Grantsmanship – Hypothesis
Generation and Testing
H. F. Gilbert
Outline
• Hypothesis driven and discovery driven
science
• Coming up with models/hypotheses and
ways to test their predictions
• The Abstract and Specific Aims
A tumor-specific endonuclease
+
You have just isolated and purified an
endonuclease that is over-expressed specifically in
estrogen-dependent tumor cell lines. It cleaves
specifically at the junction of a single-double
stranded region of DNA.
How would you investigate this
endonuclease further?
Science
Non-hypothesis driven science
A collection of facts &
observations
We want to determine the
DNA sequence of the human
genome
Hypothesis-driven science
A method to construct
models that predict the way
the world works
We want to genotype cancer
patients
We want to know all proteins
that interact with X
Alberts, et al Mol. Biol. of Cell
The Scientific Method
Observations
Hypothesis
or Model
Truth
falsifiable
Predictions
Experiments
controls
Thought Processes for HypothesisGeneration
1. What is it that I don’t understand about some
experimental observations (yours or others) based
on what I already know about how the world
works
- I don’t understand .......... (make a list)
2. What is already known that I don’t know
- this is a search of the literature to find out what is already
known
3. #count list 1 - #count list 2
- if <=0 then find another set of observations to wonder about
Thought Processes for HypothesisGeneration
4. What is a likely explanation (model) that could
account for the experimental observations. Why
are you thinking this (rationale)
• I think that ..... happens because I know that .......
– the explanation should be reasonable based on what you and
others know already (extraordinary explanations require
extraordinary experimental verification)
– it should be sufficient to account for the unexplained
behavior/observation
– you should be able to draw it with balls and sticks (or math)
– you should consider any other likely model
Thought Processes for HypothesisGeneration
4. What predictions does your model make
• If my model is correct then if I do ...... then ...... should happen
– prediction should be able to falsify your model, i.e. if the
predicted result is not obtained it should show that your model is
wrong
– prediction should lead to a clear experiment that would
distinguish your model from other likely models
5. Does the observation generate any new
hypotheses
Specific Aims
• Designed to capture how you think
– How knowledgeable you are about current
thinking/models
– How well you can assemble known facts into a
model/hypothesis that can describe something
that is not known
– How well you can design experiments and
controls to critically test your model
Specific Aims
• Summarize the WHOLE GRANT in 1 page
• Don’t make the reviewer think/guess
• Consider who/how/process of review
– Write for a generally well-informed scientist, NOT AN
EXPERT
– Grab reviewer’s attention – significance, logic,
approach
– avoid words like novel, exciting, first-time, prove,
routine, characterize
– use words like model, hypothesis, test, predict, analyze,
control
Specific Aims Page
• 1st paragraph
– general significance of research
– health relatedness (mention specific diseases)
– how your research fits in with the above
• 2nd paragraph
– state long-term goal of research
– describe your model(s)/hypothesis (es) and why you
think it’s a good model (i.e. rationale for the
hypothesis)
– what will we know when you’ve completed the
research
• keep at about ½ page
Specific Aims Page
• 3rd-7th paragraphs (3-4 specific aims)
– Give each specific aim a short title so you can refer to
them later
– Include, in 3-4 sentences
•
•
•
•
what part of the model does this aim test
what does the model predict (rationale)
what experiments will be done and how data will be analyzed
how the potential/likely results provides a critical test of the
validity of the model
• what you will know that wasn’t know before when the
experiments and analysis are complete
– Last paragraph
• restate significance and how your proposed experiments, when
completed, will add to knowledge, ability, understanding
Specific Aim Paragraph
• 1st sentence
– “The model/hypothesis predicts/suggests..”
– “Experiments in this aim will test...
– “XXX and YYY are known so ZZZ (unknown)
is likely correct, ,
Next steps
• Write and re-write for clarity and
conciseness
• Share with colleagues for their comments
• Write the grant to parallel the specific aims
page
• Iteratively change grant and specific aims to
produce a consistent presentation of your
thought processes
A tumor-specific endonuclease
+
You have just isolated and purified an
endonuclease that is over-expressed specifically in
estrogen-dependent tumor cell lines. It cleaves
specifically at the junction of a single-double
stranded region of DNA.
Now design a specific aims page