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The therapeutic potential of stem cells from adults


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The therapeutic potential of stem cells from adults

  1. 1. Clinical review The therapeutic potential of stem cells from adults Ingrid Kuehnle, Margaret A Goodell Adult stem cells seem to have the capacity to “transdifferentiate” into cells of many different tissue types; now further work is needed to establish their role in treating degenerative diseasesCenter for Cell and The discovery of adult tissue specific stem cells, such asGene Therapy,Baylor College of haematopoietic stem cells, which have the ability to Summary pointsMedicine, Houston, “transdifferentiate” into other tissues, has generatedTX 77030 USA much excitement among cell biologists and transplantIngrid Kuehnle Pluripotent embryonic stem cells divide clinicians. It opens new avenues for basic biologicalassistant professor indefinitely and ostensibly generate all cell typesMargaret A Goodell research by using stem cells from adults as an alterna-assistant professor tive to stem cells from embryos. It also carries Stem cells from adults regenerate their residentCorrespondence to: important implications for the treatment of many liver, tissue but may have broader potential forM A Goodell heart, and neurodegenerative diseases. Despite strong differentiation (multipotential)goodell@bcm. evidence that multipotent stem cells (stem cells the potential to differentiate into several cell types) Further work must establish the broadBMJ 2002;325:372–6 reside in many adult organs and can be manipulated in differentiation and functional potential of stem ways that may confer a therapeutic advantage, several cells from adults questions remain to be addressed before the development of clinical applications. We review recent Clinical utility of all stem cells awaits further findings on the “plasticity” of adult stem cells to adopt validation and development a fate different from their originally intended one, and we discuss the potential clinical importance of this finding. We also point out some directions for research marrow and stem cells. By contrast, despite the well in the future. documented presence of stem cells in several mature tissues, including muscle, brain, skin, liver, and Methods mammary gland, they remain poorly defined and underexploited in the clinic.1 Recent reports suggest We searched Medline with both general keywords such that some of these stem cells can differentiate outside as “stem cells,” “stem cell plasticity,” “adult stem cells,” of their tissue of origin (box and fig 1). and “embryonal stem cells” and with more specific terms such as “haematopoietic, hepatic or muscle stem cells,” “Parkinson’s disease,” and “osteogenesis imper- Adult stem cells versus embryonic fecta.” We also cite published and unpublished data stem cells generated in our laboratory. Since the isolation of stem cells from human embryos two years ago, the prospect of using such cells to Adult stem cells reconsidered After development of the embryo most tissues are Muscle Endothelial cells fully differentiated, and further growth or repair of stem cells Blood vessels damaged sites is undertaken by stem cells residing in particular tissues. Adult stem cell populations have been most thoroughly characterised in mouse and Muscle Bone marrow Resident Haematopoietic cells, osteoblasts, human bone marrow, where they continuously Liver haematopoietic endothelial cells, fibroblasts, replenish the differentiated cells of the peripheral stem cells mesenchymal cell precursors blood lost through attrition. From studies of the haematopoietic system it has been possible to define a Central nervous system stem cell as a cell with the capacity to self renew and to generate cells of multiple diverse lineage within the tissue in which the stem cell resides. The ability of the Fig 1 Possible pathways for differentiation in adult stem cells. Cells within bone marrow may give rise to tissues such as endothelial haematopoietic stem cells within bone marrow to give cells, liver, muscle, and neurones (red arrows). Alternatively rise to all blood elements has been extensively haematopoietic stem cells in muscle or muscle stem cells in bone exploited in the clinic for transplantation of bone marrow give rise to respective progeny (blue arrows)372 BMJ VOLUME 325 17 AUGUST 2002
  2. 2. Clinical review haematopoietic system after bone marrow transplanta- Recent reports of potential plasticity of tion, and haematopoietic cells infiltrated all tissues. The stem cells investigators therefore had to distinguish between donor blood cells and donor cells that had become The following reported experiments involved something else, such as hepatocytes. The most striking transplantation of marked donor cells into whole suggestion of stem cell plasticity was published in 1998 animals or directly into injured tissue and examination of the recipient tissue for incorporation of the marked by an Italian group, which found that genetically donor derived cells marked bone marrow cells from a mouse can migrate Whole bone marrow reportedly generated: to sites of muscle injury and participate in muscle Skeletal muscle2 regeneration, albeit at low efficiency.2 The implication Cardiac muscle3 of this and similar studies performed with whole bone Liver4–6 marrow—that the diverse donor cell types observed Endothelial cells7 Brain8–10 after transplantation could all be derived from the Muscle reportedly generated: haematopoietic system—captured the imagination of Bone marrow11 12 13 researchers in tissue specific stem cells. It seemed that Neural stem cells reportedly generated: given the appropriate environmental signals, adult Blood14 cells derived from bone marrow have the capacity to Skeletal muscle15 transdifferentiate into cells of many different organs, Multiple embryonic tissues16 Enriched or purified haematopoietic stem cells including liver hepatocytes, endothelial cells, and even reportedly generated: neurones. Skeletal muscle11 Two studies found that transplanted bone marrow Cardiac muscle17 18 19 cells from adults could migrate into the brain and dif- Endothelial cells17 ferentiate into cells expressing proteins specific for Liver hepatocytes and bile duct20 neuronal cells.8 9 These findings suggest that cells con- Multiple epithelial tissues21 tained within the bone marrow of the adult transdifferentiated and assumed a neuronal fate. The flaw in this interpretation is that besides haematopoi-generate cells and tissues for cell therapy has etic stem cells, whole bone marrow contains astimulated much scientific and public interest. The spectrum of diverse cell types (for example, differenti-stem cells are obtained from the inner cell mass of the ated haematopoietic cells, osteoblasts, endothelialblastocyst (fig 2). As numerous studies with their mouse cells, fibroblasts, mesenchymal precursors that can dif-counterparts have shown, the stem cells from human ferentiate into cartilage, bone, and fat23 24), which areembryos are inherently primitive, can proliferate transferred to the recipient and which couldindefinitely, and have the capacity to generate all cell participate in the apparent differentiation events oftypes of the adult.22 Yet because the embryo is non-haematopoietic origin.destroyed to isolate the cells, a host of ethical issues hasdeeply divided researchers and politicians alike. Some researchers argue that stem cells derived Turning blood into muscle, liver,from adults have sufficient developmental potential and brainthat they can be substituted for stem cells from the To garner support for the hypothesis that stem cellsembryo in therapeutic situations, without any appreci- from the haematopoietic system are capable ofable loss of regenerative efficacy. Others contend that participating in the differentiation into diverse tissuethe extensive capacity of adult stem cells to types, several groups have transplanted purified cellsdifferentiate has not been proved and that their capac- in a variety of settings. Gussoni and othersity proliferation is more limited than that of embryonic transplanted several thousand haematopoietic stemstem cells, so they may not provide a long term source cells from male mice into female mdx mice, a model ofof progenitor cells to replace tissue lost to chronic dis- Duchenne muscular dystrophy.11 They were able toease. Clearly there is a need to rigorously evaluate track the fate of the transplanted cells by detecting theclaims of differentiation “plasticity” of adult stem cells Y chromosome with fluorescent in situ hybridisation.and their long term therapeutic potential. The donor cells efficiently replenished the bone mar- row of the recipients as expected, and cells from the males expressing dystrophin were found at low levelsEvidence for stem cell plasticity in host muscle fibres, indicating differentiation of theThe first suggestion that stem cells from one tissue ofan adult could generate cells of an unrelated tissuecame from studies of whole bone marrow transplanta-tion in humans and animal models, in which the trans-planted cells could be distinguished from therecipient’s tissues by using conventional histologicaltechniques. Examination of several different organs ofthe recipient showed the presence of cells derived fromthe donor in tissues other than the blood, includingendothelial, skeletal, and cardiac muscle cells, liver ovalcells, hepatocytes, and cells of the central nervous Fig 2 (Left) Embryonic stem cells from mouse (Wright Giemsa). Large pale staining cellsystem.2–9 22 All of these studies were technically difficult (upper right) is either a stromal cell, with which these cells were grown, or a differentiatedbecause the donor cells formed most of the daughter of an embryonic stem cell. (Right) Haematopoietic stem cells from mouseBMJ VOLUME 325 17 AUGUST 2002 373
  3. 3. Clinical review transplanted cells into muscle. As in previous What does the future hold for adult stem studies,evidence of the ostensibly multipotent capacity cells of non-haematopoietic origin? of haematopoietic stem cells was based on the Haematopoietic stem cells can be isolated prospec- examination of tissues with markers specific for that tively by using combinations of surface markers, but tissue, such as dystrophin in skeletal muscle, and such strategies have not yet been exploited for stem markers that distinguish resident cells from those of cells specific for other organs. These are usually identi- the donor. Because of the low level of engraftment and fied by their anatomical location or by markers associ- the lack of clinically evident weakness in the mdx mice, ated with their tissue progenitor cells. Surface markers it was not possible to assess the contribution of the that may be specific for adult stem cells are beginning engrafted cells to cardiac function or muscle strength. to emerge and may soon allow a prospective Analogous studies in our laboratory have shown evaluation of the transdifferentiative capacity of adult that the progeny of transplanted haematopoietic stem stem cells of non-haematopoietic origin. cells can also contribute to the repair of capillaries (fig 3) and cardiomyocytes in a mouse model of Muscle stem cells coronary artery infarction.17 Orlic and others also Skeletal muscle contains a potent myogenic stem cell observed that when a population enriched in haema- population with the ability to regenerate muscle in topoietic stem cells was injected directly into injured vivo. Our group transplanted mice with a crude mixture of muscle derived mononuclear cells that dis- hearts it could participate in the regeneration of played the hallmarks of primitive haematopoietic stem cardiac muscle, leading to an apparent improvement cells. The transplanted cells gave rise to all haemato- of cardiac function.18 They also recently showed that poietic cells and possessed the capacity for self renewal, treatment of mice with granulocyte colony stimulating as shown by their ability to contribute to blood factor, which is known to mobilise stem cells from production after serial transplantation into secondary bone marrow into blood, protected mice from some of recipients.12 This suggested that the haematopoietic the damage of induced myocardial infarction.19 This activity of muscle originated from myogenic stem cells suggested that the increased number of circulating that had switched fate on introduction to the regener- stem cells was protective, perhaps through engraft- ating bone marrow, which had been highly stimulated ment of cells into the heart, although this was after lethal irradiation. Equally tenable interpretations not shown. were that a progenitor common to both the haemato- Lagasse and others were the first to provide strong poietic and the myogenic lineage was present in the support for the concept of transdifferentiation at a muscle specimens or, more likely, that true haemato- functional level by using small numbers of purified poietic stem cells were present in muscle, for unknown stem cells. They showed that as few as 30 highly reasons. Recent data from Ogawa’s and our own group purified haematopoietic stem cells injected into mice suggest that bone marrow derived haematopoietic with an inducible lethal hereditary liver disease, tyrosi- stem cells contained within the muscle are responsible naemia type 1, could repopulate the haematopoietic for the haematopoietic potential initially thought to be system as well as differentiate into hepatocytes and res- derived from muscle cells.25 26 This finding emphasises cue the animals from hepatic failure and death.20 the need for caution when interpreting the results of Although these studies support the idea of the dif- studies in transdifferentiation. ferentiation “plasticity” of adult stem cells, definitive Neuronal stem cells proof is still lacking. In all of these experiments multi- Over the past two decades the transplantation of cells ple cells were transplanted, from between 30 and or stem cells has emerged as an attractive approach to several thousand. Even with as few as 30 highly purified the restoration of function in neurodegenerative cells, multiple stem cell types could be present—for diseases such as Parkinson’s and Alzheimer’s. Implan- example, a progenitor of both haematopoietic and tation of dopaminergic neuroblasts, from embryos, non-haematopoietic origin—accounting for differen- which are already committed by fate into the brains of tiation into multiple tissue types. Definitive proof patients with Parkinson’s disease has yielded promis- requires experiments to show that a single stem cell ing results, including clinical improvement in some can differentiate into more than one tissue type. patients.27 28 The problems with this strategy—need for embryonic tissue, localised delivery of dopaminergic cells, and limited graft survival—have impeded its broader use. Neuronal stem cells have also been isolated from the brains of embryos and adults.29 30 Adult neural stem cells have the potential to differen- tiate into multiple cell types of the brain, mainly oligodendrocytes, astrocytes, and neurones, giving them a major therapeutic advantage over committed progenitor cells such as those used in transplants for Parkinson’s disease. Moreover, these neural stem cellsFig 3 Enriched haematopoietic stem cells engrafted in endothelial layer of blood vessels. may be multipotent: when injected into blastocysts of(Left) lacZ-positive cells derived from stem cells (arrow). (Right) Endothelial cells (arrow). mice they contributed to multiple types of tissues inHaematopoietic stem cells were purified from Rosa26 transgenic mice, which express the lacZ the embryos.16 One study reported the generation oftransgene ( galactosidase) widely, and transplanted into the bone marrow of irradiatedrecipients. Several months after transplantation the tibialis anterior was injured by injection of blood from neuronal stem cells when transplantedcardiotoxin. Two weeks later, cryosections were made and stained with X-gal, to detect into lethally irradiated recipients, but this has not yetgalactosidase, and anti-PE-CAM1 antibody, to detect endothelial cells been reproduced.14 These neuronal stem cells have374 BMJ VOLUME 325 17 AUGUST 2002
  4. 4. Clinical reviewalso been observed to generate skeletal muscle whencultured with a cell line capable of differentiating into Additional educational resourcesmuscle or when injected into regenerating muscle.15Further experiments are needed to determine Useful publicationswhether the transdifferentiative potential of neuronal Lagasse E, Shizuru JA, Uchida N, Tsukamoto A, Weissman IL. Toward regenerative medicine. Immunitystem cells resides in specific clones or defines this cell 2001;14:425-36type in general and whether these properties will be Very good overview of the properties and potential ofgeneralisable to neural stem cells in humans. haematopoietic stem cells Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? CellRecent clinical observations 2001;105:829-41 Provides historical account of plasticity of stem cellsAlthough most published information on adult stem from adultscells draws heavily from studies with animal models, Wulf GG, Jackson KA, Goodell MA. Somatic stem cellthere is increasing clinical evidence to support the plasticity: current evidence and emerging concepts.concept of stem cell transdifferentiation. Theise and Exp Hematol 2001;29:1361-70others examined the livers of patients who received Comprehensive review of the specialty of stem cellseither bone marrow from someone of the opposite sex from adults, with summary of published dataor liver transplants. In both cases the authors found Lachmann P. Stem cell research—why is it regarded as a threat? EMBO Rep 2001;2:165-8hepatocytes and cholangiocytes from the opposite sex, An investigation of the economic and ethicalsuggesting that a circulating bone marrow cell could arguments made against research with stem cells fromhome to and transdifferentiate in the liver.6 Horwitz human embryosand others showed engraftment of donor osteoblasts Useful websitesand enhanced bone formation after bone marrow National Institute of Health Stem Cell Primertransplantation in children with the most severe form ( osteogenesis imperfecta, a genetic disorder of colla- Defines pluripotent stem cells, how they are derived,gen production.31 The patients also showed major and why they are important to science and forclinical benefits, including fewer fractures and advances in health care. Also defines stem cells fromincreased growth velocity. The authors concluded that adultsfunctional mesenchymal progenitor cells residing in Report on stem cell research from the American Association for the Advancement of Sciencethe bone marrow compartment were responsible for ( changes, although part of the therapeutic effect and have derived from haematopoietic stem cells with Discussion of scientific and ethical issues and policiesthe capacity for transdifferentiation. surrounding stem cell research St Jude’s Children’s Hospital ( Recent trials of bone marrow transplantation andStem cells derived from bone marrow, whether mesenchymal progenitor cell therapy in osteogenesis imperfectamultipotent haematopoietic stem cells or other tissue National Institutes of Health ( stem cells resident in the bone marrow, have a parkinsonsweb/nigral.htm)major advantage over stem cells from other organs: Recent trials of fetal tissue transplantation inthey are well defined, easy to isolate, and can be Parkinson’s diseaseinjected systemically, reaching other tissues throughthe bloodstream. Moreover, transplantation of bonemarrow or haematopoietic stem cells leads to chance or do they reflect a genetic programme that caninduction of donor tolerance, permitting transdifferen- be activated by specific signals?tiation or transplantation of other tissue specific stem As studies are published, some of the earlier resultscells from the same donor without the need for are being questioned. Do some of the reported obser-prolonged immunosuppression of the recipient. None vations of transdifferentiation represent events of cellthe less, the transdifferentiation events described in fusion, as recently suggested for bone marrow andmost of these studies were rare, even under extreme neural progenitor cells?32 33 Are there other potentialselective pressure. Do such events occur simply by explanations for this apparently unorthodox behav- iour of stem cells? Before adult stem cells are used therapeutically in patients with degenerative disorders Key progress needed in research into plasticity of the liver, heart, or brain, the properties of such cells of stem cells from adults must be characterised, the factors responsible for their regulation defined, and functionality proved. Proof that a single stem cell from an adult can differentiate into more than one cell or tissue type MAG is a scholar of the Leukemia and Lymphoma Society of Proof of functionality: that progeny of America. We thank Maryellen R Goodell for critical reading of “transdifferentiated” adult stem cells functionally the manuscript and Kathyjo A Jackson for producing figure 3. integrate in the new tissue Competing interests: None declared. Proof of functional benefit in non-autochtonous tissue Improvements in efficiency of engraftment and 1 Lagasse E, Shizuru JA, Uchida N, Tsukamoto A, Weissman IL. Toward regenerative medicine. Immunity 2001;14:425-36. transdifferentiation 2 Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Establishment of practical utility: histocompatibility Cossu G, et al. Muscle regeneration by bone marrow-derived myogenic issues? Expansion and differentiation of stem cells? progenitors. Science 1998;279:1528-30. Clinical delivery issues? 3 Bittner RE, Schofer C, Weipoltshammer K, Ivanova S, Streubel B, Hauser E, et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat Embryol (Berl) 1999;199:391-6.BMJ VOLUME 325 17 AUGUST 2002 375
  5. 5. Clinical review 4 Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase M, 20 Lagasse E, Connors H, Al Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Bone marrow as a potential source of hepatic oval cells. Science et al. Purified hematopoietic stem cells can differentiate into hepatocytes 1999;284:1168-70. in vivo. Nat Med 2000;6:1229-34. 5 Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, et al. 21 Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Derivation of hepatocytes from bone marrow cells in mice after et al. Multi-organ, multi-lineage engraftment by a single bone radiation-induced myeloablation. Hepatology 2000;31:235-40. marrow-derived stem cell. Cell 2001;105:369-77. 6 Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, 22 Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from et al. Liver from bone marrow in humans. Hepatology 2000;32:11-6. human embryonic stem cell lines. Stem Cells 2001;19:193-204. 7 Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, et al. Evidence for cir- 23 Pereira RF, Halford KW, O’Hara MD, Leeper DB, Sokolov BP, Pollard culating bone marrow-derived endothelial cells. Blood 1998;92:362-7. MD, et al. Cultured adherent cells from marrow can serve as long-lasting 8 Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning precursors for bone, cartilage, and lung in irradiated mice. Proc Natl Acad blood into brain: cells bearing neuronal antigens generated in vivo from Sci USA 1995;92:4857-61. bone marrow. Science 2000;290:1779-82. 24 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et 9 Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: al. Multilineage potential of adult human mesenchymal stem cells. Science expression of neuronal phenotypes in adult mice. Science 1999;284:143-7. 2000;290:1775-9. 25 Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors 10 Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and stem cells in murine muscle. Blood 2001;98:2008-13. and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 26 McKinney-Freeman SL, Jackson KA, Camargo FD, Ferrari G, Mavilio F, 1997;94:4080-5. Goodell MA. Muscle-derived hematopoietic stem cells are hematopoietic 11 Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, et in origin. Proc Natl Acad Sci USA 2002;99:1341-6. al. Dystrophin expression in the mdx mouse restored by stem cell trans- 27 Lopez-Lozano JJ, Mata M, Bravo G. Neural transplants in Parkinson dis- plantation. Nature 1999;401:390-4. 12 Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells iso- ease: clinical results of 10 years of experience. Group of Neural lated from murine skeletal muscle. Proc Natl Acad Sci USA Transplants of the CPH. Rev Neurol 2000;30:1077-83. 1999;96:14482-6. 28 Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al. 13 Pang W. Role of muscle-derived cells in hematopoietic reconstitution of Transplantation of embryonic dopamine neurons for severe Parkinson’s irradiated mice. Blood 200;95:1106-8. disease. N Engl J Med 2001;344:710-9. 14 Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning 29 Reynolds BA, Weiss S. Generation of neurons and astrocytes from brain into blood: a hematopoietic fate adopted by adult neural stem cells isolated cells of the adult mammalian central nervous system. Science in vivo. Science 1999;283:534-7. 1992;255:1707-10. 15 Galli R, Borello U, Gritti A, Minasi MG, Bjornson C, Coletta M, et al. 30 Gage FH. Mammalian neural stem cells. Science 2000;287:1433-8. Skeletal myogenic potential of human and mouse neural stem cells. Nat 31 Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WWK, Gordon PL, Neel M, Neurosci 2000;3:986-91. et al. 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Proc Natl Acad Sci USA 2001;98:10344-9. 19 Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-5. (Accepted 24 June 2002) A memorable patient The headache and the rabbi “The sudden onset of severe headache, in someone shouldn’t wait, which is what GPs usually do, but just who doesn’t usually get headaches, especially a young get her into hospital as soon as possible.” person. . . .”—the professor’s words, as best as I recall. The next day, I helped him with the removal of a A woman in her mid-30s accompanied her mother deep seated arteriovenous malformation that had been to my surgery one afternoon. The appointment was for leaking. The patient’s recovery was uncomplicated. the mother, who asked if, instead, I could attend to the I was therefore surprised when she returned a few daughter, who had a severe headache and didn’t weeks later: “I want to see you again, because I’ve got normally get headaches. that same headache.” This time, the computed She said that the headache had started suddenly that tomogram showed an abscess at the site of the excised morning. Asked what she was doing at the time, she vascular anomaly. At a repeat performance of the said that she was at the children’s school’s speech day. operation, we removed a 7-8 mm diameter ball of Which school? “You know, the one on the hill.” bacteroides pus. She has had no trouble since. This reply made me suspicious, as there were four When I meet her now, 20 years later, at the local schools on the hill behind our surgery. I pressed her shopping centre she always gives me a hug and a kiss further: “You know, the one my children go to.” and tells any surprised bystander, “He saved my life.” I I tried another tack: “Who was giving the speech?” suppose I did, and, for a general practitioner in a fairly “Rabbi Fraser.” pedestrian suburban practice, this was indeed a Prime Minister Malcolm Fraser had many attributes, memorable experience. but being rabbinical was not one of them. Settled on Peter Arnold general practitioner the diagnosis, I meticulously examined her nervous system but found nothing else. I telephoned my usual We welcome articles of up to 600 words on topics such neurosurgeon, who lived nearby and was, fortunately, as A memorable patient, A paper that changed my practice, not working that afternoon. He was at my rooms My most unfortunate mistake, or any other piece within half an hour, took the patient’s history, conveying instruction, pathos, or humour. If possible conducted a more thorough examination but with the the article should be supplied on a disk. Permission is same result, and took me to another room to discuss needed from the patient or a relative if an identifiable his thoughts before telling the patient and her mother. patient is referred to. We also welcome contributions “I’m always upset when GPs don’t get patients with for “Endpieces,” consisting of quotations of up to 80 subarachnoid haemorrhages to us early enough,” he words (but most are considerably shorter) from any said, “but that’s what she has, even though there’s source, ancient or modern, which have appealed to the nothing to confirm the diagnosis. I suppose we reader.376 BMJ VOLUME 325 17 AUGUST 2002