Writing a Fundable Proposal
National Cheng Kung University
Tainan Taiwan
Tainan,
Tien-Hsien Chang 張 典顯
Genomics Research Center
中央研究院
D
Department
t
t off M
Molecular
l
l Genetics
G
ti
Ohio State University, Columbus, Ohio
Nov. 26, 2010
Patient
• 45-year-old Caucasian male
• Associate professor
• Had renewed a NIH RO1 once before
• Now “lower
lower half
half” in both recent
submissions
Symptoms
• Loss of libido
• Feelings of worthlessness
• Thinking
g about starting
g a small p
pizza
company
• Mother asks weeklyy whyy he didn’t go
g to
med school
Patient
• 41-year-old male, uncertain ethnic
background
• Assistant professor
• Up to tenure review (year 5)
• Has submitted 14 NIH grants in 5
years
Symptoms
y p
• Told his chair: will write a grant every
week until successful
• Recently seen eating his 6% SDSpolyacrylamide gel for lunch
Patient
• 32-year-old Caucasian female
• Spent 7 years for Ph
Ph.D.
D in
molecular genetics
• Now into her 4th year postdoc
Symptoms
• Spent last two years trying to get
started on her first RO1
• Has written and discarded 2,356
Specific Aims and 3 boyfriends
• Has considered an alternative career
as a stand-up comedian
In US, Early Stage is
Getting
g Later
• First
Fi t iindependent
d
d t position:
iti
38
((median age)
g )
• First
Fi t R01:
R01 42 (median
( di age))
• NIH awards to new investigators: 4%
Albert Einstein
Marshall Nirenberg
Tom Cech
1st Position: 32
33
31
Nobel Prize: 42
41
42
These guys will NOT even get their 1st RO1,
when they get their Nobel Prize!
Science ((Sept.
p 10,, 2010)) 329,, 1257.
The results are not pretty. With success rates for
acquiring an NIH grant below 10% in some cases,
achieving a stable research career now has elements
of a lottery, with one’s future depending on a chance
ranking assigned through a peer-review process that
is unable to discriminate adequately among a sea of
research proposals.
Reality
y Check: US vs. TW
NIH
NSC
1-10%
1
10%
> 38% (~50%)
( 50%)
US$170-250K
$24-75K
3 cycles
1 time a year
3-4 years
1-3 years
15 pages
???
2 3 months
2-3
> 2 days
writing
Shifting
g Paradigm
g for Grant Writing
g
Grant writing: We All Hate to Love!
• But
But, it is an inevitable way of
life
• Actually, a creative
i process
• Learn to take the ups and
downs in stride
Conceptual Framework for Grant
Writing
“The 5 Be’s Principle”
Be professional, be serious
Be sympathetic to reviewers
Be communicative and educating
Be persuasive: powerful arguments,
not just statements
• Be ready to tell a SIGNIFICANT and
good scientific story
•
•
•
•
EXPERIMENTAL
PLAN
PRELIMINARY STUDIES/
PROGRESS REPORT
BACKGROUND AND SIGNIFICANCE
SPECIFIC AIMS
Be Professional,
Be Serious
Page 1
Table of Content
Be Professional,
B serious
Be
i
1- 1.5 Page
off
Specific Aims
=
Exceutive Summary
V
Very
Very
V
Very
V
Important
I
t t
Be Professional, Be serious
3 Pages
of
Background
&
Significance
Be Professional,
Be Serious
5-7 pages
of
Preliminary
Studies
Organized into
Publication Format
Be Professional,
B S
Be
Serious
i
5-7 pages
of
Preliminary
Studies
organized into
publication format
Be Professional,
Be Serious
Up to 15 pages
of
Research Design
&
Methods
Be Sympathetic to Your Reviewers
• Think from y
your reviewers’ perspectives,
p p
, make
their lives easy! (They may or may not directly
in y
your field))
• Write as though you were teaching a 1st or 2nd
year grad student
• Write as if you were submitting a Scientific
American paper
• Teach, teach, teach the reviewers. Then you
don’t have to “sell” hard.
Plowing the Soil & Sewing the
Seeds of a Successful Grant
“You can’t cram farming”
• International/national meetings: find
out the state
state-of-the
of the art
• Cultivate true collaborations with good
experts. Go to their presentations.
Establish ongoing scientific dialogue.
dialogue
• Develop
D
l necessary ttechniques
h i
and
d establish
t bli h
preliminary “feasibility data” for you ideas.
• Develop a “stable” of good ideas to draw from
How to get started: Exercise Stage
• Ongoing log of ideas: months ahead!
• Thinking in Question Format: write out all
interesting questions related to the project
• Thinking in Experiment Format: write out all
possible experiments, with no regard to money,
expertise or equipment
• Thinking in Hypothesis Format: write out all
untested hypotheses related to the project
• Incubate the ideas and try it again
Exercises, cont.
Begin building an inductive model of reasoning
Observations
H0
H1
H2
Disprove hypotheses based
on the literature and/or
preliminary data
H3
H4
H5
Specific aim 1 will
test between
b
these
h
two hypotheses
Specific Aims: Executive Summary of a
B i
Business
Plan
Pl to
t Ask
A kM
Money From
F
VC
Very
Important!
EXPERIMENTAL
PLAN
Write it first
over weeks
PRELIMINARY STUDIES/
PROGRESS REPORT
BACKGROUND AND SIGNIFICANCE
SPECIFIC AIMS
Writing Effective Specific Aims
• Test a hypothesis, whenever possible. You wish
your work to be referred to as “hypothesis
hypothesis driven
driven”
• Use the word mechanism in the specific aims and
title, whenever possible.
• Most grants do best if there are only 3-4 specific
aims DO NOT tie Aims in sequence!!!
aims.
• Make the aims specific but far reaching.
reaching Avoid
making the aims a simple list of experiments.
• Write aims you are excited about!
Avoid Too Many
y Jargons
g
1st Attempt
Specific Aim 1: To test the hypothesis that the
Klothos mouse will develop premature emphysema
when on a low protein diet.
Better
Specific Aim 1: To test the hypothesis that
nutritional protein deficiency is a critical variable
influencing the loss of lung parenchyma in aging.
The “DON’Ts of Writing Specific Aims
1.
DO NOT state hypotheses that you cannot
actually test with your experiments.
experiments
2
2.
AVOID using the phrases “to
to correlate
correlate,” “to
to
describe,” or “to develop”, which are tagged as
“descriptive”
descriptive
3
3.
DO NOT use wishy-washy,
wishy washy passive tense,
tense or
flowery language. Write your aims in the “active
form” with strong,
form
strong meaningful verbs
verbs.
4
4.
DO NOT write aims that can be viewed as a
“fishing expedition”, e.g., microarray experiment
a. Specific Aims
Unlike most tissues, skeletal muscles are exposed to relative extremes in their microenvironment during what might be considered "normal"
activity of intense exercise. These extreme environments would induce a cellular stress response in most tissues, with subsequent stress protein
expression Several kinds of stressful stimuli appear to be present in intensely exercising muscle
expression.
muscle, including heat stress,
stress over
over-stimulation
stimulation (fatigue) and
tissue hypoxia. Though these stimuli may be quite different at a molecular level, they have common features. For example, the loss of contractile
function, which is associated with each condition is attenuated by antioxidant (AOX) treatment (2,34,64,82,113). Furthermore, marked changes in the
passive mechanical characteristics and metabolic energy status are partially blocked by AOXs (preliminary data). From these observations we have
generated a working hypothesis that appears to be paradoxical, i.e.: low levels of reactive O2 induce coordinated adaptive responses which are designed to
shut down muscle function and protect the sarcomere from subsequent injury.
Specific Aim 1: To test the hypothesis that conditions of stress, commonly associated with intense exercise, result in
significant increases in ROS production that are related to disorders of O2 supply and demand.
Rationale 1: Reactive oxygen species (ROS) formation has been identified by our laboratories and others in conditions of intense muscle activation
resulting
res
lting in fatigue
fatig e (36,92,104),
(36 92 104) heat stress (140) or in conditions of hypoxia
h po ia (21,38).
(21 38) Ho
However,
e er the latter has never
ne er been observed
obser ed before in skeletal m
muscle
scle
and the most convincing evidence for ROS formation in the other forms of stress have been obtained from preparations that are compromised with respect to
O2 availability. In this specific aim, we will use fluorescent techniques to directly observe ROS formation under stress conditions and explore the
relationships between formation of ROS and O2 supply and demand in a perfused diaphragm preparation.
Specific Aim 2: To test the hypothesis that shifts toward more reducing intracellular redox environments during
stress result in alterations in energy metabolism that decrease the formation of energy metabolites, such as Pi and
increase the formation of creatine phosphate.
Rationale 2: Our laboratory and others have shown that exogenous AOX treatments preserve muscle contractile function in fatigue (34,64,113),
hypoxia (82) and heat stress (2). Our preliminary data suggest that the effects of AOXs may be due, in part, to the preservation of creatine phosphate (CrP)
and, by inference, an accompanying decrease in [Pi]. Paradoxically, AOX-induced preservation of CrP and decreases in Pi in stress may override inherent
mechanisms by which muscles naturally lower their capacity to perform intense contractions, thus preventing potential injury. We will test this hypothesis
by treating skeletal muscles with physiologically relevant AOXs during stress and measuring high energy phosphate metabolism and mitochondrial
function. Transgenic models of antioxidant over-expression will be used to evaluate the potential for endogenous antioxidant up-regulation to override
contractile and metabolic inhibition in stress. Further experiments will test potential sites of redox modification of metabolism such as creatine kinase,
glycolysis
l l i or other
h pathways
h
leading
l di to cell
ll acidification,
idi i i alterations
l
i
in
i citric
i i acid
id cycle
l activity
i i or mitochondrial
i h d i l electron
l
transport.
Specific Aim 3: To test the hypothesis that shifts to more intracellular reducing environments decrease cytoskeleton
"stiffness" under resting conditions and during exposure to stressful stimuli.
R ti
Rationale
l 3:
3 During
D i stressful
t
f l stimuli
ti li suchh as heat
h t stress
t
andd hypoxia,
h
i we observe
b
rapid
id elevations
l ti
in
i resting
ti baseline
b li tension
t i andd increased
i
d muscle
l
"stiffness." These effects are greatly attenuated by AOX treatment. In this aim, we will study the biophysics of muscle "stiffness" in stress, to try to
understand the mechanical adaptations of the cytoskeleton that occur under these conditions and their dependence on ROS/AOX balance. We propose that
changes in muscle stiffness may reflect one component of an orchestrated response to cell stress that is initiated by ROS formation.
“How much preliminary data do I need?”
You don’t
don t have to do all the
experiments before submission.
You want to show the reviewers:
1) You can perform the necessary
techniques and methods.
2) You are committed to this area of
research and are off and running.
3) New techniques are feasible.
feasible
4) Stay in order of specific aims
Draft the Experimental Plan
• St
Startt early,
l because
b
some specific
ifi aims
i
may
fall apart
• Experimental plan should be a plan, a
paradigm or a map
map; m
must
st be logical
• Tr
Try not to leave
lea e an
anything
thing to the imagination of
the reviewer, e.g., # subjects, dose response
curves etc.
curves,
etc
• A well-designed
well designed figure says 1000 words
Formatting Experimental Plan
• Specific Aim 1 = 1st subtitle; Specific Aim 2 = 2nd
• Overview the overall approach
• Rationale for the experiments
• Evaluation and arguing for the best method
among
g competing
p
g methods
• Expected
p
Results and Brief Analysis
y
• Experimental
p
Problems and Alternative
approaches
The “DON’Ts of Writing an
Experimental Plan
• Excessive details of methods.
methods Overview with graphic
figures will help.
• Wander off into superfluous new experiments that don’t
address the Specific Aims.
• Too self-critical: provide ammunition for reviewers
• Leave impression of being naïve. Make them see that
you know the limitations of your experiments. DEFEND
YOUR APPROACH.
• Put techniques in just because they are sexy: avoid
“methods driven” research.
Writing Background and Significance
• Teach, Teach, Teach, Teach, Teach. Pictures
are worth
h a thousand
h
d words.
d
• Showing your command of a full knowledge of
li
literature
in
i your area. You
Y are the
h state-of-the
f h
art.
• Where
Wh
your experiments
i
t fit into
i t history.
hi t
Where
Wh
your building blocks fit in the wall.
• Enough
E
h background
b k
d to
t understand
d t d iindividual
di id l
specific aims. Refer to them.
• Know
K
how
h
the
th workk relates
l t to
t a particular
ti l
problem or disease. How could it influence the
f t
future
off medicine?
di i ? Don’t
D ’t overstate.
t t
“The Only
y Good Writing
g is Re-writing”
g
• Start Over, Rewrite, Rewrite, Rewrite
• Have other scientists read the grant after
you have put together your best shot
shot.
• Have a non-scientist or grad student read
grant for understanding
g and English.
g
the g
• Rewrite,
Rewrite Rewrite Rewrite
Final Formatting
• Stay with the Page/Font requirements.
requirements
• Embed figures into the text
text. MAKE THEM
LARGE ENOUGH TO BE READABLE.
• Learn how to use MS Word properly (not until the
last minute)
• If you found 20 misspellings and typos in a
$1,000,000 application, would you trust that
person with the money?
Rating NIH Grants (1-9)
Impact
• address an important problem?
• will scientific knowledge be advanced?
• effect on concepts or methods in this field?
Approach
• experimental design and methods appropriate to aims?
• acknowledge problem areas and consider alternative
tactics?
IInnovation
ti
• employ novel concepts, approaches or methods?
• challenge existing paradigms or develop new
methodologies?
Investigator
• appropriately
i t l ttrained
i d tto carry outt work?
k?
• appropriate work for experience of P.I. and collaborators?
Environment
• contribute to the probability of success?
• evidence of institutional support?
Impressions of Grants: US vs. TW
NIH
NSC
Well organized
Disoriented
Clear writing
Confusing
For reviewers
For themselves
Significance
g
1st
Just g
give me $
Arguments
Statements
Conceptual Framework for Grant
Writing
“The 5 Be’s Principle”
Be professional, be serious
Be sympathetic to reviewers
Be communicative and educating
Be persuasive: powerful arguments,
not just statements
• Be ready to tell a SIGNIFICANT and
good scientific story
•
•
•
•
Succeeding
g in Science: Rules of
Thumb by Jim Watson
Rules #1
To succeed in science,
science you
have to avoid dumb people.
Learn from
L
f
the
th Wi
Winners.
Get a copy
py of outstanding
g
proposal for template.
Succeeding
g in Science: Rules of
Thumb by Jim Watson
Rules #2
To make
T
k a huge
h
success,
you have to be prepared to
get into deep
g
p trouble.
Succeeding
g in Science: Rules of
Thumb by Jim Watson
R l #3
Rules
Be sure you always have
someone up your sleeve
who will save you when
you find yourself in deep
s--t (= shit).
Succeeding
g in Science: Rules of
Thumb by Jim Watson
Rules #4
Never do anything that bores
you.
Have fun and stay
y connected!