How to Craft a Well-Written Grant Proposal

1. How to Craft a Well-Written Grant Proposal MBP 1018Y Introductory Lecture January 09, 2008

2. Outline • Components of a good grant • Generating appropriate hypotheses • What grants are evaluated based on • The science in a good grant • Translational application

3. “The Matrix”

4. Components of a Successful Proposal • Abstract • Introduction/Background • Specific Aims • Hypotheses • Methodology • Probable Outcomes/Contingencies • Translational Application • Significance • Conclusions

5. Abstract • Not counted in the page limit • Should be concise, clear, easy to read • Within 250 words, describe the relevant background, your goals, and proposed study design, as well as the relevance and impact of your research

6. Introduction/Background • Review the RELEVANT literature • This is not meant to be an exhaustive literature review, but rather a discussion of what is most important to what you want to do • Provide background for the disease and questions you will be addressing • Also provide background about any novel technical approaches • Include a succinct rationale for the project (concept and approach)

7. Specific Aims • Should address: • What are the major questions your project is designed to address? • What are the objectives of your project? • How will each objective address the project-specific questions?

8. Hypotheses • VERY IMPORTANT TO INCLUDE THESE!! • Each hypothesis should correlate, where possible, with a specific objective or question being addressed • EXCEPT when you are addressing a technical objective (e.g., the creation of an experimental system)

9. Methodology • Describe your experiments in detail • Focus on study design • Study design should match up with objective • Reference previously established techniques, except for specific modifications • For example, no need to describe RNA isolation in detail…unless that’s your project! • Need to address where your samples are coming from

10. Probable Outcomes/Contingencies • What do you expect to observe? • What are your plans in case your experimental system goes awry? • You should not merely describe your experimental plan – the reader would not be expected to know how the studies are supposed to turn out • Under what circumstances will your hypothesis be: • Proved? • Disproved? • What will you do if something doesn’t work out that the rest of the project is dependent upon?

11. Translational Application • How is your project relevant to the human condition, and to patients? • Describe the relevance and importance of your work to the diagnosis, prevention and treatment of cancer or the appropriate disease • Be careful – sometimes use of patient samples is not sufficient for translational application!

12. Conclusions • Be brief! • Restate your goals, hypotheses and expected outcomes • Underscore the importance of your work • Make the “big picture” connections

13. Feasibility of Studies • Most grants are funded for a 2-5 year timeframe • You need to ensure that, whatever you propose, it can be accomplished within that window • Aim for 3 years, knowing that you have margin for error in that regard • Be careful about # samples and types of experiments you propose • For e.g., a microarray study on a cohort of 100 patients, prospectively over time (collecting 5 samples total) amounts to 500 array experiments, plus controls! • For Affymetrix GeneChip expression arrays, that’s easily $300K

14. Referencing • Be consistent in terms of style • # references provided are often an indicator of effort put into proposal development • At a graduate level, anything less than 20 references is NOT acceptable

15. Hypotheses

16. Hypotheses • Are supposed to be falsifiable • Can be specific • It’s OK if they end up being WRONG! • Hypotheses MUST agree with the objectives under investigation

17. A Bad Hypothesis • Objective: • To determine the association between Gene X and patient outcome in AML • Hypothesis: • Gene X is associated with AML • Gene X is involved in the DNA damage response • AML patients that demonstrate impaired DNA damage have a poor prognosis

18. A Good Hypothesis • Objective: • To determine the association between Gene X and patient outcome in AML • Hypothesis: • Expression of Gene X is associated with poor prognosis in AML

19. What Grants Are Typically Evaluated Based On…

20. Proposal • Clear, testable hypothesis or central research problem • Originality and innovation in concept or approach • Significance and relevance to health • Feasibility of work plan, usefulness of results • Knowledge of the field (cited literature)

21. Clarity • Grant should be written as if it were directed at a general scientific audience • You are the most knowledgeable person with respect to what you have written • Do NOT make assumptions about what the reviewer knows or not • Be CLEAR • EXPLAIN yourself • Your work should be able to be intuitively followed by the reviewer

22. When Writing a Grant… • …Explain: • WHAT you want to do • WHY this is a reasonable thing to do • WHY this is important • HOW you will do it • WHO is going to benefit • WHERE samples will be obtained from • WHEN you expect to have data

23. Explain… • What you want to do • central hypothesis/research question: the big idea • plus specific objectives • Why this is a reasonable thing to do • review of previous work by you and others, • succinct rationale for project (concept and approach) • Why this is important • significant new knowledge to be obtained • improvements to health which will result

24. Explain… • How you are going to do it • detailed work plan, logical sequence and timelines • analysis and interpretation of results • pitfalls and ways round them • Why you should do it • relevant prior experience and skills • collaborators for technical gaps • preliminary data showing feasibility

25. What to Make Sure You Do When Writing A Grant • Follow formatting guidelines carefully • 10 double spaced pages • Page count does not include figures, tables, references • 1” margins • 12 point font • Include a Title Page • Include Page #’s! • Include section headings • Include your hypotheses, clearly stated • Clearly delineate your goals and study designs • Reference your work carefully

26. Before Submitting your Proposal • PROOFREAD! • Spelling/grammar and wording or style errors will impair the readibility of your proposal • Avoid: • Run-on sentences • Short paragraphs • Grandiose claims • Colloquial phrasing • Vague wording

27. Evaluation Criteria for Final Exam • Translational nature of proposal: Inclusion of a translational aim • Significance section (40%) • Conciseness and appropriateness of introduction • Clearly stated goals and hypotheses • Delineation of experimental design • Logical, easy-to-follow, one step leads directly and intuitively from the previous one • Feasibility • Quality of Science • Minor criteria: • Quality of abstract • Clarity of writing • Effort put into proposal • Formatting and referencing • Spelling/Grammar • Subjective “Style”

28. The Science in a Good Grant

29. A Note About The Science • For the 1018 Final Exam, you are encouraged to base the grant proposal on your current research • You are expected to have “good science” in your proposal already • Egregious errors will be penalized • For e.g., Northern Blots used to detect protein samples

30. Good Science… • …Answers a well-defined question • …Will contribute to human knowledge • …Has falsifiable hypotheses • …Recognizes its own limitations • …Is well thought-out

31. Case Study: The Cancer Stem Cell Hypothesis • What is the Cancer Stem Cell Hypothesis? • Modeled on normal development (e.g., hematopoiesis) • A small fraction of cells in the tumor have the capability to give rise to the tumor • These cells are – in contrast to the bulk tumor population – not in cycle, and often not treatable by conventional chemo- or radio-therapy • In contrast to the “Stochastic Model” of Cancer Development

32. Cancers Known to Follow the CSC Hypothesis • AML • Brain • Breast • Colon • Others?...

33. How Do We Identify a CSC? • A Stem Cell can only be identified FUNCTIONALLY. • A CSC can only be identified through its ability to recapitulate a tumor in vivo.

34. Appropriate Functional Assay • Flow sort tumor cells based on cell surface markers • Potential enrichment for CSCs in one population over another • Xenotransplantation into immune compromised mice • Score tumor development

35. Examples of Inappropriate (Inconclusive) Assays • In vitro colony formation assays • Assay of transformation • Gene/protein expression analysese • Expression microarrays • miRNA arrays • Immunohistochemistry • Identification of a “Stem Cell” signature • In vitro over-expression/knock-down of putative “Stem Cell” genes

36. Translational Oncology

37. What is Translational Research? • For the purposes of this grant, “Translational Research” is defined to be use of clinically obtained samples in at least one major aim of the proposal • Specifically, use of: • Human subjects (with malignancy or disease) • Primary tissues/fluids (e.g., bone marrow samples or tumour biopsies) derived from patients with malignancy or disease • You CANNOT use for this purpose: • Mice or other animal models • Cell lines derived from patients • Other cell culture systems

38. But I Don’t Do Translational Research! • Don’t worry! Fewer of us than you might think do purely translational research • Objective of MBP 1018 is to develop your ability to conceive of and integrate translational concepts into your thinking • If you do: • Basic research (with cell lines or animal models) • Structural research • Photonics or imaging research • …There are translational applications in the future – just think about them!

39. But I Don’t Do Oncology Research! • That’s OK – think about the pathways you work on. • Do they have application to cancer in some way? • Can you draw connections outside of your own immediate sphere of research? • If you can, write about those connections.

40. TA Contact Information • Dr. Mahadeo Sukhai • Email: m.sukhai@utoronto.ca • Phone: 416-946-4501 x 5036 • Location: • PMH/OCI 610 University Ave. • Room 9-620/9-621 • No set office hours; please check to see whether I’m available before coming to see me