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BBSRC David Phillips Research Fellowship an interdisciplinary perspective

BBSRC David Phillips Research Fellowship an interdisciplinary perspective. Context: Current research Career . Fellowship Applications: Personal perspective Hints and Tips. Dr. Ed Tate, Department of Chemistry, ICL. Research fellowship: Advantages, challenges.

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BBSRC David Phillips Research Fellowship an interdisciplinary perspective

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  1. BBSRC David Phillips Research Fellowship an interdisciplinary perspective • Context: • Current research • Career • Fellowship Applications: • Personal perspective • Hints and Tips Dr. Ed Tate, Department of Chemistry, ICL • Research fellowship: • Advantages, challenges

  2. Faculty of Medicine Fellowships DayJuly 2009 Research interests • Development & application of new technologies in chemical biology • New chemical approaches for site-specific protein labelling • Chemical tools for exploring post-translational modification of proteins • Reactive probes for in vitro & in vivo enzyme activity profiling & imaging • Design and synthesis of small molecule inhibitors of: • Protein-protein interactions: site-specific disruption of multi-protein complexes • Martin Buck (CBC), Xiaodong Zhang (CBC), Tony Holder (NIMR) • Protein-ligand interactions: transferase and protease inhibitors • Neil Fairweather (CMMI), Miguel Seabra (NHLI), Debbie Smith (York) Dr. Ed Tate, Department of Chemistry BBSRC David Phillips Research Fellow (since 2006) e.tate@imperial.ac.uk; http://www3.imperial.ac.uk/people/e.tate/research

  3. What is chemical proteomics? • Chemical proteomics • Applied organic chemistry of living systems • Targets complex post-translational phenomena: PTMs, enzyme activity in living systems, protein-protein interactions… • Proteomic complement of chemical genetics • Protein labelling, imaging, biomarker analysis… Transcription Translation • RNA • Protein • DNA Post-translational modification • >300 types: Phosphorylation, glycosylation, lipidation, acetylation, proteolysis…

  4. Post-translational Modifications Origin Phosphorylation Signalling Glycosylation Immune system Cell adhesion Prenylation Trafficking Acylation Membrane association Acetylation Transcriptional regulation Proteolysis Apoptotic cascade Ubiquitination Protein degradation Site Dynamics Function Chemical Proteomics Sulfenic acids Redox response

  5. Site-specific labelling of proteins Metabolic tagging - + ++ Target proteins tagged at site of PTM Live- and fixed-cell imaging Tagged PTM applied to cells/animal Drug mode-of-action studies Bioorthogonal ligation chemistry Proteins labelled site-specifically Chemical or enzymatic tagging Protein bearing site-specific chemical feature (active site, PTM) ID proteins and site of PTM

  6. A platform for Chemical Myristomics (‘Azido-myristic’acid) Secondary Labels MudPIT analysis Bioorthogonal ligation Secondary Labels On-bead purification 2D-DIGE

  7. Activity-based probesSurface layer formation in C. difficile • C. difficile • Spore-forming anaerobe • Most lethal hospital superbug • Resistant to most antibiotics • Lack of genetic tools • Excretes a crystalline S-layer • Post-translational cleavage • Unknown cysteine protease Warhead Linker Specificity element Label Feed to C. difficile Affinity purify, ID

  8. Future perspectives Chemical Technologies • New chemical labelling technologies • New chemistries • Extend to other PTMs • ABPs for new enzyme activities • Discovery of new PTMs • Pull out after metabolic labelling • Nucleotide tagging • Protein-DNA interactions • Transcriptional activation Biomedical Applications • Chemical genetics • Drug screening • Biomarker analysis • Synthetic biology • Introducing new chemistries • Live cell & in vivo imaging • Trafficking due to PTM • Cell-surface display • Systems biology • Dissect pathways • Probes for protein-protein & protein-membrane interactions

  9. Career OverviewPhD and Postdoctoral Work 1993- 1996 • BSc in Chemistry (Durham) 2002 - 2003 2004 - 2006 • BBSRC-funded PDRA (ICL) 1996 - 1999 2000 - 2001 • PhD in Organic Chemistry • (Cambridge) • 1851 Research Fellowship • (EcolePolytechnique) • Howard Trust Research Fellowship • (Institut Pasteur) New C-glycosidation reactions Total synthesis of natural products Radical cyclisation chemistry Total synthesis of natural products Role of DNA helix stability & upstream sequences in transcriptional regulation Protein/peptide synthesis and engineering Library generation and screening techniques

  10. Application Stage Situation as of August 2005 • Prior Applications: • WT fellowship application in 2005 rejected – insufficient biochemical track record • Never been involved in writing a standard grant application! • Research Track Record: • Good chemical research track record • No biochem research track record at time of application • Personal Situation: • Current PDRA contract due to expire 1 month after expected fellowship decision, no follow-on funding… • Baby due 22nd November!

  11. Application Stage Plan of Action • Novel proposal: chemical proteomics • Topical and interdisciplinary • Very limited literature precedent • Minimal preliminary data, and no prior track record! • Applied for multiple fellowships • EPSRC Advanced Research Fellowship (ARF) • BBSRC David Phillips Fellowship • Royal Society URF • Wellcome Trust • MRC • Plan B: other grant proposals • Co-I on MRC Discipline-Hopping grant (related subject) • ‘Researcher Co-I’ on BBSRC responsive mode grant (different subject)

  12. Application Stage Making Multiple Applications • Advantages • Spreads the risk of hitting a referee with strong negative bias • Not always clear in advance of submission which funder is most appropriate • Address Remit • Direct your proposal towards the funder’s remit • BBSRC: basic biology, complete independence (PI), 3-year postdoc • MRC: medical emphasis, strong training/career development component • Wellcome: technician for 5 years, previously had to have HoD as PI • EPSRC: steer clear of biological outputs (stick to technology only) • Royal Society: two FRS’s strongly supporting application, no support grant. • Remit is strictly based on the research outputs (‘deliverables’) of your project (not the methodology and techniques applied) • Be flexible, rewrite application to take account of funding available, in particular in justifying your costs

  13. Application Stage Writing Applications • Writing the proposal • Steep learning curve, very time-consuming (2-3 months) • Sole PI, so responsible for all aspects of the proposal: financial, planning, scientific • Very good practice for later PI grant applications! • Costing the proposal • Costing may feel rather abstract on the application, but you will appreciate careful costing if you get the fellowship. • Acquire a working knowledge of Full Economic Costing (fEC) • The headline cost can be big: >£1 million for BBSRC DP Fellowship – but 30%+ goes direct to Faculty under fEC… • Request costs at the upper limit allowed if you can justify them for the proposed work. • You can usually move cash around later (within limits!)

  14. Application Stage General Tips • Create a career narrative • Justify your career choices (in hindsight) • Highlight why you are ready to go independent • Salary level • Most funders don’t fix the level arbitrarily • You don’t usually need to justify your own salary level • Fellowship proposals vs. grant proposals • An original, cutting-edge idea can carry more weight than a strong track record (esp. when compared to standard grants) • You can get away with having (much) less preliminary data • Interdisciplinary research may fare better in fellowship applications than in standard grant applications.

  15. Application Stage Writing Applications • Some more things to think about… • Scientific merit – external peer review (it is a grant proposal!) • Address important questions – originality, fresh thinking • Has to be feasible– you have to convince the referees that you are capable of doing the work proposed, in the time available • Show them that you have considered the riskier elements, and propose contingency plans; don’t have the whole project dependent on a risky proposition • Mention preliminary data if you have it – I would say this is not absolutely essential, but you do need to be able to convince the referees that the riskier aspects could work • Know your competition in the scientific field – cite the key work of others in your background section • Cheaper proposals do not mean more chance of success; but high-cost proposals where costs are not justified will also not impress.

  16. Application Stage Stay or Go? • Stay… • Access to existing equipment and collaborations • Minimal start-up time • Can you achieve independence? • Or go? • Start afresh on your own terms • Will take time to get started • May help to get out of the ‘golden triangle’… • In either case… • Ensure your expectations (support, space, teaching etc.) are understood by host institute • Be prepared to justify choice of institute in the application and at interview • Be prepared for questions regarding future independence if you decide to stay

  17. Interview Stage Some suggestions • Presentation • Practise in front of a diverse audience • Keep it simple! • Interview • BBSRC interview is very brief (20min), and (relatively) friendly. • Interviews for other funders can be more intense… • Be prepared for questions on: • Past career choices • How will a fellowship benefit you and your research? • Minimal teaching, independence, opportunity to apply for further grants during fellowship. • How will you achieve independence? • Where do you see yourself in 5 years, 10 years… • Permanent position in academia, leader of a vibrant research group

  18. Award Stage Challenges and Benefits • Challenges • Making the transition from PDRA to PI  • Managing & applying for grants, recruitment • Supervising a group on your own • Dealing with internal departmental politics • You only have a few years to find a permanent position!  • Start looking after 1-2 years • May entail a move to another institute • Consider whether fellows have routinely been taken on permanently at the host department/institute • Benefits • Minimal teaching load (vs. lectureship) • = Time to set up collaborations, supervise research, write new grants… • Support from BBSRC • Once in post, be pro-active in applying for further funding: • From October: 18 (4 PDRAs, 12 PhD + 2 UG research students) • Over £1 million in PI research income (+ £1 million fellowship)

  19. Acknowledgements • Members of the Tate group Dr. Will Heal, Dr. Sasala Wickramasinghe, Dr. Lucia de la Riva Perez, Martyna Snopek, Kavita Ramji, Irvine Howson, Vlad Turek, Tam Dang, Jemima Thomas, Lucy Rayner, Alex Berry, Neki Patel, Richard Bradshaw, Megan Wright, Pinar Tulay, Jenny Früh • Collaborators • Prof. Miguel Seabra (NHLI) • Neil Fairweather (CMMI) • David Mann (Biology)

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