National Institute For Medical Research Research Articles

Body, heal thyself

‘The stem‐cell genie is out of the research bottle,’ columnist William Safire wrote on July 16 in the New York Times editorial page, continuing, ‘If we command it sensibly, this unexpected servant will help us lead much healthier, longer lives.’ Safire is not alone in having these expectations. Since research using embryonic stem cells has been dragged into the limelight of public debate, its supporters have never tired of emphasising the potential medical breakthroughs that might slumber in these undifferentiated cells. But will stem cell transplants and therapeutic cloning become the new medicine of the future, and what are the prospects for tapping this spring of eternal youth, the mysterious stem cell? Since the political debate has been shaped mainly by future expectations, it is therefore appropriate and necessary to take stock of where research with embryonic stem cells is right now. A recent symposium organised by the European Molecular Biology Laboratory examined the scientific and technical state of the art in stem cell research and therapeutic cloning. Prominent scientists presented the latest results in a field as beset by ethical problems as it is fast‐moving. Lovell‐Badge, from the National Institute for Medical Research in London, presented a slide of a brown and white mottled mouse, a chimera made by replacing cells in a white mouse 8‐cell embryo with embryonic stem (ES) cells from a brown mouse. The mouse is perfectly healthy: proof that in mice, at least, ES cells are totipotent. And they can be cryopreserved indefinitely: cells such as these have been used for 20 years and still perform, noted Lovell‐Badge. In vitro these cells can be differentiated into cardiac and skeletal muscle, blood vessels, haematopoietic cells, insulin secreting cells and various neural cells. As far back as 1975 scientists with foresight were considering the prospects of using …

How the immune system works to protect the host from infection: a personal view.

When I was a young medical student, an interesting discussion was going on about how antibody diversity was encoded; was the antibody molecule encoded in many genes, one for each specificity, or were they general adaptor proteins that were formed on an antigen template. I understood the arguments, which were laid out by my laboratory instructor, Hugh McDevitt. He had just discovered immune response genes in the mouse and was soon to map them to the major histocompatibility complex, which was at that time only known to encode the antigens that provoked rapid graft rejection. I worked the summer after my second year at Harvard Medical School in Hugh's lab, after which I went to the National Institute for Medical Research to work with John Humphrey. In Hugh's lab, I was given the project of trying to make antibodies to L- and D-enantiomers of the same basic amino acids, called L- and D-TGA (for tyrosine, glutamic acid, and alanine). I spent 2 years in Humphrey's laboratory, spent much time in the library reading papers, and published three or four of my own. This was a period when little was known about immunology, as the idea of cutting and splicing genes lay ahead in the future. Antibodies were the only known specific products of lymphocytes, so we measured them in detail. But everyone I talked to in those years was full of ideas about how antibody diversity was generated and how, once generated, it remained the same or very similar throughout the course of a specific immune response. What I will describe in this essay is the growth of three ideas. The first is that the immune system is actually made up of two arms, one specific for infectious non-self, and the other specific for …

Twenty years of the National Institute for Medical Research: Contributions of the Amani Research Centre

Twenty years of the National Institute for Medical Research: Contributions of the Amani Research Centre

Cell biology of virus entry, replication, and pathogenesis.

The Keystone Symposium on Cell Biology of Virus Entry, Replication, and Pathogenesis held in Taos, New Mexico February 29 to March 5, 2000 to a large degree fulfilled its purpose to facilitate interdisciplinary exchange of information. The Keynote Address by Sir John J. Skehel (National Institute for Medical Research, London) initiated discussion on the antigenic analyses of influenza virus hemagglutinins. Subsequent topics covered the earliest events in viral receptor-mediated entry through membrane fusion to virus assembly, genetics, pathogenesis, and immunology. While a significant number of taxonomically different viruses was discussed, several common themes emerged from plenary sessions and poster workshops. A few selected topics are highlighted below.

Discovering the role of the major histocompatibility complex in the immune response.

The discovery that genes in the major histocompatibility complex (MHC) play an important role in the immune response depended on the chance interaction of several unrelated events. The first, and most important, was the decision by Michael Sela to synthesize a series of branched, multichain, synthetic polypeptides based on a backbone of poly-l-lysine. The prototype compound, (T,G)-A-L, was tipped with short random sequences of tyrosine and glutamic acid. This resulted in a restricted range of antigenic determinants composed of only two or three amino acids with a variable length-ideal for binding to the peptide binding groove of MHC class II molecules. The second was the decision by John Humphrey to immunize various strains of rabbits with this synthetic polypeptide. Two of these rabbit strains showed very large quantitative differences in antibody response to (T, G)-A-L. In transferring this system to inbred mouse strains, the third bit of good fortune was the availability at the National Institute of Medical Research, in Mill Hill (London), of the CBA (H2(k)) and C57 (H2(b)) strains. The H2(b) haplotype is the only one mediating a uniform high antibody response to (T,G)-A-L. The fourth critical ingredient was the availability of numerous congenic and H2 recombinant inbred strains of mice produced earlier by Snell, Stimpfling, Shreffler, and Klein. A search for congenic pairs of mice expressing the responder and nonresponder H2 haplotypes on the same background revealed that these strains responded as a function of their H2 haplotype, not of their inbred background. Extensive studies in a variety of inbred strains carrying recombinant H2 haplotypes, as well as a four-point linkage cross, mapped immune response to (T,G)A-L within the murine MHC, between the K and Ss loci. The demonstration that stimulation in the mixed lymphocyte reaction (MLR) mapped to the same region quickly led to attempts to produce antisera in congenic H2 recombinant strain combinations. These antisera identified I-region associated (Ia) antigens. Immunoprecipitation and blocking studies showed that the gene products controlling specific immune responses, the mixed lymphocyte reaction, and the structure of Ia antigens were one and the same-now designated as the I-A MHC class II molecules. These antisera and inbred strains enabled Unanue to demonstrate the peptide binding function of class II MHC molecules.

A brief history of developmental biology at the National Institute for Medical Research.

A brief history of developmental biology at the National Institute for Medical Research.

Antimalarial drug policy: making systematic change

Andrew Y Kitua graduated as a medical doctor in 1979 from the State University, Milan, Italy. He has worked In epidemiological research in the Seychelles and Tanzania. He is currently director-general of the National Institute for Medical Research, Tanzania.

Molecular genetics, natural history and the demise of childhood leukaemia

After graduating at University College (BSc) and Middlesex Hospital Medical School (Ph.D), Mel worked at the Karolinska Institute, Stockholm, and the National Institute for Medical Research before joining the Imperial Cancer Research Fund, heading up an immunology laboratory in 1976. In 1984, he was appointed Director of the Leukaemia Research Fund's first specialist centre, at the Institute of Cancer Research, London, where he is still based.The patterns of genetic change, clonal evolution, natural history and latency are very different in the paediatric leukaemias compared with adult epithelial cancers but are similar to those in other childhood cancers of mesenchymal stem cell origin. This distinction has a biological logic in the context of the selective pressures for clonal emergence in different developmental and cellular contexts and has a major impact on curability. Most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasise without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the ‘bad news’ genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option.

A matter of life or death

“Animal rights hunger striker sends message from his deathbed,” announced the Observer in a front-page splash on 6 December, reporting a letter to his supporters from Barry Horne, who had refused food for the previous 60 days. “This is not for me, it is for every animal in every torture laboratory,” said Horne, who had been admitted to York District Hospital in the UK, from prison where he was serving an 18-year sentence for firebombing.The Observer accompanied the story by a second long piece headed “Animal lover ready to die to end vivisection” and an editorial saying that some animal experiments were “a cruel but necessary evil.”Horne's protest, later abandoned, was occasioned by the failure of the UK government to honour (yet) its pre-election pledge to support a Royal Commission to review the justification for animal experimentation. The Observer and many other newspapers amply described this political background, together with information about Horne's incendiary attacks on a variety of shops, including a cancer charity shop, in the south of England.A remarkable feature of the reportage was the almost total absence of scientific arguments over laboratory animals. Tabloid newspapers, in particular, treated the Horne story purely as news, while the broadsheets explored every possible angle except the science. Even those papers that criticised Horne's actions in editorials set a rather different tone in their (much more widely read) news pages through the use of terms such as “cruelty”, “vivisection” and “vivisector”.Journalists, seeking fresh perspectives, turned not to science but to human interest and the many nuances of protest. On behalf of the Times, Vanora Bennett visited York, recorded the “sullen group huddled outside the hospital grounds” and complained to her readers: “The night is bone-chilling, yet no one moves to make a space for me.” With far more important matters at stake, here was a reporter following the tradition of those who used to portray industrial actions solely in terms of pickets and braziers at the factory gate.Imminent martyrdom is, of course, news. At the same time, media neglect of its context, together with careless use of emotive language, can perpetuate stereotypes and impair understanding. Imminent martyrdom also calls forth sympathy, however horrendous the crimes for which someone like Barry Horne has been convicted. “Instinctively, one responds to his plight with compassion, the same compassion that goes out to cancer victims,” said the Times, while also recording the £3 million cost of the damage caused by his firebombing campaign on behalf of animal rights.The question that remains is why these human reactions so dominated coverage of the affair as to exclude from most accounts the underlying evidence about humane animal experimentation. Part of the answer lies with the scientific community itself, with decades of reluctance to engage in public discussion of these issues combined, on occasions, with willingness to defend the indefensible.In May 1990, the Independent published a story about an elderly, distinguished pharmacologist, working on under-anaesthetised rabbits at the National Institute for Medical Research in north London. This was based on first-hand videotape evidence obtained by undercover researchers on behalf of Advocates for Animals. The Medical Research Council, after a diligent enquiry, subsequently issued a report acknowledging mistakes at various levels within the Institute and elsewhere, and recommending appropriate changes. This did not, however, prevent some scientists from seeking to minimise the seriousness of what had happened, nor from trying to argue that the whole episode reflected little more than journalistic mischief.Of course, it's not surprising that scientists are often reluctant to go on record in the animal experimentation debate. The neuroscientist Colin Blakemore from Oxford University — a vocal defender of humane animal experimentation — was among those scientists threatened with death by an animal rights organisation in the eventuality of Horne's death. But extreme actions like these simply underline the need for better public understanding of the issues.When faced with a development such as Barry Horne's hunger strike, reporters and their editors do not simply respond to the immediate details of the event. They set the story within a framework determined in part by their understanding of what has gone before. If, through the failures of others, they have little awareness of the case for animal experimentation, then this will be reflected in their style of coverage.A singular error made by some medical researchers, vis-a-vis the media and the community at large, is to believe that the necessity of using animals in research and in safeguarding public health is self-evident. Despite the fact that UK legislation was thoroughly overhauled as recently as 1986, one good that might come from recent events would be an enquiry ensuring comprehensive ventilation, through the media, of the case for (and against) animal experimentation.

Isolation of Avian Influenza A(H5N1) Viruses From Humans—Hong Kong, May-December 1997

A strain of influenza virus that previously was known to infect only birds has been associated with infection and illness in humans in Hong Kong. The first known human case of influenza type A(H5N1) occurred in a 3-year-old child who died from respiratory failure in May 1997. In Hong Kong, the virus initially was identified as influenza type A, but the subtype could not be determined using standard reagents. By August, CDC; the National Influenza Center, Rotterdam, the Netherlands; and the National Institute for Medical Research, London, United Kingdom, had independently identified the virus as influenza A(H5N1). An investigation conducted during August-September by the Hong Kong Department of Health and CDC excluded the possibility of laboratory contamination. Since this initial case was identified, six additional persons in Hong Kong have been confirmed to have influenza A(H5N1) infection, and two possible cases have been identified. This report summarizes the nine cases identified thus far and describes preliminary findings from the ongoing investigation, which indicate that multiple influenza A(H5N1) infections have occurred and that both the source and mode of transmission are uncertain at this time.

Launching microsatellites: a review of mutation processes and methods of phylogenetic interference.

From the Department of Zoology, South Parks Road, University of Oxford, Oxford 0X1 3PS, England (Goldstein), and the Department of Mathematical Biology, National Institute for Medical Research, London, England (Pollock). We thank Dr. Stephen O'Brien and members of the Laboratory of Genomlc Diversity lor encouraging us to write this review. D.D.P. is a Hltchlngs-Ellon Fellow of the Burroughs Wellcome Fund. A computer program written by Minch et al., which calculates statistics for microsatellite data. Is available on L. L. Cavalli-Sforza's home page at http://lotka.stanford.edu or by writing to Dr. Eric Mlnch at minch6malecot.stanford.edu.

My interests in protein and glycoprotein chemistry.

My interests in protein and glycoprotein chemistry.

Shaping a new biological factor, 'the interferon', in room 215 of the National Institute for Medical Research, 1956/57.

Shaping a new biological factor, 'the interferon', in room 215 of the National Institute for Medical Research, 1956/57.

Interleukin-1 alpha (IL-1 alpha) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) as potential inducers of supravital chemotaxis.

The phenomenon of artificially induced local leucocyte reactions during the supravital period could be of practical importance, but has not yet been comprehensively investigated. For a more detailed evaluation, experiments with the chemotactic agents interleukin-1 alpha (IL-1 alpha) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) were performed by subcutaneous injection into various anatomical regions (back, abdomen, limbs) of NMRI-mice (National Medical Research Institute) and pigs 0-5 min after circulatory arrest. Phosphate buffered saline (PBS) without effective components was administered to equivalent areas of the animals as a control. Tissue specimens were collected at 6 h postmortem (mice) and 12-14 h postmortem (pigs), cut into serial sections, stained with H & E and examined under the microscope. A leucocyte reaction did not develop in pigs (n = 10, 30 tissue samples) following injection of FMLP, however, dermal, subcutaneous and perivascular infiltration of leucocytes (in particular mononuclear cells and a few granulocytes) was found in 3 out of 30 tissue specimens in murine experiments. In addition intravascular cell accumulations were detected in 2 out of 30 samples. The injection of IL-1 alpha to mice gave similar results, i.e., aggregations of leucocytes and intravascular cell accumulations in 4 out of 30 and 3 out of 30 tissue samples, respectively. In negative controls no leucocyte reaction was detectable. This shows that potent chemotactic factors such as IL-1 alpha and FMLP administered in the early supravital period can induce moderate local leucocyte reactions in animal models in at least some cases. A clear morphological differentiation between vital and supravital chemotaxis does not seem to be possible. The supravitally stimulated accumulations of leucocytes are interpreted as an aggregation of resident macrophages in combination with a slight migration of blood leucocytes. Presumably, these alterations are restricted to the very early supravital period as long as sufficient energy reserves are available. It must be stated that the observed changes are reactions, not spontaneous actions, so that the general validity of the phenomenon of leucocyte infiltration as a vital parameter is not affected.

Intracellular Ca2+ release by InsP3 in cerebellar Purkinje neurones.

Acta Physiologica ScandinavicaVolume 157, Issue 3 p. 381-394 Intracellular Ca2+release by InsP3 in cerebellar Purkinje neurones D. OGDEN, D. OGDEN National Institute for Medical Research, Mill Hill, London, UKSearch for more papers by this authorK. KHODAKHAH, K. KHODAKHAH National Institute for Medical Research, Mill Hill, London, UKSearch for more papers by this author D. OGDEN, D. OGDEN National Institute for Medical Research, Mill Hill, London, UKSearch for more papers by this authorK. KHODAKHAH, K. KHODAKHAH National Institute for Medical Research, Mill Hill, London, UKSearch for more papers by this author First published: July 1996 https://doi.org/10.1046/j.1365-201X.1996.28252000.xCitations: 6 D. Ogden National Institute for Medical Research, Mill Hill, London NW7 1AA, UK We thank David Trentham, John Corrie and John Wootton for caged InsP3 and caged 5-thio-InsP3. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume157, Issue3July 1996Pages 381-394 RelatedInformation

Peter Goodfellow: sex, drugs and poetry

Peter Goodfellow: sex, drugs and poetry

Sara Courtneidge: swimming with Srcs

Sara Courtneidge has recently been appointed vice-president of research in the California-based biotechnology company, Sugen, Inc. Her pioneering research into how the Src tyrosine kinase is involved in cellular transformation has provided the basis for understanding how members of the src gene family act in normal signal transduction pathways. In her new position, Dr Courtneidge will be trying to identify components of signal transduction pathways as targets for pharmaceutical intervention.Dr Courtneidge's career began when, at the age of eight, she announced that she was going to be a scientist. Thirteen years later, she obtained an Honours degree in Biochemistry at the University of Leeds and moved to the National Institute for Medical Research (NIMR) at Mill Hill, England for her doctoral studies. There, under the supervision of Mike Crumpton and John Skehel, she studied how cells infected with influenza virus are recognized and destroyed by cytotoxic T cells. During this time, Dr Courtneidge's critical and analytical skills were sharpened by the continual barrage of questions on seminars and papers from John Skehel, who worked on the lab bench opposite hers. Throughout her postgraduate studies, Dr Skehel encouraged her to think about her future scientific direction, a process that resulted in her securing a postdoctoral research position in J. Michael Bishop's lab at the University of California, San Francisco.Having only ever spoken to Dr Bishop on the telephone, Dr Courtneidge was initially overwhelmed on her arrival at the lab in San Francisco. The combined Bishop and Varmus laboratories were, at that time, beginning to identify the cellular genes that had been incorporated into RNA tumour viruses and which gave them the ability to transform cells. This was, and has continued to be, a large, energetic laboratory at the cutting edge of molecular biology research and Dr Courtneidge was the youngest and newest member. However, she soon adjusted to the dynamic environment and began her work on identifying the structural and functional domains of the transforming protein isolated from Rous sarcoma virus, pp60v−src, or Src.On her return to England, she was offered a junior staff position at NIMR where, together with Alan Smith, she demonstrated that the transforming protein of polyomavirus, middle T antigen, acquired its tyrosine kinase activity by association with the cellular homologue of pp60v−src. From this work, Dr Courtneidge was inspired to examine the normal role of the Src protein in cells and discovered that the cellular Src protein is, itself, negatively regulated by tyrosine phosphorylation.In the mid-1980s, Dr Courtneidge accepted an offer to join the European Molecular Biology Laboratories (EMBL) in Heidelberg, Germany. The organization of EMBL, with several, small interactive research groups and a multi-cultural composition, provided an exciting and stimulating backdrop for Dr Courtneidge to develop her research interests. During this time, a number of groups throughout the world began to identify other cellular tyrosine kinases that were related to, and shared certain domains with, the cellular Src protein. Dr Courtneidge's laboratory demonstrated that these proteins were absolutely required for the normal control of cellular growth. She also showed that members of this family were components of normal signal transduction pathways, regulating the pathways by virtue of their kinase activity. This provided a valuable means for studying how cellular growth is regulated in normal cells and also how this regulation is disrupted in transformed cells.Figure 1Figure 1Figure 1Sarah Courtneidge.View Large Image | View Hi-Res Image | Download PowerPoint SlideDespite having the rare privilege of an open-ended position at EMBL, Dr Courtneidge recently decided it was time for a new challenge. This came in the form of an offer to direct the research division of Sugen, Inc. There, her laboratory will be trying to identify components of signal transduction pathways which can act as new therapeutic targets for the treatment of diseases such as cancer. While there is no doubt that the application of her work to a commercial setting will be very challenging, Dr Courtneidge has successfully been swimming with Srcs for most of her research career and has always managed to tame them.Figure 2Figure 2Figure 2The Courtneidge laboratory at Halloween.View Large Image | View Hi-Res Image | Download PowerPoint Slide

A biological analysis of individuality.

A biological analysis of individuality.

Novel topology of a zinc-binding domain from a protein involved in regulating early Xenopus development.

Xenopus nuclear factor XNF7, a maternally expressed protein, functions in patterning of the embryo. XNF7 contains a number of defined protein domains implicated in the regulation of some developmental processes. Among these is a tripartite motif comprising a zinc-binding RING finger and B-box domain next to a predicted alpha-helical coiled-coil domain. Interestingly, this motif is found in a variety of protein including several proto-oncoproteins. Here we describe the solution structure of the XNF7 B-box zinc-binding domain determined at physiological pH by 1H NMR methods. The B-box structure represents the first three-dimensional structure of this new motif and comprises a monomer have two beta-strands, two helical turns and three extended loop regions packed in a novel topology. The r.m.s. deviation for the best 18 structures is 1.15 A for backbone atoms and 1.94 A for all atoms. Structure calculations and biochemical data shows one zinc atom ligated in a Cys2-His2 tetrahedral arrangement. We have used mutant peptides to determine the metal ligation scheme which surprisingly shows that not all of the seven conserved cysteines/histidines in the B-box motif are involved in metal ligation. The B-box structure is not similar in tertiary fold to any other known zinc-binding motif.

Networked information resources for medical librarians

Networked information resources for medical librarians: an overview and some case studies in the UK. Examines some of the information resources available to medical librarians via the Internet and describes the use of these by 3 UK medical libraries: for sending and receiving electronic mail locally, nationally and internationally; for transferring documents, images and sets of records from a remote computer to a local one (file transfer protocol (ftp)); and for logging on to other computers and online services (telnetting). Other applications of the Internet for medical librarians described include: gopher; World Wide Web (WWW); the use of mailing lists for medical information; announcement of meetings and conferences; job advertisements; electronic bulletin boards; access to remote databases; and electronic periodicals. Reports on case studies involving visits to: the National Institute of Medical Research (NIMR); the Wessex Medical Library; and University of Wales, College of Medicine. Concludes with a summary of contemporary Internet ini tiatives by UK medical dlibraries and related organizations.