LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE (University of London) DEPARTMENT OF INFECTIOUS AND TROPICAL DISEASES IMMUNOLOGY UNIT SCIENTIFIC OFFICER – SC03 FURTHER PARTICULARS 1. ADVERTISEMENT SCIENTIFIC OFFICER We are seeking to appoint a Scientific Officer to work on two anti-leishmanial drug discovery projects. The successful candidate will hold a degree in biology, biological sciences or microbiology. They will have a keen interest in the identification of new drugs for the treatment of parasitic diseases as well as proven experience in molecular biology techniques. She or he will be organised, able to adopt a precise & systematic approach to work with excellent data recording and basic computer literacy skills. The ability to communicate and work well within a laboratory community is essential. The post is full time funded by the European Commission & The University of Mississippi for a period of 26 months. Salary is on the Professional Support Pathway Grade 4 from £26,352 to £29,996. The successful candidate will be placed on the scale according to skills and experience. Informal enquiries can be made by email to Prof. Simon Croft (Simon.Croft@lshtm.ac.uk) or Dr Vanessa Yardley (Vanessa.Yardley@lshtm.ac.uk). Applications should be made on-line via our website at jobs.lshtm.ac.uk. The closing date is Monday 14 June 2010 and the reference for this post is SC03. Applications should also include a CV and the names and email contacts of 2 referees who can be contacted immediately if shortlisted. Online applications will be accepted by the automated system until midnight of the closing date. Any queries regarding the application process may be addressed to jobs@lshtm.ac.uk or telephone 0207 927 2173. The London School of Hygiene & Tropical Medicine is committed to being an equal opportunities employer 2. GENERAL INFORMATION The London School of Hygiene & Tropical Medicine The London School of Hygiene & Tropical Medicine is Britain's national school of public health and a leading postgraduate institution worldwide for research and postgraduate education in global health. Part of the University of London, the London School is the largest institution of its kind in Europe with a remarkable depth and breadth of expertise encompassing many disciplines. The School was ranked one of the top 3 research institutions in the country in the Times Higher Education’s 'table of excellence', which is based on the 2008 Research Assessment Exercise (RAE), ahead of the London School of Economics, Oxford, Imperial and University College, London. The institution also achieved the largest increase in ranking compared with 2001, of any of the top 10 institutions in the RAE rankings. In 2009, the School became the first UK institution to win the Gates Award for Global Health. The School’s environment is a rich multicultural one: there are almost 4000 students from 100+ countries following 22 taught masters courses delivered either in London (~650) or through distance learning (~2700), and undertaking research degree training (~400). Over 40% of these students are from non-European countries. The largest growth has been in distance learning students (>40% over 3 years), though the London-based student population (where accommodation limits growth) is at its highest level ever. Alumni are working in more than 180 countries. The School has about 1300 staff drawn from over 60 nationalities. There are research collaborations with over 100 countries throughout the world, utilizing our critical mass of multidisciplinary expertise which includes clinicians, epidemiologists, statisticians, social scientists, molecular biologists and immunologists. At any one time around 80 School staff are based overseas, particularly in Africa and Asia. We have a strong commitment to partnership with institutions in low and middle income countries to support the development of teaching and research capacity. The School has expanded greatly in recent years. Its research funding now exceeds m£60 per annum, much of it from highly competitive national and international sources. The commitment of staff to methodological rigour, innovative thinking and policy relevance will ensure that the School continues to occupy a leadership position in national and global health, adapting quickly to new challenges and opportunities. Mission The School's mission is to contribute to the improvement of health worldwide through the pursuit of excellence in research, postgraduate teaching and advanced training in national and international public health and tropical medicine, and through informing policy and practice in these areas." Department of Infectious and Tropical Diseases The Department of Infectious and Tropical Diseases encompasses all of the laboratory-based research in the School as well as that on the clinical and epidemiological aspects of infectious and tropical diseases. It is headed by Simon Croft, who is Professor of Parasitology. The range of disciplines represented in the department is very broad and inter-disciplinary research is a feature of much of our activity. The spectrum of diseases studied is wide and there are major research groups with a focus on malaria, tuberculosis, HIV/AIDS and other sexually transmitted diseases, vaccine development and evaluation, and vector biology and disease control. The Department is organised into four large research units comprising: Pathogen Molecular Biology, Immunology, Disease Control and Vector Biology, and Clinical Research. There is close interaction between scientists in different research teams. The Department has strong overseas links, which provide a basis for field studies and international collaborations in developed and developing countries. The teaching programme includes MSc courses, taught in-house and by distance learning, which are modular in structure, a variety of short-courses and an active doctoral programme (PhD and DrPH). Immunology Unit (Head: Professor Eleanor Riley) Research in the Immunology Unit centres on analysis of the host response to infection at the molecular, cellular and population levels. The goals are to develop a greater understanding of basic mechanisms of immunological protection versus pathology, and to apply this knowledge to the development of immunological interventions and the identification of correlates of immune status. Our work involves application of state-of-the-art cellular and molecular approaches to the in vitro analysis of pathogen-host cell interactions, to in vivo studies in models and to the study of immunity at the population level in disease endemic areas. Main areas of research include the regulation of acute and chronic inflammation; macrophagepathogen interactions; cellular pharmacology; the production of cytokines during innate and acquired immune responses; T-cell function and antigen recognition; the mechanisms of immunopathology; the development of vaccines; and delivery systems for vaccines and drugs. Current research includes the role of acute phase proteins in resistance to infection, homeostasis and inflammatory disease, mechanisms of macrophage activation, control of cytokine synthesis and mammalian lectin interactions (J. Raynes); intracellular trafficking and secretory pathways of cells of the immune system (T. Ward); the role of innate responses in resistance to the bacterial pathogens, Mycobacterium tuberculosis and Burkholderia pseudomallei, activity and regulation of natural killer cells and their effect on macrophage activation and recruitment, regulation of chemokine receptors during infection and granulomatous tissue responses in the lung against Cryptococcus neoformans and Mycobacterium tuberculosis (G. Bancroft); correlates of protection against tuberculosis and studies of BCG vaccination, human CD8+ T-cell responses to mycobacterial antigens and synthetic peptides, use of whole blood assays in immuno-epidemiology (H. Dockrell); cytokine and chemokine responses to leprosy, cellular composition and effects of steroids on skin and nerve lesions of reactional leprosy, identification of specific peptides for immunodiagnosis of leprosy (S. Young); innate and adaptive immunity to malaria including activation of natural killer cells, cytokine regulation in clinical immunity and immunopathology, regulation of antibody production and immunoglobulin class switching (E. Riley); transmission of Plasmodium falciparum malaria including antibody responses to gametocyte-infected erythrocyte surface antigens, effect of gamete antigen variability on transmission, gametocyte sequestration and development and gametocyticidal drug therapy (C. Sutherland); characterisation of protective immune mechanisms and defined antigens in attenuated vaccine models of schistosomiasis (Q. Bickle); impact of concomitant viral, bacterial, protozoal and helminth infections on induction of immune responses and immunopathology and T cell regulation and induction of mucosal immune responses during intestinal nematode infections (H. Helmby); the identification and evaluation of novel drugs and drug delivery systems for leishmaniasis, trypanosomiasis and malaria, interaction between antiprotozoal drugs and the immune response (L. Vivas, V. Yardley) Pathogen Molecular Biology Unit (Head: Professor Brendan Wren) Research in the PMB Unit focuses on the molecular biology and genetics of pathogens and their hosts in the context of improving the understanding and control of infectious diseases. Aspects of pathogen biology of interest include: (i) determining the mechanisms of infection of globally important viral, bacterial and parasitic pathogens; (ii) deciphering the genetic diversity of selected disease agents in natural populations and to determine its epidemiological impact, (iii) studying immune evasion mechanisms of particular disease agents, (iv) exploiting parasitic, bacterial and viral pathogens as model biological systems and (v) developing practical applications including improved diagnostic tests and the identification and characterisation of vaccine candidates and drug targets. PMBU currently has funding to investigate, amongst others, the malaria parasite (Plasmodium spp), Chagas disease (Trypanosoma cruzi), African sleeping sickness (Trypanosoma brucei), amoebic dysentery (Entamoeba), the Leishmania species, bacterial food borne pathogens (Campylobacter jejuni and Yersinia enterocolitica), gastric ulcers/cancer (Helicobacter pylori), pseudomembranous colitis (Clostridium difficile), plague (Yersinia pestis), paddy field melioidosis (Burkholderia pseudomallei), Tuberculosis (Mycobacterium tuberculosis), Pneumonia (Streptococcus pneumoniae), Bluetongue viral disease of livestock, Herpesviridae, SARS, the hemorrhagic fever virus (RVFV) and the enteric rotavirus that cause significant diarrhoeal disease in infants developing countries. The long-term aim of PMBU research is to gain a fully rounded understanding of the complex and dynamic ways by which pathogens modulate virulence and interact with the human host. Such a holistic approach will vastly increase the scope for the rational of design of long-term intervention strategies to reduce the burden of infectious disease. In recent years such a mission has been significantly enhanced by the availability of whole genome sequences. Members of the Unit are, or have been, involved in several pathogen genome projects including Herpes, Campylobacter jejuni, Yersinia pestis, Clostridium difficile, Entamoeba and Trypanosome species. In particular, post genome studies have facilitated research on more complex parasites such as Plasmodium, Entamoeba and Trypanosome species. The interpretation and exploitation of this basic information is the platform for numerous new avenues of research on pathogenesis, epidemiology and the evolution of virulence. Clinical Research Unit (Head: Dr Alison Grant) The Clinical Research Unit addresses infectious diseases of major public health importance in developing countries. Activities include trials of new therapies, vaccines and educational interventions; the development of new diagnostic tests; studies to elucidate the immunological and molecular correlates of pathogenesis and protective immunity, and to identify genetic polymorphisms conferring protection or susceptibility to infectious diseases; health services research which aims to identify the most efficient and cost-effective way to deliver health care; and health policy analysis. In addition to our many overseas collaborations, we have close links with the Hospital for Tropical Diseases, in new, purpose-built accommodation on the main UCL Hospital campus, five minutes walk from the School. The Wellcome Trust Bloomsbury Centre for Clinical Tropical Medicine is based in the Unit, and currently supports five Clinical Training Fellows and two Career Development Fellows, most of whom are based overseas. Much of the Unit's research concerns HIV and related infections; in particular, the interaction between HIV infection and other sexually transmitted diseases, and between HIV infection and tuberculosis. We have longstanding and fruitful collaborations addressing these issues in Tanzania, Zambia, Uganda and South Africa. Brian Greenwood FRS is leading an initiative to strengthen malaria research in the School through new collaborative links in Africa. Research and teaching on blinding diseases in developing countries has been greatly strengthened by the recruitment of Allen Foster, who is Medical Director of CBM International, an NGO with programmes for the prevention of blindness and disability in over 100 countries; our research on trachoma has played an important part in framing the strategies adopted by the WHO and the new International Trachoma Initiative for the elimination of blinding trachoma by the year 2020. Disease Control and Vector Biology Unit (Head: Professor Daniel Chandramohan) This multidisciplinary Unit includes epidemiologists, entomologists, anthropologists and social scientists, clinical scientists, public health engineers, and geographers. This range of expertise provides us with a battery of tools for focusing on the control of diseases that are insect-borne, water-borne or associated with poor hygiene – mostly in developing countries. Much of the research can be categorised as: evaluating disease control interventions; investigating implementation strategies including working with the private sector; understanding the factors underlying household behaviour in relation to family health; or determining how control resources can be targeted most efficiently. Particular attention is paid to research directed at current health policy issues, including the gap between policy and practice. The DFID Resource Centre for Water and Environmental Health (WELL) and the Hygiene Centre make up the Unit's Environmental Health Group, which plays a leadership role in research and operational support for hygiene promotion, water supply and sanitation. The Unit also houses the largest research group in LSHTM working on malaria control, including the DIFD Team for Applied Research to Generate Effective Tools and Strategies for communicable disease control (TARGETs) and many staff in the Gates Malaria Partnership. The Unit’s valuable mosquito colonies are used for testing repellent products and insecticides in the laboratory. The Unit also includes a major grouping of researchers using spatial analysis in public health. Teaching The School offers 22 one year full-time taught courses leading to the Master of Science (MSc) degree of the University of London and the Diploma of the London School of Hygiene and Tropical Medicine (DLSHTM). The Department of Infectious and Tropical Diseases runs or contributes substantially to ten of these courses and the “Immunology of Infectious Diseases” course is run from within the Immunology Unit. In addition, the Department is responsible for the three-month Diploma in Tropical Medicine and Hygiene (DTM&H) and offers a range of specialist short courses lasting usually one or two weeks. Three MSc courses are also offered by Distance-based Learning, including one on Infectious Diseases. Research Training The School offers two doctoral training programmes. The MPhil/PhD degrees are designed for those who wish to go on to a full time research career. The DrPH is directed towards those who expect their careers to be more in the practice of public health. Project information LEISHDRUG: Targeting the Leishmania kinome for the development of novel anti-parasitic strategies. Visceral leishmaniasis is caused by the protozoan parasites Leishmania donovani and Leishmania infantum and is a potentially fatal disease in endemic areas around the world. During the infectious cycle, Leishmania alternate between the insect promastigote stage and the vertebrate aflagellate amastigote stage that proliferates inside infected host macrophages provoking the pathology of the disease. This consortium uses a highly interdisciplinary approach to reveal Leishmania signaling molecules associated with amastigote virulence, with the major aim to exploit parasite-specific pathways for anti-leishmanial drug development. We use innovative drug screening concepts not applied previously on parasitic systems. We will utilize visual high-content screening to discover compounds capable to kill intracellular Leishmania amastigotes without deteriorating the host cell. This phenotype-based strategy relies on fluorescent parasites and macrophages as read-outs and will allow simultaneous assessment of antileishmanial activity and host cell toxicity under physiological conditions. We will apply a target-based strategy utilizing recombinant Leishmania protein kinases for inhibitor identification and structure-guided drug design. The identification of appropriate target kinases, with only limited homology to their mammalian counterparts will rely on (i) in silico analysis by applying novel bioinformatic tools developed by consortium members, and (ii) in vitro assay based on their phospho-transferase activity towards recombinant Leishmania phospho-proteins. The major objectives of this proposal are (i) to screen small molecule and peptide libraries for hit compounds with leishmanicidal activity using phenotype- and target-based strategies, (ii) to identify anti-parasitic lead compounds and assess their pharmacokinetic profiles using cellculture and experimental infection models for leishmaniasis, and (iii) to initiate lead optimization by structure-based drug design. As a partner in the LEISHDRUG consortium, LSHTM will be involved in the evaluation and validation of novel anti-leishmanial compounds in macrophage and mouse models of infection, part of the hit-to-lead cluster. This Project is funded by the European Commission (FP7). Natural product leads for new drug discovery against Leishmaniasis. Natural products provide a rich source of novel prototypes– particularly as previously unexplored biosphere niches are investigated, new molecular targets are discovered, more sensitive and robust assay methods are developed, and technological advances in dereplication, isolation, and structure elucidation are achieved (Clardy and Walsh, 2004). The biological diversity displayed in the natural world reflects an even richer underlying chemical diversity – and a vast source of novel structures with biological activities such as chemical defence or other functions (Koehn and Carter, 2005). Secondary products, isolated from natural sources, predominantly microorganisms and plants, have provided us with many of the therapeutic agents currently on the market (Butler, 2008). Past and current natural product antileishmanial drug discovery efforts have mostly evaluated the extracts and natural products derived from plants. Large number of plant extracts and the purified natural products have been identified with promising anti-leishmanial activity in vitro. A few them have also been evaluated in vivo mostly in VL models. However none of them have advanced to clinical level. No significant efforts have been made regarding evaluation of marine and microbial natural products for anti-leishmanial drug discovery. In vivo efficacy evaluation against viscerotropic species of Leishmania (LSHTM); the compounds will be initially tested at single dose, which will be decided on the basis of maximum tolerated dose assay carried with a limited number (2- 3) of healthy, normal mice. The compounds showing >80% inhibition of the amastigote load in liver and spleen will be screened for dose response evaluation. Mice (BALB/c) will be infected with 1-2 x 107 L. donovani (MHOM/ET/67/HU3) amastigotes intravenously. The test compounds will be administered 7 days post infection. Mice will be dosed daily subcutaneously for 5 days once/day, and the other compounds (NPC1 161B and sitamaquine) will be given orally. The compounds will be prepared in an appropriate vehicle to achieve a good solubility or uniform suspension. Mice will be sacrificed 14 days post-infection. Liver impression smears will be made, and parasite burdens will be counted and compared to the untreated control group. Fifty percent effective doses (ED50) will be calculated by linear regression analysis (Prism™). Confidence limits for ED50 and ED90 values will be derived using MS Excel and Prism. 3. JOB DESCRIPTION Post: Scientific Officer Grade: Professional Support Pathway Grade 4 Responsible to: Prof. Simon Croft and Dr Vanessa Yardley Prof. Eleanor Riley (Head of Immunology Unit) Unit: Immunology Unit Start date: ASAP Main duties and responsibilities: Maintain Leishmania spp. parasites in in vitro culture and in in vivo models of infection, under Cat 2 and Cat 3 Codes of Practice. Record activity of compounds against Leishmania spp. Keep meticulous records on compound arrival in database, record experimental details and analysis of results. Assist with the development of new methodologies for drug evaluation. Assist in the day-to-day running of the laboratory. Monitoring essential laboratory equipment and reagents to ensure smooth day-to-day running of the project, including ordering reagents and materials. Attend necessary courses and training in aseptic techniques, computer skills and handling of radioactive substance if necessary to enable full participation in the project. Attend regular lab meetings to discuss research progress and work planning with Dr. Vanessa Yardley in order to meet deadlines required by the project. Observe School and Departmental Safety Guidelines relating to good laboratory practices and the handling of pathogenic materials. Assist with teaching of students and visiting workers in the laboratory when required. Draft SOPs of new techniques developed during the course of the projects. 4. PERSON SPECIFICATION Qualifications, Skills and Knowledge: Essential: Degree in a relevant area of biological sciences. Experience or willingness to work under Category 3 regulations. Experience or willingness to learn relevant in vitro aseptic culture techniques, preferably with particular reference to maintenance of Leishmania spp. parasites in culture and in vivo experimental models of Leishmania. Ability to record experimental details and analyse results Ability to organise his/her own work. Ability to work to deadlines. Basic computer skills (Word, Excel, Prism) A flexible approach to working hours Experience in molecular biology techniques – specifically development of quantitative PCR protocols, transfection techniques. Desirable: To be a holder of a Personal Home Office License MSc in a related discipline Interest in searching scientific literature relevant to the project, in particular new techniques to evaluate drug activity. Communication and interpersonal skills: Ability to interact effectively with other members of the team and also with colleagues in the shared culture facilities Ability to develop and maintain excellent relationships with all categories of staff and students to ensure productive work together. Ability to work independently and as part of a team. Willingness to assist in the training of students, visiting workers or new staff in the laboratory. Ability to interact with international partners in a highly professional manner. 5. SALARY AND CONDITIONS OF APPOINTMENT The post is funded by European Commission and the University of Mississippi for a period of 26 months. Salary is on the Professional Support Pathway Grade 4 Salary scale from £26,352 to £29,996, inclusive. The successful candidate will be placed on the scales according to skills and experience. Annual leave entitlement is 30 working days per year for all staff (pro-rata for part-time staff). In addition to this there are 6 fixed-date "Director's Days". 6. APPLICATIONS Applications should be made on-line via our website at http://jobs.lshtm.ac.uk The reference for this post is SC03. Applications should also include a CV and the names and email contacts of 2 referees who can be contacted immediately if shortlisted. Any queries regarding the application process may be addressed to jobs@lshtm.ac.uk. Closing date for the receipt of applications is Monday 14 June 2010. Interviews are scheduled to be held week commencing 28 June 2010. The supporting statement section should set out how your qualifications, experience and training meet each of the selection criteria. Please provide one or more paragraphs addressing each criterion. The supporting statement is an essential part of the selection process and thus a failure to provide this information will mean that the application will not be considered. An answer to any of the criteria such as “Please see attached CV” will not be considered acceptable. Please note that if you are shortlisted and are unable to attend on the interview date it may not be possible to offer you an alternative date. The London School of Hygiene & Tropical Medicine is committed to being an equal Opportunities employer