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PERSPECTIVES OPINION Cell therapy in Parkinson’s disease – stop or go? Stephen B. Dunnett, Anders Björklund and Olle Lindvall The results of the first double-blind placebocontrolled trial using grafts of embryonic tissue to treat Parkinson’s disease have aroused widespread interest and debate about the future of cell replacement therapies. What are the key issues that need to be resolved and the directions in which this technology is likely to develop? The recent publication in The New England Journal of Medicine of the first double-blind placebo-controlled trial of embryonic tissue transplantation in Parkinson’s disease (PD)1 has stimulated widespread media interest and scientific debate about the whole future of cell replacement therapies2. Whereas some of the concerns might have been overplayed3, it is appropriate to review the current status of clinical trials of cell-based therapies for PD in the context of the historical development of the field. We consider here the key issues still to be resolved and the directions in which this technology is likely to develop in the near future. Cell-based therapies for PD have been developed over the past three decades (TIMELINE) within a relatively simple conceptual framework: if the human disease is attributable to a primary degeneration of the dopamine neurons of the substantia nigra and a corresponding loss of dopamine innervation of the neostriatum (caudate nucleus and putamen), then replacement of the lost dopamine neurons by transplantation should yield recovery of the associated motor symptoms. As we learn more, not just about whether but also about how grafts exert their functional effects, it becomes apparent that effective therapies can only be developed hand-in-hand with acquiring a rational understanding of the neurobiological principles that underlie the integration and function of grafted cells in the damaged nervous system. Successful transplantation of catecholamine-secreting cells in the nervous system was first achieved by Olson and colleagues in the early 1970s by grafting adrenal chromaffin cells or embryonic dopamine neurons into the rat anterior eye chamber4,5. These studies established that survival, neurite outgrowth and formation of contacts with the host nervous system are best achieved using developing embryonic neurons. The dopaminergic fate of the implanted cells is determined before implantation and depends on accurate dissection of the relevant ventral mesencephalic cell groups from embryos harvested during a critical stage of development6. Initial attempts to transplant embryonic neurons into the adult brain proved more difficult and required rather complex technical protocols to provide adequate nutrient support for newly grafted tissue pieces7. However, these limitations were largely overcome with the development of techniques for preparation of dissociated cell suspensions, allowing stereotactic implantation of embryonic dopamine neurons directly into deep brain sites8. The first reports of functional recovery in simple tests of motor asymmetry in hemi- NATURE REVIEWS | NEUROSCIENCE parkinsonian rats were based on solid graft implants into the lateral ventricles9 or cortical cavities10,11. However, this was soon replicated using the then new cell-suspension technology, revealing the importance of topographic placement and terminal reinnervation in determining functional efficacy of the grafted cells12,13. At the technical level, subsequent experimental studies have identified treatments for cool storage (‘hibernation’) of donor tissues14, refinements in the methods of cell preparation and implantation15, and improved trophic/neuroprotective support of grafted tissues16. Further behavioural analysis has demonstrated recovery in a range of more complex motor functions17 and extended functional validation to primates18,19. In parallel, a combination of electrophysiological, in vivo neurochemistry and behavioural analyses have provided a clearer understanding of the mechanisms of graft function20. It is not simply sufficient for the grafted cells to secrete dopamine at physiological levels into the host neuropil; rather, full functional activity is dependent on a synaptic integration of the grafted cells into the host neural circuitry. Open-label clinical trials The first clinical trials of cell transplantation in PD used adrenal autografts21. In this procedure, one adrenal medulla of the person with PD is removed for dissection of the relevant cells, and implanted back into the brain, either as solid pieces into a ventricular cavity or by stereotaxic injections of cell suspensions into the striatal neuropil. Following a single report of an apparently profound effect22, several hundred patients received this operation in the late 1980s in a series of rather poorly controlled trials worldwide. However, it soon became apparent that the grafts did not survive long-term and that, at best, modest clinical effects were accompanied by significant side effects and an unacceptable level of morbidity and mortality23. This procedure, therefore, is generally not considered to offer an acceptable option. VOLUME 2 | MAY 2001 | 3 6 5 © 2001 Macmillan Magazines Ltd PERSPECTIVES Timeline | A brief history of cell therapies for Parkinson’s disease Successful transplantation of adrenal medulla and fetal nigral cells in the anterior eye chamber4,5. 1970–1972 1976 First published report of functional nigral grafts in hemiparkinsonian rats9,10. 1979 Successful transplantation of fetal nigral cells in the rat brain7. Functional recovery by nigral grafts in a range of behavioural tests (dependent on placement and extent of reinnervation)54–56. 1980 Introduction of the cell-suspension transplantation method in rats8. The alternative was to pursue a clinical strategy based on that which works best in experimental model systems, namely human embryonic tissue allografts. The complex ethical and legal issues associated with the use of human embryonic tissues from elective abortions have now been considered in detail in most western countries, resulting in approved guidelines that permit use of embryonic tissues subject to stringent conditions for selection, consent, collection, handling and application24. The first patients to receive human embryonic nigral grafts, in Sweden and Mexico, had only very limited benefit25,26. However, subsequent improvements in technique have resulted in clear-cut and long-lasting symptomatic improvement (in the order of 30–50% on the the motor examination part of the unified Parkinson’s disease rating scale) as reported in open-label trials from several centres around the world (TABLE 1). The issue of how to determine whether a novel surgical treatment in PD is having significant benefit is not straightforward. PD is a slowly progressive disorder and symptoms can fluctuate markedly depending on time of day and position in the drug cycle, as well as being sensitive to mood and motivation. Placebo effects are well known. Moreover, transplanted cells require many months to develop and integrate into the host nervous system and the grafts cannot easily be removed (other than as a result of graft failure or rejection), so an experimental design for testing patients reversibly on and off treatment is not feasible. Finally, at this stage of their development, we consider that graft technologies are not yet optimized and so need to be refined and developed on a caseby-case basis. Consequently, most centres have adopted the strategy of undertaking detailed 366 1981 First published report of fetal nigral grafts in patients with Parkinson’s disease (operations in 1987)25,26,57. 1985 First published report of adrenal medulla grafts in patients with Parkinson’s disease (operations in 1982) 21. 1988 1990 First post-mortem evidence of nigral graft survival in patients with Parkinson’s disease42. 1995 First evidence of nigral graft survival and functional recovery in patients with Parkinson’s disease30. First report of surviving nigral xenografts in a patient with Parkinson’s disease (operations in 1994)46. longitudinal analysis of individual cases under defined conditions of drug administration. A consortium of European and US centres has developed a standardized Core Assessment Protocol for Intracerebral Transplantations (CAPIT), which defines regular neurological and imaging assessments at defined time intervals to provide an extended baseline over a minimum of three months pre-operation and one to two years post-operation27,28. Adoption of the CAPIT protocol provides two distinct advantages: it allows data to be pooled from several centres to provide large sample sizes even when each contributing centre might study only a few cases, and it allows direct comparison between different tissue preparations and surgical methods used in different centres according to a common set of baseline and outcome assessments28. “It is only through the study of a progressively modified technology in small numbers of patients using standardized, well-validated assessment protocols that we can determine whether the refinements identified experimentally translate into clinical benefit.” On the basis of such open-label longitudinal analysis of small numbers of cases using defined assessment protocols, there is now clear evidence of both clinical benefit and graft | MAY 2001 | VOLUME 2 1997 Positron-emission tomography (PET) evidence of regulated dopamine release from nigral grafts in a patient with Parkinson’s disease37. 1999 2000 PET evidence of graftinduced restoration of movement-related cortical activation in patients with Parkinson’s disease48. survival after embryonic tissue transplantation (TABLE 1). This can be illustrated from the series of 18 patients studied in Lund, with collaborators in London and Munich/Marburg29. These patients have been followed longitudinally for up to ten years; the substantial majority show significant increases in the proportion of time spent in the ‘on’ phase (that is, with few or no motor symptoms), improvements in the speed and accuracy of movements (as observed, for example, in timed series of pronation/supination) in defined ‘off ’ (that is, after drug withdrawal), and maintenance of the improvement with progressive reduction (or complete cessation in several cases) of concurrent L-DOPA (3,4dihydroxyphenylalanine) treatment30–35. In parallel with the neurological testing, the patients have received regular [18F]-DOPA positron-emission tomography (PET) scans in which [18F]-DOPA uptake, as measured by the Ki uptake constant, is seen to return towards normal levels30–37. However, in this and other patient series operated with the current transplantation procedure, [18F]-DOPA uptake in the putamen has reached only 48–68% of that measured in healthy volunteers (TABLE 1), with the exception of one patient with a unilateral graft where restitution was seen to reach 100% (REF. 37), indicating that there is room for considerable improvement. The step-by-step approach adopted in these studies has made it possible to introduce, for example, modifications in the surgical technique38, and improvements in storage and preparation of the tissue34. We are confident that this stepwise approach has been successful in yielding significant refinements in methodology without the risk of affecting large numbers of patients with a poor or ill-conceived technique. www.nature.com/reviews/neuro © 2001 Macmillan Magazines Ltd PERSPECTIVES Table 1 | Functional outcome after bilateral intrastriatal nigral grafts in clinical trials* Surgical Trial centre design No. of cases No. of ventral mesencephalon per putamen Graft placement [18F]-DOPA uptake (%increase/ %normal) UPDRS motor score (% change) L-DOPA Time in ‘off’ doses (% change#)(% change#) Lund‡ OL OL OL 4 2 5 4.9 2.5 2.8 (+L) Put C + Put C + Put 60/52 87/68 55/48 –30 –50 (total) –40 –59 –50, NR –43 –37 0, –70 –45 Tampa OL 6 3.0–4.0 P Put 61/55 –30 –43 –16 49 Créteil OL 3 6 1.0–1.5 3.0 Put NR§ –6 –33 15 –66 NR 50 Halifax OL 2 3.25 (+G) P Put 107/62 –32 (total) –50 NR 51 NR No change Denver DBPC 19 2.0 Put 40/NR –18 || References 33 35 34,48 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 transplants 26,37 and one patient with possible multiple-system atrophy 32,33. Three patients 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 donors in 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.) Denver/New York trial The recent Denver/New York surgical trial1 is distinctive for providing the first published double-blind placebo-controlled trial of neural transplantation in PD. Although such a design is considered necessary by some to provide unequivocal scientific evidence of efficacy of any treatment modality39, there are significant ethical problems associated with using sham procedures in surgical trials40. Three other surprising features of the design of this trial were: clinical assessment was not conducted according to established CAPIT protocols (which would have allowed comparability with other studies); assessments were only undertaken up to one year after grafting (which would maximize placebo effects but which is likely to be too early to assess the level of slowly developing graft-induced therapeutic benefit); and the selection of patients’ retrospective global self-assessment as the primary outcome measure (which showed considerable variation but no difference between placebo and control groups). Moreover , the technique for cell transplantation in this trial differed from most other studies in the number of embryonic donors, methods of cell preparation and long-term storage, absence of immunosuppression and the use of an unconventional surgical approach, so that it was unclear from the outset whether this controlled trial would in fact be informative41. Nevertheless, even at the early one-year time point, modest but significant improvement was obtained in two neurological rating scales, in particular in young patients. There was no improvement in the sham-operated group. This was accompanied by a 40% increase in [18F]-DOPA uptake, and survival of 7,000–40,000 tyrosine-hydroxylase-positive (presumed dopamine) cells per side in two post-mortem cases (compared with 80,000–135,000 cells per side using conventional methods in other post-mortem analyses42). As such, the outcome using this distinctive surgical approach follows that seen in the open label trials, with a level of functional benefit commensurate with the modest survival of the grafts obtained (TABLE 1). However, what has attracted widespread attention about this trial has been the reports of severe and uncontrollable dyskinetic side effects after 1–3 years in 5 of 33 patients in the trial. This has been taken in various media reports as a serious blow to the acceptability of dopamine neuron transplantation per se2. However, it should be noted that side effects of the dramatic severity reported from the Denver/New York trial have not been evident in the open-label trials, and amelioration rather than induction of dyskinesias has been observed after dopamine neuron transplantation in animal models of PD43. We believe that once the reported dyskinesias are properly characterized, they might be found to be attributable to one or several features of the particular protocol used in this trial — in particular, the use of tissue stored in culture for up to four weeks before grafting and the unconventional surgical approach using needle trajectories passing through the frontal lobes, and perhaps also the lack of any immunosuppressive treatment — rather than being a general feature of dopamine-cell replacement using experimentally validated methods. Freed et al.1 have suggested that the late-appearing dyskinesias observed in the Denver/New York trial might be due to a dopamine overdose effect in their grafted patients. However, the low dopamine neuronal survival observed in their study clearly argues against this possibility. Furthermore, NATURE REVIEWS | NEUROSCIENCE the most successfully treated person reported so far, in whom the grafts had restored dopamine storage and release in the striatum to normal levels37, has not developed any significant dyskinesias. What do we still need to know? With the development of new effective treatments for patients with advanced PD, in particular deep-brain stimulation, it is necessary to ask whether it is justified to make any further efforts to develop cell-based therapies for this disorder. We would argue that cell therapy, if successful, offers several unique features and distinctive advantages over other treatment strategies. Cell therapy aims to restore dopamine transmission in the striatum, that is, in the precise area that has lost its intrinsic dopamine afferent innervation. In successful cases, this has given major clinical improvements and allowed the patient to stop L-DOPA medication, without major side effects. The grafted neurons are not destroyed by the disease process up to at least ten years after surgery, indicating that the symptomatic relief can be maintained for many years31–33,37. The further development of the cell replacement approach, however, is severely hampered by the lack of well-characterized, standardized and quality-controlled cell material. As long as neural transplantation has to rely on the access to embryonic donor tissue, widespread application will always be limited. For this reason, the past decade has seen an active search for alternative sources of cells for therapeutic application44. The main alternatives under active investigation are xenografts, stem cells and other genetically manipulated or immortalized cells and cell lines. Each has significant advantages over VOLUME 2 | MAY 2001 | 3 6 7 © 2001 Macmillan Magazines Ltd PERSPECTIVES primary embryonic cells in the prospects of providing regular supplies of large numbers of cells, availability on demand and options for standardized preparation protocols to enhance reproducibility, quality and safety. Moreover, there is good experimental evidence that, under certain conditions, each can provide functionally effective dopamine replacement in the striatum45. Nevertheless, there remain significant hurdles to overcome: effective immunosuppression and safety from zoonoses in the case of xenografts, and controlled differentiation into neurons that develop and connect with a mature dopamine phenotype in the case of stem cells and other cell lines. In our judgement, none of these approaches is yet developed to the stage of being ready for clinical application, notwithstanding a first clinical study using porcine embryonic mesencephalic tissue in which graft survival was poor and functional benefit very modest46,47. Whatever the hopes of long-term alternatives, primary embryonic cells remain the one effective source for clinical transplantation at this stage of development of the field, and they remain the gold standard for efficacy against which other cell types need to be compared, not only in experimental models but ultimately in the clinic. Although much refined since the first surgical trials were started 15 years ago, the present protocols for primary embryonic cell preparation and transplantation are not yet optimal, and further improvement is almost certainly achievable. For example, refinements in tissue protocols to provide more effective neuroprotection both in vitro and after transplantation — by a combination of antioxidant, anti-excitotoxic, anti-apoptotic and trophic strategies — can be expected to provide higher dopamine cell survival16. On the surgical side, at present, grafts are implanted in a standard set of placements, mostly in the putamen alone. We clearly need to acquire a better understanding of the topography of striatal function as it relates to the pattern of disease symptoms in people with PD. This should be combined with improved resolution of diagnostic imaging to provide selective targeting of graft placements tailored to the distribution of dopaminergic denervation and the profile of symptoms in the individual patient. Do we need further clinical trials now? It is only through the study of a progressively modified technology in small numbers of patients using standardized, well-validated assessment protocols that we can determine whether the refinements identified experimentally translate into clinical benefit. It is 368 argued by others that we can only be confident that the effects seen are not simply attributable to placebo effects by undertaking double-blind trials involving control patients receiving sham operations39. However, the large number of cases in which suboptimal grafting techniques yield relatively poor graft survival and at best modest clinical benefit, alongside the sham-operated patients in the Denver/New York trial1, already provide a substantial body of relevant surgical control data. The time for a full-scale double-blind surgical-controlled trial will come when the grafting methods approach optimization. At such time, neural transplantation should be properly compared against the best surgical alternatives (such as subthalamic stimulation) rather than against sham-operated controls. However, in our judgement, that level of optimization is not yet achieved, and the time and effort required for undertaking such a trial at this stage would simply slow steady progress in surgical refinements. Stephen B. Dunnett is at the School of Biosciences, Cardiff University, Cardiff CF10 3US, Wales. Anders Björklund and Olle Lindvall are at the Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden. Correspondence to S.B.D. e-mail: [email protected] Links FURTHER INFORMATION Virtual hospital: functional anatomy of the basal ganglia ENCYCLOPEDIA OF LIFE SCIENCES Parkinson disease 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. MIT ENCYCLOPEDIA OF COGNITIVE SCIENCE Basal ganglia 23. 1. 24. 2. 3. 4. 5. 6. 7. 8. 9. Freed, C. R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344, 710–719 (2001). Kolata, G. Parkinson’s disease is set back by failure of fetal cell implants. NY Times 8 March, 381 (2001). Editorial. Prospects for Parkinson’s disease. Nature Med. 7, 381 (2001). Olson, L. & Malmfors, T. Growth characteristics of adrenergic nerves in the adult rat. Fluorescence histochemical and 3H-noradrenaline uptake studies using tissue transplantation to the anterior chamber of the eye. Acta Physiol. Scand. 348, S1–S112 (1970). Olson, L. & Seiger, Å. Brain tissue transplanted to the anterior chamber of the eye. I. Fluorescence histochemistry of immature catecholamine and 5-hydroxytryptamine neurons innervating the iris. Z. Zellforsch. 195, 175–194 (1972). Olson, L., Seiger, Å. & Strömberg, I. Intraocular transplantation in rodents: a detailed account of the procedure and examples of its use in neurobiology with special reference to brain tissue grafting. Adv. Cell. Neurobiol. 4, 407–442 (1983). Stenevi, U., Björklund, A. & Svendgaard, N.-A. Transplantation of central and peripheral monoamine neurons to the adult rat brain: techniques and conditions for survival. Brain Res. 114, 1–20 (1976). Björklund, A., Schmidt, R. H. & Stenevi, U. Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra. Cell Tissue Res. 212, 39–45 (1980). Perlow, M. J. et al. Brain grafts reduce motor | MAY 2001 | VOLUME 2 25. 26. 27. 28. 29. 30. 31. 32. abnormalities produced by destruction of nigrostriatal dopamine system. Science 204, 643–647 (1979). Björklund, A. & Stenevi, U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral transplants. Brain Res. 177, 555–560 (1979). Björklund, A., Dunnett, S. B., Stenevi, U., Lewis, M. E. & Iversen, S. D. Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 199, 307–333 (1980). Dunnett, S. B., Björklund, A., Schmidt, R. H., Stenevi, U. & Iversen, S. D. Intracerebral grafting of neuronal cell suspensions. V. Behavioral recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions. Acta Physiol. Scand. 522, S39–S47 (1983). Schmidt, R. H., Björklund, A., Stenevi, U., Dunnett, S. B. & Gage, F. H. Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta Physiol. Scand. 522, S19–S28 (1983). Sauer, H. & Brundin, P. Effects of cool storage on survival and function of intrastriatal ventral mesencephalic grafts. Rest. Neurol. Neurosci. 2, 123–135 (1991). Nikkhah, G. et al. A microtransplantation approach for cell suspension grafting in the rat Parkinson model: A detailed account of the methodology. Neuroscience 63, 57–72 (1994). Brundin, P. et al. Improving the survival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant. 9, 179–195 (2000). Winkler, C., Kirik, D., Björklund, A. & Dunnett, S. B. Transplantation in the rat model of Parkinson’s disease: ectopic versus homotopic graft placement. Prog. Brain Res. 127, 233–265 (2000). Taylor, J. R. et al. Grafting of fetal substantia nigra to striatum reverses behavioral deficits induced by MPTP in primates: a comparison with other types of grafts as controls. Exp. Brain Res. 85, 335–348 (1991). Annett, L. E., Torres, E. M., Ridley, R. M., Baker, H. F. & Dunnett, S. B. A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions. Exp. Brain Res. 103, 355–371 (1995). Dunnett, S. B. & Björklund, A. in Functional Neural Transplantation (eds Dunnett, S. B. & Björklund, P.) 531–567 (Raven, New York, 1994). Backlund, E. O. et al. Transplantation of adrenal medullary tissue to striatum in parkinsonism. J. Neurosurg. 62, 169–173 (1985). Madrazo, I. et al. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N. Engl. J. Med. 316, 831–834 (1987). Quinn, N. P. The clinical application of cell grafting techniques in patients with Parkinson’s disease. Prog. Brain Res. 82, 619–625 (1990). Boer, G. J. Ethical guidelines for the use of human embryonic or fetal tissue for experimental and clinical neurotransplantation and research. J. Neurol. 242, 1–13 (1994). Madrazo, I. et al. Transplantation of fetal substantia nigra and adrenal medulla to the caudate nucleus in two patients with Parkinson’s disease. N. Engl. J. Med. 318, 51 (1988). Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in 2 patients with severe Parkinson’s disease: a detailed account of methodology and a 6-month follow-up. Arch. Neurol. 46, 615–631 (1989). Langston, J. W., Widner, H. & Goetz, C. G. Core assessment program for intracerebral transplantation (CAPIT). Mov. Disord. 7, 2–13 (1992). Defer, G. L., Widner, H., Marié, R. M., Rémy, P. & Levivier, M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSITPD). Mov. Disord. 14, 572–584 (1999). Lindvall, O. & Hagell, P. Clinical observations after neural transplantation in Parkinson’s disease. Prog. Brain Res. 127, 299–320 (2000). Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247, 574–577 (1990). Lindvall, O. et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann. Neurol. 35, 172–180 (1994). Wenning, G. K. et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann. Neurol. 42, 95–107 (1997). www.nature.com/reviews/neuro © 2001 Macmillan Magazines Ltd PERSPECTIVES 33. Hagell, P. et al. Sequential bilateral transplantation in Parkinson’s disease — effects of the second graft. Brain 122, 1121–1132 (1999). 34. Brundin, P. et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brain 123, 1380–1390 (2000). 35. Widner, H. et al. Bilateral fetal mesencephalic grafting in 2 patients with parkinsonism induced by 1-methyl-4phenyl-1,2,3,6- tetrahydropyridine (MPTP). N. Engl. J. Med. 327, 1556–1563 (1992). 36. Sawle, G. V. et al. Transplantation of fetal dopamine neurons in Parkinson’s disease: PET [F-18] 6-Lfluorodopa studies in 2 patients with putaminal implants. Ann. Neurol. 31, 166–173 (1992). 37. Piccini, P. et al. Dopamine release from nigral transplants visualised in vivo in a Parkinson’s patient. Nature Neurosci. 2, 1137–1140 (1999). 38. Brundin, P. in Neural Transplantation: A Practical Approach Transplantation (eds Dunnett, S. B. & Björklund, P.) 139–160 (IRL, Oxford, 1992). 39. Freeman, T. B. et al. Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson’s disease. N. Engl. J. Med. 341, 988–992 (1999). 40. Macklin, R. Placebo surgery in trials of therapy for Parkinson’s disease. Reply. N. Engl. J. Med. 342, 355 (2000). 41. Widner, H. et al. NIH neural transplantation funding. Science 263, 737 (1994). 42. Kordower, J. H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N. Engl. J. Med. 332, 1118–1124 (1995). 43. Lee, C. S., Cenci, M. A., Schulzer, M. & Björklund, A. Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson’s disease. Brain 123, 1365–1379 (2000). 44. Dunnett, S. B. & Björklund, A. Parkinson’s disease: prospects for novel restorative and neuroprotective treatments. Nature 399, S32–S39 (1999). 45. Dunnett, S. B. et al. in Neurochemistry Transplantation (eds Teelken, A. W. & Korf, J.) 249–257 (Plenum, New York, 1997). 46. Deacon, T. et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nature Med. 3, 350–353 (1997). 47. Schumacher, J. M. et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology 54, 1042–1050 (2000). 48. Piccini, P. et al. Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts. Ann. Neurol. 48, 689–695 (2000). 49. Hauser, R. A. et al. Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch. Neurol. 56, 179–187 (1999). 50. Nguyen, J. P. et al. Bilateral intrastriatal grafts of fetal mesencephalic neurons in Parkinson’s disease: long-term results in 9 patients. Mov. Disord. 15, S53–S54 (2000). 51. Mendez, I. et al. Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell linederived neurotrophic factor in patients with Parkinson’s disease — report of two cases and technical considerations. J. Neurosurg. 92, 863–869 (2000). 52. Defer, G. L. et al. Long-term outcome of unilaterally transplanted Parkinsonian patients. 1. Clinical approach. Brain 119, 41–50 (1996). 53. Rémy, P. et al. Clinical correlates of [18F]fluorodopa uptake in five grafted Parkinsonian patients. Ann. Neurol. 38, 580–588 (1995). 54. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D. Behavioral recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. 2. Bilateral lesions. Brain Res. 229, 457–470 (1981). 55. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D. Grafts of embryonic substantia nigra reinnervating the ventrolateral striatum ameliorate sensorimotor impairments and akinesia in rats with 6-OHDA lesions of the nigrostriatal pathway. Brain Res. 229, 209–217 (1981). 56. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D. Behavioral recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. 1. Unilateral lesions. Brain Res. 215, 147–161 (1981). 57. Lindvall, O. et al. Fetal dopamine-rich mesencephalic grafts in Parkinson’s disease. Lancet 2, 1483–1484 (1988). 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 of urine … it is due to the breaking of the spinal cord caused by dislocation of a cervical vertebra. This is a condition which 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. OPINION Olfactory ensheathing cells — another miracle cure for spinal cord injury? Geoff Raisman Several recent publications describe remarkably promising effects of transplanting olfactory ensheathing cells as a potential future method to repair human spinal cord injuries. But why were cells from the nose transplanted into the spinal cord? What are olfactory ensheathing cells, and how might they produce these beneficial effects? And more generally, what do we mean by spinal cord injury? To what extent can we compare repair in an animal to repair in a human? Nerve cells in the brain and spinal cord communicate with each other by means of myelinated axonal processes, which can be up to a metre or more in length, and which travel through pathways, called white matter tracts, to reach their destinations. The white matter tracts consist of a highly organized cellular substrate, made up of several types of glial cell (astrocytes, oligodendrocytes, which produce myelin, and microglia). The glial cells are far greater in number than the nerve cells, and NATURE REVIEWS | NEUROSCIENCE are woven into a complex tapestry of almost crystalline regularity1. During development, the progressive assembly of this glial cell array provides cues that are essential for the nerve fibres to find their correct pathways2. The nervous system is subject to two unique types of injury: one (typified by spinal cord injury and strokes affecting fibre pathways) in which the axons are severed (axotomy), and another (typified by multiple sclerosis) in which the axons lose their myelin sheaths. Axotomy leads to the disconnection of nerve cells. Demyelination impairs conduction. Both result in loss of function. After axotomy in the adult central nervous system (CNS), the cut ends of the axons sprout, but the sprouts are unable to grow back along their original pathways, and the functional loss is permanent. The injury also damages the glial cells and disrupts the regularly aligned glial array of the white matter. The response of the glial cells to damage leads to death of oligodendrocytes3,4, changes the anatomical arrangement of astrocytes (often VOLUME 2 | MAY 2001 | 3 6 9 © 2001 Macmillan Magazines Ltd