa OL 6 3.0–4.0 P Put 61/55 –30 –43 –16 49

Créteil OL 3 1.0–1.5 Put NR§ –6 15 NR 506 3.0 –33 –66

Halifax OL 2 3.25 (+G) P Put 107/62 –32 (total) –50 NR 51

Denver DBPC 19 2.0 Put 40/NR –18|| NR No change 1

*Trials involved objective longitudinal assessment protocols and had positron-emission tomography evidence of graft survival.‡The Lund series also comprises three patients that have received only unilateral transplants26,37 and one patient with possible multiple-system atrophy32,33. Threepatients have not yet been reported.§Five patients in the Créteil series showed 60% increase in striatal [18F]-dopa uptake, reaching 37% of the normal mean after unilateral grafting of tissue from 1–3 donorsin Put (n=1) or C + Put (n=4) 52,53.||–34% in the younger patients (≤60 years old).# Negative scores indicate reductions, that is improvements, in response.(C, caudate nucleus; DBPC, double-blind placebo-controlled; DOPA; 3,4-dihydroxyphenylalanine; +G, with glial cell-line-derived neurotrophic factor; +L, with lazaroids;NR, not reported; OL, open-label; P, posterior; Put, putamen; UPDRS, unified Parkinson’s disease rating score.)

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abnormalities produced by destruction of nigrostriataldopamine system. Science 204, 643–647 (1979).

10. Björklund, A. & Stenevi, U. Reconstruction of thenigrostriatal dopamine pathway by intracerebraltransplants. Brain Res. 177, 555–560 (1979).

11. Björklund, A., Dunnett, S. B., Stenevi, U., Lewis, M. E. &Iversen, S. D. Reinnervation of the denervated striatumby substantia nigra transplants: functional consequencesas revealed by pharmacological and sensorimotortesting. Brain Res. 199, 307–333 (1980).

12. Dunnett, S. B., Björklund, A., Schmidt, R. H., Stenevi,U. & Iversen, S. D. Intracerebral grafting of neuronal cellsuspensions. V. Behavioral recovery in rats with bilateral6-OHDA lesions following implantation of nigral cellsuspensions. Acta Physiol. Scand. 522, S39–S47(1983).

13. Schmidt, R. H., Björklund, A., Stenevi, U., Dunnett, S. B.& Gage, F. H. Intracerebral grafting of neuronal cellsuspensions. III. Activity of intrastriatal nigral suspensionimplants as assessed by measurements of dopaminesynthesis and metabolism. Acta Physiol. Scand. 522,S19–S28 (1983).

14. Sauer, H. & Brundin, P. Effects of cool storage on survivaland function of intrastriatal ventral mesencephalic grafts.Rest. Neurol. Neurosci. 2, 123–135 (1991).

15. Nikkhah, G. et al. A microtransplantation approach forcell suspension grafting in the rat Parkinson model: Adetailed account of the methodology. Neuroscience 63,57–72 (1994).

16. Brundin, P. et al. Improving the survival of grafteddopaminergic neurons: a review over currentapproaches. Cell Transplant. 9, 179–195 (2000).

17. Winkler, C., Kirik, D., Björklund, A. & Dunnett, S. B.Transplantation in the rat model of Parkinson’s disease:ectopic versus homotopic graft placement. Prog. BrainRes. 127, 233–265 (2000).

18. Taylor, J. R. et al. Grafting of fetal substantia nigra tostriatum reverses behavioral deficits induced by MPTP inprimates: a comparison with other types of grafts ascontrols. Exp. Brain Res. 85, 335–348 (1991).

19. Annett, L. E., Torres, E. M., Ridley, R. M., Baker, H. F. &Dunnett, S. B. A comparison of the behavioural effects ofembryonic nigral grafts in the caudate nucleus and in theputamen of marmosets with unilateral 6-OHDA lesions.Exp. Brain Res. 103, 355–371 (1995).

20. Dunnett, S. B. & Björklund, A. in Functional NeuralTransplantation (eds Dunnett, S. B. & Björklund, P.)531–567 (Raven, New York, 1994).

21. Backlund, E. O. et al. Transplantation of adrenal medullarytissue to striatum in parkinsonism. J. Neurosurg. 62,169–173 (1985).

22. Madrazo, I. et al. Open microsurgical autograft of adrenalmedulla to the right caudate nucleus in two patients withintractable Parkinson’s disease. N. Engl. J. Med. 316,831–834 (1987).

23. Quinn, N. P. The clinical application of cell graftingtechniques in patients with Parkinson’s disease. Prog.Brain Res. 82, 619–625 (1990).

24. Boer, G. J. Ethical guidelines for the use of humanembryonic or fetal tissue for experimental and clinicalneurotransplantation and research. J. Neurol. 242, 1–13(1994).

25. Madrazo, I. et al. Transplantation of fetal substantia nigraand adrenal medulla to the caudate nucleus in twopatients with Parkinson’s disease. N. Engl. J. Med. 318,51 (1988).

26. Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in 2 patients with severeParkinson’s disease: a detailed account of methodologyand a 6-month follow-up. Arch. Neurol. 46, 615–631(1989).

27. Langston, J. W., Widner, H. & Goetz, C. G. Coreassessment program for intracerebral transplantation(CAPIT). Mov. Disord. 7, 2–13 (1992).

28. Defer, G. L., Widner, H., Marié, R. M., Rémy, P. &Levivier, M. Core assessment program for surgicalinterventional therapies in Parkinson’s disease (CAPSIT-PD). Mov. Disord. 14, 572–584 (1999).

29. Lindvall, O. & Hagell, P. Clinical observations after neuraltransplantation in Parkinson’s disease. Prog. Brain Res.127, 299–320 (2000).

30. Lindvall, O. et al. Grafts of fetal dopamine neuronssurvive and improve motor function in Parkinson’sdisease. Science 247, 574–577 (1990).

31. Lindvall, O. et al. Evidence for long-term survival andfunction of dopaminergic grafts in progressiveParkinson’s disease. Ann. Neurol. 35, 172–180 (1994).

32. Wenning, G. K. et al. Short- and long-term survival andfunction of unilateral intrastriatal dopaminergic grafts inParkinson’s disease. Ann. Neurol. 42, 95–107 (1997).

argued by others that we can only be confi-dent that the effects seen are not simplyattributable to placebo effects by undertakingdouble-blind trials involving control patientsreceiving sham operations39. However, thelarge number of cases in which suboptimalgrafting techniques yield relatively poorgraft survival and at best modest clinicalbenefit, alongside the sham-operated patientsin the Denver/New York trial1, already pro-vide a substantial body of relevant surgicalcontrol data. The time for a full-scale dou-ble-blind surgical-controlled trial will comewhen the grafting methods approach opti-mization. At such time, neural transplanta-tion should be properly compared againstthe best surgical alternatives (such as sub-thalamic stimulation) rather than againstsham-operated controls. However, in ourjudgement, that level of optimization is notyet achieved, and the time and effortrequired for undertaking such a trial at thisstage would simply slow steady progress insurgical refinements.

Stephen B. Dunnett is at the School of Biosciences,Cardiff University, Cardiff CF10 3US, Wales.

Anders Björklund and Olle Lindvall are at theWallenberg Neuroscience Center, Lund University,

221 84 Lund, Sweden.Correspondence to S.B.D.

e-mail: DunnettSB@cardiff.ac.uk

Links

FURTHER INFORMATION Virtual hospital:functional anatomy of the basal gangliaENCYCLOPEDIA OF LIFE SCIENCES ParkinsondiseaseMIT ENCYCLOPEDIA OF COGNITIVE SCIENCE

Basal ganglia

1. Freed, C. R. et al. Transplantation of embryonic dopamineneurons for severe Parkinson’s disease. N. Engl. J. Med.344, 710–719 (2001).

2. Kolata, G. Parkinson’s disease is set back by failure offetal cell implants. NY Times 8 March, 381 (2001).

3. Editorial. Prospects for Parkinson’s disease. Nature Med.7, 381 (2001).

4. Olson, L. & Malmfors, T. Growth characteristics ofadrenergic nerves in the adult rat. Fluorescencehistochemical and 3H-noradrenaline uptake studies usingtissue transplantation to the anterior chamber of the eye.Acta Physiol. Scand. 348, S1–S112 (1970).

5. Olson, L. & Seiger, Å. Brain tissue transplanted to theanterior chamber of the eye. I. Fluorescencehistochemistry of immature catecholamine and 5-hydroxytryptamine neurons innervating the iris. Z. Zellforsch. 195, 175–194 (1972).

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9. Perlow, M. J. et al. Brain grafts reduce motor

primary embryonic cells in the prospects ofproviding regular supplies of large numbersof cells, availability on demand and optionsfor standardized preparation protocols toenhance reproducibility, quality and safety.Moreover, there is good experimental evi-dence that, under certain conditions, eachcan provide functionally effective dopaminereplacement in the striatum45. Nevertheless,there remain significant hurdles to over-come: effective immunosuppression andsafety from zoonoses in the case ofxenografts, and controlled differentiationinto neurons that develop and connect with amature dopamine phenotype in the case ofstem cells and other cell lines. In our judge-ment, none of these approaches is yet devel-oped to the stage of being ready for clinicalapplication, notwithstanding a first clinicalstudy using porcine embryonic mesen-cephalic tissue in which graft survival waspoor and functional benefit very modest46,47.Whatever the hopes of long-term alterna-tives, primary embryonic cells remain theone effective source for clinical transplanta-tion at this stage of development of the field,and they remain the gold standard for effica-cy against which other cell types need to becompared, not only in experimental modelsbut ultimately in the clinic.

Although much refined since the first sur-gical trials were started 15 years ago, the pre-sent protocols for primary embryonic cellpreparation and transplantation are not yetoptimal, and further improvement is almostcertainly achievable. For example, refine-ments in tissue protocols to provide moreeffective neuroprotection both in vitro andafter transplantation — by a combination ofantioxidant, anti-excitotoxic, anti-apoptoticand trophic strategies — can be expected toprovide higher dopamine cell survival16. Onthe surgical side, at present, grafts areimplanted in a standard set of placements,mostly in the putamen alone. We clearly needto acquire a better understanding of thetopography of striatal function as it relates tothe pattern of disease symptoms in peoplewith PD. This should be combined withimproved resolution of diagnostic imaging toprovide selective targeting of graft placementstailored to the distribution of dopaminergicdenervation and the profile of symptoms inthe individual patient.

Do we need further clinical trials now? Itis only through the study of a progressivelymodified technology in small numbers ofpatients using standardized, well-validatedassessment protocols that we can determinewhether the refinements identified experi-mentally translate into clinical benefit. It is

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are woven into a complex tapestry of almostcrystalline regularity1. During development,the progressive assembly of this glial cell arrayprovides cues that are essential for the nervefibres to find their correct pathways2.

The nervous system is subject to twounique types of injury: one (typified byspinal cord injury and strokes affecting fibrepathways) in which the axons are severed(axotomy), and another (typified by multiplesclerosis) in which the axons lose theirmyelin sheaths. Axotomy leads to the discon-nection of nerve cells. Demyelination impairsconduction. Both result in loss of function.

After axotomy in the adult central ner-vous system (CNS), the cut ends of the axonssprout, but the sprouts are unable to growback along their original pathways, and thefunctional loss is permanent. The injury alsodamages the glial cells and disrupts the regu-larly aligned glial array of the white matter.The response of the glial cells to damage leadsto death of oligodendrocytes3,4, changes theanatomical arrangement of astrocytes (often

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Several recent publications describeremarkably promising effects oftransplanting olfactory ensheathing cells asa potential future method to repair humanspinal cord injuries. But why were cellsfrom the nose transplanted into the spinalcord? What are olfactory ensheathingcells, and how might they produce thesebeneficial effects? And more generally,what do we mean by spinal cord injury? Towhat extent can we compare repair in ananimal to repair in a human?

Nerve cells in the brain and spinal cord com-municate with each other by means of myeli-nated axonal processes, which can be up to ametre or more in length, and which travelthrough pathways, called white matter tracts,to reach their destinations. The white mattertracts consist of a highly organized cellularsubstrate, made up of several types of glial cell(astrocytes, oligodendrocytes, which producemyelin, and microglia). The glial cells are fargreater in number than the nerve cells, and

NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | MAY 2001 | 369

Olfactory ensheathing cells — anothermiracle cure for spinal cord injury?

Geoff Raisman

O P I N I O N

Instructions concerning a dislocation of a vertebra in the neck. “If you examine a man with a neck injury …and find he is without sensation in both arms and both legs, and unable to move them, and he is incontinent ofurine … it is due to the breaking of the spinal cord caused by dislocation of a cervical vertebra. This is a conditionwhich cannot be treated.” Edwin Smith Surgical Papyrus, Case 31. Thebes, c. 1550 BC. Taken from Breasted, J. H.(ed.) The Edwin Smith Surgical Papyrus © The University of Chicago Press, 1930.

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