As Mary Poppins says, let’s start at the very beginning. What is your hypothesis? Since the entire grant revolves around this one statement, it’s important that put some thought into generating a good one. What is a good hypothesis? One that is clear, testable, provable, and supported by rationale (aka your preliminary data). We’ll go into the specifics of how to write a good hypothesis in part 2 of this post, for now I want to make sure you have one. Chances are, if this is your first grant, or first grant on this topic, you haven’t written a hypothesis yet. We have vague hypotheses in our heads as we do experiments, but usually we don’t write these down. Now’s the time to get those visions of sugarplums out of your head and onto paper.
Let’s go through a couple examples of hypotheses to get a better sense of what I’m talking about. This morning when I woke up, the last piece of chocolate cake was gone. There was a plate and fork with cake crumbs in the sink. My son was in bed when I went to sleep but my husband was up watching TV. My husband really likes chocolate cake. In addition, my son is a teenager, and once asleep he does not get up (sometimes for days). Based on my husband’s love of chocolate cake, the fact that he was awake when I went to bed, and my son’s sleeping habits, I hypothesize that my husband ate the cake. When questioned, he denies it, saying the dishes were in the sink when he went to bed. Fingerprinting of the fork and plate revealed all 3 family members plus the dog had touched the fork and plate. In the end, hard to prove that my husband ate the cake. Criminal lawyers face this challenge daily. My hypothesis was clear, testable, and supported by rationale. However, it was not provable.
Here’s another one. My dog is super skinny. He’s always been thin but he’s lost more weight recently. In addition to his weight loss, there are these weird bits of stuff that look like rice surrounding his favorite dog bed. Google informs me that dried pieces of flat, rice-like looking stuff might be dried tape worm segments. Based on the rice-like segments and his weight loss, I hypothesize that my dog has tapeworms. This hypothesis is testable and provable. His stool can be examined for worms (yay) or the rice-like bits can be taken to the vet for assessment. I’m kind of cheap, so I’ll just skip all that diagnostic stuff and treat him but that’s another story.

The hypothesis is analogous to the neck of an hourglass. You sift through your preliminary data and choose the data (rationale) that best support your hypothesis. This is the data that will go into your grant. Data most important to supporting your hypothesis approaches the neck of this hourglass – this data go on the specific aims page. If there is data missing, now’s the time to get it. Developing your hypothesis sooner rather than later will ensure that you have the preliminary data necessary to support it.
Flowing out from your hypothesis is the approach. Your specific aims, sub-aims, etc. At the expense of sounding like Captain Obvious, it’s important that your aims truly address your hypothesis. We’ll go into this in more detail in the next post. Once you have your aims, think about how you’ll carry out each aim. What techniques will you use? Do you need a collaborator or consultant? New equipment? Thinking about your approach ahead of time will make sure you fill in the gap between what you can do and what you can’t. The best approach will fall short if reviewers don’t believe that you can do the work. The convincing is on you. Planning your approach early will make sure you have time to contact potential collaborators/co-investigators who have expertise in a field or technique new to you. If the technique is one your lab can do but has not done yet, a pilot experiment demonstrating this technique is “up and running” in your lab will show reviewers that you can do the work. Let me give you an example. I recently wrote a grant that required using immunoprecipitation. For those not familiar with this technique, it involves using an antibody to capture a protein of interest from cell or tissue preparations. This technique is not difficult, but not all antibodies are good for immunoprecipitating. Plus, it’s one of those techniques that is mechanistically easy but can require the sacrifice of a small chicken to get it to work. Because I had a specific antibody that I wanted to use for immunoprecipitating, it was important to demonstrate that the technique worked with this antibody. In addition, it was good to show that our lab had experience with this technique. I didn’t have a lot of time (clearly not following my own advice) so I bought a kit and after a few tries got the immunoprecipitation to work. I added the figure a few days before the grant went out. I was lucky, though, and was close to not having this data. The moral of this story is don’t do as I do, but do as I say – plan ahead.
On that note, plan ahead to read part 2 of this post on generating a testable hypothesis.

 In Part I of my series on the Specific Aims page I talked about the first paragraph of this page, which sets up the problem. Although a whole paragraph dedicated to the problem might seem like a lot, remember that the problem includes: (1) a couple background sentences to put the problem in context for your reviewer, (2) what has been tried and failed, (3) the gap or obstacle that has to date prevented solving the problem. In paragraph 2, the hero in a red cape and carefully quaffed hair (that’s you), swoops in and saves the day with a solution. A solution, of course, that is not quite there yet but can be had with 1.25 million dollars over 5 years. Because that’s a big chunk of change, bestowing this award on a hero such as yourself requires a strong premise (supporting data). Read on, dear hero, to see how I transition from problem to supporting preliminary data and to the next logical conclusion, your hypothesis.
 
Second paragraph
            As previously stated, in the second paragraph you introduce your solution and any information the reviewer will need to understand your specific aims. I usually transition between the first and second paragraphs by indicating there is an overlooked area that may provide a solution or there is information necessary to move the field forward and your work will provide it. By taking the space to clearly define the problem the reviewer is now interested in your solution. You begin by introducing the solution, and then follow with the rationale as to why this solution will work. The rationale is, of course, any background information and your preliminary data that supports the hypothesis. 
            In this paragraph, you need to provide any information that is essential to your hypothesis. This information is still fairly general - you’ll have space for details later in the proposal. The second paragraph is also a place to mention or define anything critical to the understanding of your specific aims. In my work, for example, I’m using a “home grown” peptide to change the intracellular location of a receptor. Because I used this peptide in one of my aims, I introduced it in the second paragraph. You don’t have a lot of space for explaining in the aims themselves, so you want to make sure you’ve set the stage properly in the paragraph above. If care is not taken to set up the aims properly, your reviewer might be confused. As we know, confusion = no.
 
            To see these ideas in action, I’ve continued the sock theme below. I’m starting with paragraph 1 from the last blog post, so that you can see how the two paragraphs fit together. 
 
Every household is plagued by lost socks in the laundry. In the United States alone, lost socks cost on average 48 hours per person per year in wasted search time.1 Replacement costs for new pairs of socks reached a staggering 1.2 million dollars last year, resulting in a particularly high burden for families of 4 or more.2 Sadly, the psychological cost of the shame and embarrassment caused by wearing mismatched socks to school or work cannot be measured.  Efforts by the sock industry to decrease the number of lost socks have, to date, been ineffective. Strategies such as selling 6 pairs of socks in a pack or 3 socks at once have only increased costs and sidestepped the true problem. Without ways to specifically find the lost sock, this problem will only continue to grow. Given the exponentially rising costs of replacement socks, plus the burgeoning number of feet worldwide, by 2040 the problem of lost socks will be the number one drain on family budgets unless a way to recover lost socks is found. 
One underdeveloped resource used to find lost items is tracking technology. Tracking technology has improved significantly over the past decade and is now used to find many lost items such as pets, cars, and teenagers. Our laboratory has developed an electronically sensitive yarn (e-yarn) that can be woven into clothing for detection by passive radiofrequency identification (RFID). This yarn was generated through our development of a new metal alloy, nikean, which allows the production of smaller microcircuits with enhanced detectability (insert lab reference here). Our preliminary data show that 1 g of yarn can be detected from 100 feet away, using a standard RFID detection application on a cell phone. Our data also show that incorporation of blue/red clothing dyes into the yarn does not change the magnitude of the RFID signal, and that the signal is resistant to a 30-minute exposure to water. Based on this preliminary data, we hypothesize that socks made from e-yarn are colorful, washable, and trackable. This hypothesis will be tested through the following specific aims:
 
In the above example, I segue from the urgency of the lost sock problem in the last sentence of the first paragraph to the next by connecting back to the topic of lost items, but in this sentence, I’m changing direction by talking about a general approach to finding lost items. From there, I narrow things down by mentioning how tracking technology is used and what types of things can be found with tracking technology. From there, I introduce the lab’s preliminary data. Although I don’t repeat any words from the prior sentence, I repeat the concept by using the word detection rather than tracking. I tell the reader what the grant will be about, specifically electronic yarn for tracking. I then state the breakthrough from our lab that allowed us to take this step of making electronic yarn, the generation of a new alloy. Here I include a reference from the lab. You can have a few references in the specific aims page, but in general I try to keep them sparse. The specific aims page can be a good place to start referencing your own work, however, as you build your rationale/foundation for your hypothesis. From there, I add preliminary data that builds towards your hypothesis. This second paragraph should include the key pillars on which your aims are built. This preliminary data is described in general terms of main findings; you’ll have room to get into the specifics later in the grant. The last sentence in this paragraph is your hypothesis. 
 
Your entire grant is built around your hypothesis, so it’s worth putting some time into making it a good one. In fact, the hypothesis so important that I’ve decided to give it a separate blog post. Until next time! 
 
 


​

​Unless you are totally new to NIH grants, you already know that the specific aims page is the most important page of the entire grant. The specific aims page sets the tone for the grant. Will the grant be easy to read and understandable, or dense and frustrating? Unlike you and your organic chemistry textbook in college, your reviewer is not obligated to spend days trying to understand your grant. He/she will do their best in the context of their “grant workload” and move on. Although you can lose a reviewer after the specific aims page, if you lose them at the specific aims page you’re done. In fact, one reviewer told me they scored an entire grant based on the specific aims page. This reviewer then read the entire grant, but the score didn’t change. I mention this to underscore the importance of this page. So, let me show you how to make a good first impression.
 
First paragraph
The first paragraph is your explanation of the problem. You need to start broad enough to capture the attention of your reviewer, but not so broad as to be meaningless. For example, your problem should not be cancer or cardiovascular disease, these are too broad. You could start with a type of cancer or a subset of cardiovascular disease. From there, you quickly (in a couple sentences) narrow the focus to the specific problem you are addressing. As you narrow, it may be appropriate to include a statistic that demonstrates the scope of your problem. For example, if your research involves a relatively unfamiliar disease, a statement about the monetary impact or numbers of people affected can be helpful, especially if you think this information might be surprising. Getting the reviewer’s attention with a “Hmm I didn’t know that” thought is a great way to start your proposal. Although I’ve read this in proposals, telling the reviewer that cardiovascular disease affects millions of people or is a significant part of health care dollars spent is not a particularly engaging fact. If your grandmother wouldn’t be surprised by this information, don’t use it.
Narrowing the focus of the problem you’re addressing can be easily done if you connect sentences, as described in one of my prior blog posts (see resources). As you lead the reviewer to your problem, think about what you want to emphasize in each sentence. The location of the phrase within the sentence (beginning, middle, or end) determines its emphasis. See Writer’s toolbox: Creating Sentences that Flow for more details. Once you’ve set up the problem, you want to mention what solutions have been tried to date and why these haven’t worked or are imperfect. You, of course, have developed a better widget, so before you describe your widget you need to tell the reviewer what’s wrong with the current ones. You describe that all important “gap in knowledge”. I tend not to use the word gap, although I’ve seen it in many proposals. I prefer to describe the gap without stating “here’s the gap”. This might seem counterintuitive, as I keep talking about the importance of clarity. Why not come out and say here’s the gap? Because it’s formulaic and boring. Anyone who has read more than a handful of grants knows that the gap is coming, but using the phrase “gap in knowledge” is akin to slipping the reviewer a Xanax.  Make your grant interesting by showing the gap rather than using the word “gap”. Of course, the onus is on you to be sure the gap is clear. 
After “The Big Gap”, you should state what will happen if this problem isn’t solved and solved fast. What earth shattering event will happen? You want to be somewhere between critical need and Armageddon. Here is another spot where you can throw in an interesting factoid if you can find one. What is the rate of increase of this problem? Is it becoming more widespread? Epidemic? Perhaps not in the current climate but you get my point. I typically leave my reviewer with this “cliff hanger” and end the paragraph on this note.
As with your problem statement, you don’t want the gap to be too general. “Little is known” is a vague, general gap. A lack of understanding is also not a good gap, although I’ve read it in several grants. The NIH typically does not want to pay large sums of money to understand a disease process. I know, I hear the “but” coming. But, you say, you need to understand a disease process before you can cure it. Yep. I get that. But when you discuss the gap, you want to state how filling that gap will lead to progress in treating the disease you’re targeting. This progress does not have to directly lead to a cure for X but needs to have some relevance to human health or you’re barking up the wrong funding tree. 
Make sure that you take enough time to clearly define the problem before jumping to the solution. Many newbie grant writers are so eager to get to their work, or solution, that they don’t clearly define the problem. If you do a poor job in defining the problem, you significantly decrease the interest in or value of your solution. This is an area where the “curse of knowledge” comes into play. You’re so close to your area of research that you think the problem is obvious. Remember that your reviewer will be in your general field of research but may not be familiar with your specific area. 
 
I’ve put the above ideas together in an example below, where I revisit that age old quest for lost socks.
 
Every household is plagued by lost socks in the laundry. In the United States alone, lost socks cost on average 48 hours per person per year in wasted search time.1 Replacement costs for new pairs of socks reached a staggering 1.2 million dollars last year, resulting in a particularly high burden for families of 4 or more.2 Sadly, the psychological cost of the shame and embarrassment caused by wearing mismatched socks to school or work cannot be measured.  Efforts by the sock industry to decrease the number of lost socks have, to date, been ineffective. Strategies such as selling 6 pairs of socks in a pack or 3 socks at once have only increased costs and sidestepped the true problem. Without ways to specifically find the lost sock, this problem will only continue to grow. Given the exponentially rising costs of replacement socks, plus the burgeoning number of feet worldwide, by 2040 the problem of lost socks will be the number one drain on family budgets unless a way to recover lost socks is found. 
 
Now let’s “unpack” the above example. The first sentence states the problem and hints at the magnitude of the problem “every” household has problems with lost socks (unless you live in a culture where no one wears socks but let’s assume you do). This statement is followed by two “facts” to help the reader understand the impact of the problem. Although I suggest leaving smaller details out of the specific aims page, this is one place where they can be useful. As I mentioned above, the use of statistics to convey impact depends on the problem. Try to find information that will surprise the reviewer and get his/her attention. The next sentence builds on the problem, and I lead off the sentence with an adverb for accent. Although you’ll want to minimize the use of adverbs, sometimes they can signal the reader to pay attention to what is coming next. In this case I use the adverb “sadly”, which signals that something negative is going to follow. Adverbs are ok in small doses, just don’t overdo them. After defining and providing an idea of the magnitude of the problem, I go on to say what’s been tried so far and why this hasn’t worked. Finally, I project what will happen if the problem isn’t solved, generating a sense of urgency. 
 
There you have it! The first paragraph is done. Now that I have you on the edge of your seats (The Handmaid’s Tale, anyone?) you’ll need to wait for the next installment. Tune in next time for, wait for it, the second paragraph. 

​I am often struck by the similarities between selling methods and grant writing. Of course, grant writing is selling, but scientists don’t usually think of themselves as salesmen. I recently read a blog post about the PASTOR method, which was conceived by a well-known copywriter named Ray Edwards. This framework is used to write better specific aims, I mean sales copy. Besides being an acronym, Edwards says that the word should engender a loving, caring, protective attitude towards your customer/reviewer. Now that you’ve picked yourself off the floor following your laughing fit, give that attitude some thought as we go through the acronym.
 
P is for problem
            All grants have a problem they are trying to solve. However, the problem must be one the reviewer cares about. For example, you could be selling the best tennis shoes in the world, but if the customer is looking for loafers you’re barking up the wrong study section. Excuse me for mixing metaphors, but you need to make sure that your problem is of interest to the study section you’ve picked. If you’re not sure, use NIHReporter to see what grants your target study section has funded. If you’re in the right study section, make sure that your problem is of interest to the field. Edwards quotes another copywriter Robert Collier who said that you have to “join the conversation that is already taking place in the reader’s mind.” Get reviewers engaged by agreeing that your problem is one of urgency that needs solving.
 
A is for amplify
            Next, Edwards advises that we amplify the consequences of not solving the problem. Here’s where you create urgency through information such as cost, lives lost, etc. Even though a reviewer will likely be aware of the problem in general terms, he/she may not be aware of details that make this problem compelling. Urgency also addresses the questions “why this grant, why now?” Each field has lots of problems. Show your reviewer why your problem needs solved now.
 
S is for story and solution
            You’ve described the problem, brought the reviewer to the brink of despair with the urgency of the situation, and now it’s time for you to swoop in like Luke Skywalker and blow up the Death Star. While your solution may not be as dramatic, now is the time for you to present your solution to the problem. Edwards advises us to explain the solution as a story, like how Uncle Joe, while desperately trying to stop his early onset alopecia, mixed plant food and mayonnaise to generate world’s best hair tonic. Of course, space is limited on the aims page so we need to be strategic about the story. In my opinion, your story should introduce the key preliminary data that supports your hypothesis and that makes the aims understandable. Although space is limited, make sure that you introduce all “characters” needed to make your aims understandable. Avoid rogue characters! (for those that missed my blog on this, see resources)
 
T is for transformation and testimony (and trust)
            People usually buy things because they think the item in question will make them happy at some level – whether it is a brief escape with a good novel or movie, or a fitness program that will help them look and feel better. For example, I recently purchased driving lessons for my son. The “happiness” I’m seeking is that my son be a safe driver and not kill himself or anyone else. In considering this program, I noted that the lessons are given by former police officers, which I felt gave the program credibility. When I stumbled across a review from a friend of mine who used this school for all 3 of his kids, I was sold. In the world of grantsmanship, these “T”s are scored as environment, investigator, and significance  - none of which actually start with T. Supported by resources, biosketch, co-investigators/collaborators, letter of support, and the rigor of your preliminary data (NIH emphasis),  this information builds trust that you can get the job done.
 
O is for offer
            In the world of sales, O is the offer of what you are selling. In the world of grants, you are selling your aims or approach. Edwards advises that 80% of the copy be spent on transformation and 20% on the deliverable. In the world of grants, you want to be sure to spend sufficient time on the problem. Defining a clear solution is, of course, important but a common mistake is to jump to the solution (everyone loves their own work, right?) before the problem is sufficiently developed. Make sure to take the time/space to create that sense of priority and urgency.
 
R is for response
            Here’s where you ask the customer to buy. In the world of grants, you’re asking the reviewer to fund your grant. Of course, in the world of grants direct pleas to reviewers are a no no. However, part of his advice is applicable when he says we should not shy away from strong language when outlining the options of buying vs remaining stagnant. In writing your “copy”, your word choice will determine whether you come across as apologetic, uncertain, or overly confident. Words like perhaps, maybe, hopefully, probably, can come across as weak if used too often or in the wrong place. For example, the last paragraph of the specific aims page typically describes the pay off, or what the government will get for its money, if your hypothesis is true and your aims are completed successfully. This is not a time to be wishy washy or vague. 
 
What not to say…
This proposal, if completed successfully, may lead to the development of new therapeutics in the field of cardiovascular disease. 
 
Versus…
Successful completion of this proposal will result in defining how protein X alters metabolism of lipids, which contributes to cardiovascular disease. Determining protein X’s mechanism of action is the next step in developing novel approaches to treating atherosclerosis.
 
Taking out the word “if”, using “will” instead of “may” and being more specific about the successful outcome of the proposal leads to a stronger impact statement.
 
One way to write in a more confident tone is to “get in the mood” before you write. What I mean by this is get excited about your work. Think about what’s cool about your project, the novel things you’re finding out that no one knows (yet) and how your work might have an impact. Put on some inspiring music. Pump your fists. Get fired up! Getting in a confident, excited mood will make subtle shifts in your word choices that will come across on the page. If you’re not excited about your work, no one else will be. 
 
Did you see yourself lovingly caring for your reviewer? Probably not. However, if you care for your reviewer by writing with clarity and breaking up rows of text with an occasional space or two, your reviewer just might buy what you’re selling.
 
Resources
 
https://goinswriter.com/better-sales-copy/

As we all know, plexiglass and masks are the new norm. Sometimes these shields make it difficult to understand what someone else is saying. Have you been to the supermarket and the cashier asks you a question? Their speech is often muffled and because of the mask there’s no lip reading to help you out.  You kind of get it but not quite. I had the same feeling reading a grant the other day. I read the words, but I didn’t quite “get it”. I understood the words I was reading, but the excitement of the idea was hidden behind big words, technical terms, and writing that was vague at times.  It was vague because of undefined concepts and unnecessarily complicated language. These issues, which are common in grant writing, put a barrier between the reviewer and your work. Because I was reading the grant to give feedback, I focused on what was putting the great ideas in this proposal just a little out of reach. 

Before I get into how to break down the barriers, I want to take another stab at conveying their impact. I heard on a podcast once that selling (yes, we are all salesmen) can be defined as getting someone to want to participate in your story. It turns out that this idea has a name – insight selling. Insight selling has two categories, opportunity insight and interaction insight. In opportunity insight, the customer/reviewer doesn’t realize that they have a problem. You define their problem and give them the opportunity to fix it. In grant writing this comes in the form of the ever popular “knowledge gap”. The second category of insight selling is interaction insight. According to a blog post on business.com, interaction insight is “building connections with customers by encouraging creative thinking, inspiring "lightbulb" moments and challenging assumptions.” Although barriers can impact both of these categories, the biggest impact is on interaction. You want the reviewer to have an “aha” moment as they understand and get invested in your work. The barriers, which I will talk about below, block interaction and can lead to what I call the “blah,blah” effect. You’re reading but not taking in the words – like when adults talk on the cartoon Charlie Brown. Although I am dating myself Charlie Brown is timeless, no? If you’re lost, see the link at the end of this post. 

Hopefully I’ve conveyed the importance of de-covidizing your research – unless, of course, your research is on covid. Now on to the barriers themselves. I believe there are three main barriers – big words, technical terms, and acronyms. The way you use words, which involves the deep, dark forest of grammar, can also lead to some fuzziness. I’m saving that for round two. Although big words are very important, I covered this in depth in a previous post. See Further Reading below. 
 
Technical terms
            You will need to use some technical terms, but you want to be sure that your reviewer understands what they mean. Some terms may not even be that technical, but if don’t remind your reviewers of their meaning your grant may suffer. For example, the grant I mentioned at the beginning applied ecologic concepts to bacteria, and - big surprise - used the word ecology. When I see the word ecology, I think electric cars, cows, and recycling. However, the true biologic definition was integral to the proposal, and warranted a revisit. Defining more common “technical” terms may cause some uncertainty, because you don’t want to seem patronizing by defining a term that readers in the field probably know, but on the other hand you don’t want your reviewer to incorrectly define your technical term. A good way of handling this is to “sneak in” a definition by adding it as a phrase offset by commas. This idea comes from the book Writing Science, by Josh Schimel, which I highly recommend. Here are some examples.
 
We will determine whether the cells are undergoing apoptosis, or programmed cell death, by three distinct assays. 
 
The IL-2 receptor, comprised of alpha, beta, and gamma subunits, is expressed on T cells.   
 
If you’re not sure if your reviewers are familiar with a term, the above method serves as a way to add in needed information without a separate definition. Defining terms is especially important when you are combining two disciplines, because most likely your reviewers will only be experts in one. In general, err on the side of defining technical terms. A few years ago, I submitted a grant to a cardiovascular study section and I proposed using a mouse model that caused the mouse to have increased cholesterol. I assumed that any reviewer in a cardiovascular study section would know this model so I didn’t define it. I was wrong. One reviewer, in the written feedback, did not know that this model caused an increase in cholesterol so he/she didn’t understand why I chose it. In the next grant, I made sure to define it.  
 
Acronyms and abbreviations
            Using acronyms and/or abbreviations can be a good way to save some space, but it’s a tool that must be used judiciously. Acronyms are commonly used in science, but like technical terms you need to make sure and define them, unless you think the acronym is so common that any reviewer in your field will know the definition. If you’re writing a manuscript, journal-specific instructions usually provide a list of common acronyms that you don’t need to define. These typically include acronyms such as FBS (fetal bovine serum), FITC (fluorescein isothiocyanate), etc. for those in biologic sciences. If you’re a physicist you probably have your own acronyms that I’ll never understand. For a grant, you’ll need to use your own judgement, but for the most part you’ll want to define acronyms. 
            One good way to irritate a reviewer is to introduce 2 or 3 new acronyms at the same time. Keep in mind that even though you define an acronym your reviewer has to remember what it means. If the reviewer forgets, there’s a good chance he/she won’t bother to go back and find the definition, which means he/she might get confused, and we know that nothing good comes of confusion in grants! When I say “new” acronyms, I mean an acronym that your reviewer may not be familiar with, or one that you made up to save space. What do I mean by “making up” an acronym? Making up an acronym would be akin to abbreviating the song “I Shot the Sheriff”, originally by Bob Marley and covered by Eric Clapton, to ISS. That phrase is in the song multiple times. While using an acronym would definitely save space, readers will struggle to remember what ISS means, not to mention ruining a perfectly good song. Here’s a science-based example. In the past, I worked with a molecule called heparan sulfate proteoglycan, and studied its impact on the immune system. For those in the proteoglycan field, heparan sulfate proteoglycan would commonly be abbreviated with the acronym HSPG. However, for an immunology-based grant, most reviewers would not be familiar with this molecule and might forget what the acronym means. Because of this concern, I wrote out the name rather than abbreviating. 
Despite the above rant, there are times when you’ll need to make up an abbreviation or acronym. This situation may occur if you have a new technique or molecule that you are mentioning frequently, especially if the item in question requires a lot of words or letters. Let’s say your grant has to do with the effect of the word “supercalifragilisticexpialidocious” on viewers of the film Mary Poppins. You would want to shorten this to supercal or something along these lines. Not only does this word take up a lot of space, but continuously reading it takes a lot of mental effort. To give you a more science-based example, a few years ago I wrote a grant involving a peptide that I made. Rather than describing the peptide as the “N terminal 15 amino acids of a cytokine receptor” every time I mentioned it, I made up a name – N15AA.
            Finally, if you’re going to use an acronym, make sure that you use it at least 3 times. In other words, don’t define an acronym and then use it only once. It takes up more space to define the acronym and then not use it, and you’re burning excess brain cells of your reader.
 
I hope these ideas help you dismantle barriers between your ideas and your reviewer. In Covid terms, these barriers range anywhere from a hazmet suit to a scarf-mask, but with some interim paylines in the single digits, clarity is key. Clarity comes both from reminders as to what might be confusing to a reviewer, like the above, and through awareness of the “curse of knowledge”. The curse, in which you know your work so well that you can’t appreciate what others don’t know, is very common. Getting feedback from someone less familiar with your work will make sure you ward off this evil curse. 
 
 
Further reading
 
Big Words, by yours truly. http://www.drlucywrenshall.com/grant-writing/big-words
 
Charlie Brown’s teacher talking. https://www.youtube.com/watch?v=ss2hULhXf04
 
What is Insight Selling? A Beginner’s Guide. https://www.business.com/articles/insight-selling-guide/
 
Writing Science: How to Write Papers that Get Cited and Proposals that Get Funded, by Josh Schimel.
​https://www.amazon.com/Writing-Science-Papers-Proposals-Funded/dp/0199760241/ref=sr_1_1?dchild=1&keywords=josh+schimel&qid=1603635817&sr=8-1
 
I Shot the Sheriff, by Bob Marley, sung by Eric Clapton https://www.youtube.com/watch?v=L0xLLPJ0bOw
 
 
 
 
 
 

​The significance section of an R01 is probably the most misunderstood part of the entire NIH grant. Perhaps this should come as no surprise, as this section has been a bit of a moving target over the past several years. Another source of confusion may be that Webster’s definition of significance and the NIH’s definition are “significantly” different. A brief history lesson may shed some light on why the significance section is a bit murky and will put today’s directives in context.
 


A brief history of significance
            Way back in the dark ages, when getting your NIH review in the mail as a “pink sheet”, the R01 proposal was 25 pages long. Significance was included with background, and given the overall length of the grant, background often expanded into a verbal upchuck of information about the topic at hand. In 2009, the powers that be decided to give the reviewers a break and the 25 page limit was reduced to 12. The background and significance section slimmed down and was intended to highlight key findings rather than review the world’s literature. In 2016, spurred on by the need for public accountability, NIH grants underwent a major overhaul and the significance section had a new set of instructions. Significance was to include the word premise, which was defined by the NIH as “the quality and strength of the prior research used as the basis for the proposed research question or project; this is distinct from the hypothesis or justification.” The significance section was also to describe the strengths and weaknesses of the prior research. Since these initial instructions, the word premise has been dropped and quality and strength of prior research is addressed as, wait for it…., rigor. 
Webster defines significance as “the quality of being important”. Investigators must like this definition, as most significance sections that I have read include something about the importance of the work. However, the NIH forgot to check Webster’s, and if you only include statements about the importance of the work your significance section will miss the mark. The NIH assumes success of your specific aims and wants to know “how will your work, successfully carried out, impact the field?”. I put the word successfully in italics, because if your work is founded on weak preliminary data and/or a poor approach, successful completion of aims will not have a major impact on the field.  
 
Significance today
      Knowing the evolution of the significance section might explain the potential differences that you’ll see either as a reviewer or in reading examples of successful grants. Now let’s head back to the future. What are reviewers looking for in today’s version? The current significance section looks for impact based on the rigor of prior research.  What is rigor of prior research you ask?  Right from the horse’s orifice of choice, rigor of prior research is defined as “the quality and strength of the research being cited by the applicant as crucial to support the application; this is distinct from the hypothesis or justification.” It’s premise without the word premise. 
            As part of the rigor of prior research, the applicant is supposed to address the “strengths and weaknesses of the prior research used to support the application and describe how the proposed research will address weaknesses or gaps identified by the applicant. This may include the applicant’s own preliminary data, data published by the applicant, or data published by others.” Here is your opportunity to discuss the strengths of your preliminary data (for an R01) or published data (R21, R03) that are the foundation of your hypothesis. The weaknesses you will, of course, be addressing in the grant.  
 
Structuring your significance section
            Although the exact order isn’t critical, the elements described above must be included in your significance section. I suggest starting with a brief paragraph restating the critical need your proposal addresses and how successful completion of your proposal will change the field. Remember, this is the NIH definition of significance. If you have a surprising statistic that supports the need here’s the spot.  In the next paragraph restate the hypothesis, followed by the strengths of your key supporting data. I don’t think it’s over the top to include a sub-header entitled “Rigor of prior research”.  It’s hard for a reviewer to claim this wasn’t addressed when you have it written as a separate section.  From there you discuss the weaknesses, which prepares the reviewer for the approach section where they will be addressed. 
 
Here’s an example of a significance section, which is taken from a proposal using e-yarn as a way to detect lost socks. This example highlights my approach, but as the saying goes, there are many ways to skin a significance section.
 
Socks are the number one lost laundry item in the United States. Every household is, at some point, plagued by the problem of lost socks. Lost socks generate substantial psychological and financial burdens on many households, which escalate exponentially in families with 8 feet or more. Last year alone, replacement costs for lost socks reached 1.2 million dollars, and this cost is on the rise. Experts from the Simpson Family Foundation, a think tank focused on family issues, project that by 2040 the problem of lost socks will surpass health care as the number one drain on family budgets. New ways to find lost socks must be found now to avert this future financial catastrophe.
 
Rigor of prior research: We hypothesize that socks made with e-yarn will be detectable within an average size US home (2000 sq feet) using a barcode cell phone application. This hypothesis is built on strong data demonstrating that detectability of e-yarn is resistant to dye (Figure 1), water (Figure 2), and that 1 g of e-yarn is currently detectable up to 2000 feet (Figure 3). Based on these data, the proposal that follows will develop a unique, cost effective way to find lost socks. Successful completion of this proposal will represent a significant step towards eliminating the financial and psychological burden of lost socks. A side benefit of this approach is that, if desired, family members with similar sized feet can identify their own socks. Finally, this technology can be applied to other problematic clothing items such as cufflinks and earrings. 
This proposal will address the following weaknesses in preliminary and published data. Our preliminary data shows that 1 g of e-yarn is detectable by RFID up to 2000 feet. However, we have not yet tested smaller amounts of e-yarn. Since it is not cost effective to make an entire sock of e-yarn, we will determine the smallest amount of e-yarn that can be woven into a sock and remain detectable. This question will be addressed in Aim I. 
Many studies have taken a compensatory approach to the problem of lost socks rather than finding the sock itself, which is the goal of this proposal. Some studies, for example, suggest that purchasing a 6 pack of socks can address the lost sock problem.2-5 However, these studies have only used white athletic socks and do not take into account more expensive dress socks. Another approach, reported by Hanes, et al, was to wear mismatched socks.6 However, their study was limited to 15-25 year olds, who have been shown to enjoy wearing mismatched socks.7-9 A similar approach, wearing only one sock, was supported by findings of Scholl, et al.10 However, this study involved a more sedentary population. When tested in a younger, more active population, Adidas et al found that the one sock approach was not feasible due to foot sores and odor, particularly when studied in student athletes traveling together on buses.11,12
 
As outlined above, this example starts with a restatement of the problem, adding a little more detail than what was presented on the specific aims page. From there, I restate the hypothesis, so that it is fresh in the mind of the reviewer as he/she goes on read the key data supporting your hypothesis. These key data are the “strength” of the strength and weaknesses of supporting data. Make sure that you demonstrate the strength of your data with figure legends that support rigor and reproducibility (positive and negative controls, statistics, numbers of replicates and experiments/animals, etc). After listing the key supporting data, I describe what will happen upon successful completion of the proposal. Because this section focuses on the proposal, rather than the problem, the successful completion part flows nicely from here. I then finish by discussing the weaknesses/gaps that will be addressed.
 
Where’s the background?
            Since the NIH got rid of the “background and significance” section it’s dealer’s choice as to where to the background. Do you even need a background section and if so, how much? Yes, you need some background information. I think of background as a “need to know” section. Include what the reviewer needs to know so that he/she understands your work and its context. Some investigators still put this information in the significance section, and others put it at the beginning of the approach. I do not recommend putting your background with the significance, because you risk reviewers missing the information the NIH asks for (and you are scored on) by getting caught up in background details. 
 
If nothing else, remember that the significance is the impact of your proposal, if completed successfully, on the field. Reviewers are instructed to score grants with this idea in mind. Now time to do some laundry.

​Last time we chatted, or I like to think of it as chatting, I talked about feeling powerless. For me, feeling powerless is something I have struggled with throughout my life, and these “unprecedented times” have no doubt fostered that feeling in many people. If you think some of your unhappiness is due to feelings of powerlessness, what can you do?  It’s easy – stop thinking about it! You can thank me later.
 
Ok, so of course it’s not that easy. If it was, we’d all be like our dogs and cats, enjoying the sunshine, getting excited about a squirrel, and then going back to sleep. Actually, there’s no magic bullet to annoying, unpleasant or harmful thoughts - followed soon by their sidekick feelings - but awareness is half the battle. After countless books, podcasts, and courses, my Sparks notes summary to dealing with thoughts comes down to 3 major techniques: question your thoughts, mindfulness, and meditation. I know the words mindfulness and meditation have been thrown around a lot, but don’t check out yet because I have some specific suggestions as to how to use these tools. 
 
Before I get into each technique, I want to revisit this idea of powerlessness in the context of needing to control things. In Part I, I referred to Mo Gawdat’s Talks at Google about our need to control. When things are not in our control, we feel powerless. Mo doesn’t recommend abandoning all control, because some attempts at control move things forward. For example, if you live in a flood plain, rather than hoping that it doesn’t rain heavily it makes sense to exert some control through building barriers, moving etc. Rather than abandoning all control, Mo recommends thinking about the things you’re trying to control and pick a few high priority areas that you want to attempt some degree of control. I put the latter in italics because things are never totally under our control. Be aware of the cost of “control” and the cost to your happiness. This awareness might help you trim your “control list”. 
 
Let’s say you’ve narrowed down your control list to a few key items. What happens when life throws you a curveball?  (Spoiler alert: life will throw you a curveball at some point). How you respond makes all the difference. Mo uses the term “committed acceptance” and Eckhart Tolle, a well-known spiritual teacher, uses the word surrender. While both of these terms may seem to imply giving up, that is not the case. What they do mean is to stop arguing with reality, so that you can respond rather than react. Let’s say you’re on your way to an important dinner meeting with a potential employer. You’ve heard that this employer is really a stickler for being on time, so you leave a little early to make sure you’re not late. It’s raining heavily, and as you’re driving you swerve to miss a biker who can’t see well and end up on the side of the road in the mud. If you are angry and just react, you might choose to keep hitting the gas and getting even more stuck. Here is where the committed acceptance/surrender comes in. Committed acceptance helps you respond rather than react. Rather than continuing to “gun the engine” in an angry response, you accept that you’re stuck, which then allows you to take effective action such as finding some wood or cardboard, calling a tow truck, or cajoling a friend to help.
 
 If you’ve read any self-help literature, you’ve probably run across the phrase “what we resist persists”. To continue the story, let’s say you can’t get your car out and end up calling a tow truck. You call your potential employer and explain the situation. He understands but doesn’t really care – he’s left the restaurant and is no longer considering you for the position. Yikes! You “resist” this event for days, maybe even weeks – going over each step in your head. Why did I take that route? Who does he think he is? Each time you play the conversation over in your head the anger comes back. You’ve heard him tell you “I’m sorry but you’re no longer a candidate” 50 times in the past two weeks. What you resist persists. Sometimes your anger is perfectly justified. You tell several of your friends about this incident and they confirm that this guy is a total jerk. Maybe you even get so angry that you send an email specifically telling him he’s a jerk and you wouldn’t want to work for him anyway! Probably not the best move. Plus, you’ve spent a lot of energy over the past 2 weeks being angry with not much to show for it. I realize that anger can be motivating, but often anger comes from reaction rather than a place of perspective where more effective action can be taken. From a state of committed acceptance, perhaps you reach out to the potential employer and explain yourself again. Alternatively, you renew your job search, maybe even entertain additional schooling. Each of these actions are more effective than arguing with the reality of the situation and fueling your anger.
 
Committed acceptance sounds great you might say, but it’s one of those things that’s easier said than done. When something big happens, like job loss, divorce, the centennial pandemic, etc. how can you “leave it” as I tell my dog, so that you can move on to committed acceptance?
 
Well, it’s a good news/bad news kind of answer. The bad news -you can’t stop thinking. The good news  - you can be aware of and redirect your thoughts. This is a key skill for happiness. Not to go all Buddhist on folks, but thoughts are the major, source of suffering in our lives. Let me give you a brief explanation of three ways that I’ve found helpful to deal with the monkey mind.
 
Question your thoughts
Let’s go back to where we started - feeling powerless. Hopefully y’all are back in the lab full or mostly full tilt under the likely restrictions of masks, spacing, etc. During lock down, though, you may have had thoughts that the situation is totally out of your control and there’s nothing you can do. I say “thoughts” because often you have more power than you realize, but your brain is telling you that you’re powerless. Because the brain wants to be right, it then merrily goes along finding ways to back up that statement. In addition, the brain is a sifter. To make life easier, the brain filters all the stimuli that’s out there. Mostly that’s a good thing, so that once we learn to drive, for example, we don’t need to think about every little thing that goes into the complex task of driving. We just get in the car and go. However, the bad thing is that sometimes we only “see” things that back up our thoughts. If we think we are powerless, then the brain will tend to focus on things that support that statement. If that’s not convincing enough, then your brain will take you through your past and bring up experiences that support the thought. 
By questioning our thoughts, we take a step back and ask whether the thought is really true. When you tell yourself “Nothing ever goes right for me” or “I can’t get a break” ask yourself whether this is really true. Go back through your past and find examples where things did go right. The master of questioning your thoughts is Byron Katie. She developed 4 questions we can ask ourselves to help deal with undesirable thoughts. Katie also has tons of videos on YouTube where she takes folks through the 4 questions – definitely worth watching. Although questioning your thoughts is a good way to counter negative thoughts, it has another benefit which is to separate you and your thoughts. Who are you? You are the one questioning your thoughts. Separating you from your thoughts helps create perspective and objectivity so that you see your thoughts as they are rather than as “the truth”.
 
MIndfulness
Your thoughts can’t take you to shame town if you’re busy thinking about something else. Mindfulness is all about staying in the present and focusing on the here and now rather than mentally living in the past or the future. However, if you just had a big blow up with your significant other, “mindfully” washing the dishes is tough. You can try to pay attention to the smell of the soap, the slippery sensation of the soap and water, etc but you’ll probably drift back to that argument pretty quickly. Until you’re a mindfulness master, I recommend starting with something that demands your attention. For me, that’s playing the violin. Playing an instrument is demanding enough that you can’t ruminate and play at the same time. Other examples might be playing basketball, cooking, gardening – anything that takes enough of your attention that it’s hard to think about something else. 
 
Meditation
Meditation is another great way to practice distancing yourself from your thoughts, which makes committed acceptance much easier. As I’m sure you’re aware, one common way to meditate is to focus on your breathing. If you truly focus on the sensation of your breathing, you can’t think about the past or future. However, you will lose focus pretty quickly and thoughts will return. When you notice the thoughts, that is an example of awareness. You then go back to focusing on the breath, etc. The good thing about this type of meditation is that if you start doing this at home in a quiet space, you’ll may notice yourself taking a moment to focus on your breathing while standing in line at the check-out counter, while stuck in traffic, etc. Focusing on your breathing is a great way to take a “time out” when you’re having a stressful day. Like mindfulness, though, if a fresh hurt is really bothering you, focusing on your breathing is hard. For times like these, I recommend guided meditations. You can focus on the directions of someone else, which makes it a little easier to get away from your thoughts. Deepak Chopra (+/- Oprah) has a great series of meditations which are a combo of both “food for thought” and quiet time with music. These come in short (10-15 minutes) or extended (about 30 min) versions. Insight Timer is another great resource for meditations, with guided meditations, music only, and several classes. It also has a search function where you can search both type of meditation and length. The basic app is free or you can add on for $60/year.
 
Like anything that’s worthwhile, these techniques take practice. I promise the practice will be worthwhile, not only for yourself but for those around you. 
 
Questions? Comments? I’m a major introvert, so I’m always up for a conversation with myself, but sometimes it’s good to get out of the cave and connect with others.
 
Resources mentioned and more:
 
Byron Katie - https://thework.com. See also books on Amazon.
 
Insight Timer (found on the app store). One of my favorites is the Garden of Babylon by Jim Rajan.
 
Deepak Chopra meditations - https://chopracentermeditation.com. Paid on his website but many on YouTube. He also has a new book about meditation coming out Sept 22 via the big box internet store in the sky.
 
The Mind Illuminated by John Yates – great resource for those who want to delve deeper into meditation and mindfulness.
 
Song from the Cartoon Network show Steven Universe “Here Comes a Thought” https://www.youtube.com/watch?v=dHg50mdODFM. Great for kids of all ages.
 

​If you’re feeling anxious, fearful, demotivated, distracted, etc then you’re not alone. Given the current state of affairs in this country and worldwide, those feelings are justified. I recently spoke with an academic scientist and mentor who said that many researchers are having so much trouble focusing in the current climate that they aren’t interested in work-related topics such as productivity and writing skills. 
 
If you like feeling anxious and overwhelmed, then save yourself some time and stop reading right here. If not, let’s take a closer look at what’s going on. Feelings are always based on thoughts. The thought comes first, and then the feeling. Why is this important? Because if you don’t like the way you’re feeling, and you want to change it, you need to figure out why. 
 
As a scientist during a pandemic, what are you worried about? If you work for Gilead and research is Covid-related, then maybe it’s all good. However, if you’re studying the mating rituals of Onthophagus acuminates, aka dung beetle, potentially plenty. You may be worried about losing your job, or your spouse losing his/her job, slow progress in the lab, delayed publication of papers, delayed or weakened grant submissions, lack of toilet paper and paper towels, managing remote learning for your kids, safety and health of elderly parents, an unexplainable but chronic lack of tofu at the supermarket, and the list goes on. I’m embarrassed to admit that during the peak “personal paper crisis” I bought paper towels from China. In my pursuit of disposable cleaning tools I got taken to the cleaners, so to speak, and now I’m worried that PayPal might not make things right. With all those fears, who can work, I mean really?
 
Actually, you can. But before I give you my take on the how, let’s “unpack” these fears. You’re not going anywhere anyway, there’s a pandemic. What is common to these fears? Each one is at least partially if not entirely out of your control. That is bad news for control freaks – not that any scientists would be control freaks…..
 
So, if something is out of your control, how does that make you feel? Powerless. In a career that tends to make one feel powerless anyway, this just adds to the pile. Why might science make you feel powerless? Well, as an academic scientist your career is predicated on convincing others that your work is worth publishing and funding. You aren’t able to talk to these folks in person, so there is a time lag between your efforts and their feedback. Nothing you can do about it but wait (powerless). Often the feedback seems unreasonable, misunderstood, and highly critical, but you can’t explain yourself in real time (powerless). In fact, it’s oriented to be critical because the feedback is focused on telling you what to fix or why your work won’t be funded or published (powerless plus despair). These factors make you feel that your career is out of your hands. Add Covid and now your ability to work was or still is compromised (powerless).  Even worse, perhaps you or a family member got sick and research is off the table for a while.
 
Why is feeling powerless such a big deal? If you’ve felt it, and most of us have, then you’ll know why. In the book “The Nature of Personal Reality”, by Jane Roberts, the channeled entity Seth (yes you read that right) states “That is the source of physical life, the sense of power and action. When a man or a woman feels powerless, as you think of it, he or she will die”.  Seth also says that violence often comes from feeling powerless, which is another reason why this idea is worth some attention. I realize this is not a new concept, but one we often forget in the heat of the moment or its aftermath.
 
If statements from a channeled entity don’t sit well with you, let’s look at a more traditional source of information. Mo Gawdat, former chief business officer at Google X, has a background in engineering and a career in business strategy and communications. He applied logic to the idea of maintaining happiness in his book “Solve for Happy”. In this book, he derives an equation for happiness:
            
Happiness ≥ Reality - Expectations.
 
The expectations are, of course, your expectations as to how things should be. Reality constitutes the facts of the situation. Your thoughts are part of your expectations. They contextualize reality.  Let’s look at an example. It’s Saturday, and although the original forecast was for beautiful weather, a storm moved in and now it’s going to pour, I mean cats and dogs, hellfire and brimstone kind of pour, all day long. The woman who planned the perfect outdoor wedding, with visions of standing in a beautiful garden and sun shining on her painstakingly coiffed hair, is crushed. However, the husband anticipating a day of outdoor “honey dos” generated by his wife, is grinning from ear-to-ear as he settles down in his favorite chair for an afternoon of football. The facts are the same, but the expectations, and subsequent feelings, are quite different. On a scale of 1- 10, with reality being a 5, the husband’s expectations were a 1 and the bride’s were a 10. Without managing expectations, the bride could end up being miserable on what should be a very happy day. The more inflexible your expectations, i.e. the more strongly you want to control the outcome, the more likely it is that your expectations will not meet reality. Does this mean you should only have low expectations? No. It does mean that you will be happier with flexible expectations and being open to other outcomes besides the ones you expect. More on that in Part II.
 
Let’s go back to the downpour for another example. It rains so hard that the area floods – big time. Noah and the ark type of flooding. A man, who unfortunately lives in the flood plain, is stranded on his roof. He prays to God to save him. People come by on a surfboard, motorboat, and finally helicopter to save him, but each time he turns them away saying “No worries, God is going to save me.” Well, the guy drowns. When he gets to heaven and asks God what happened, God says – “I sent a surfboard, motorboat, and helicopter, what more did you want?”.  In this case, the expectations were so fixed that the man could only see one solution when presented with many.
 
Fixed expectations are a form of control. In his recent “Talks at Google”, Mo Gawdat illustrates this idea of control. He asks listeners to hold a pen, or similar object, at one end and let it dangle. I used a hairbrush, because being the Type A crazy that I am, I tend to consume content in the shower. After letting the object dangle, he then asks us to hold it at an angle. Because I used a hairbrush, which is much heavier than a pen, it took quite a bit of force to keep the hairbrush at an angle. This force is, of course, analogous to the equilibrium/homeostasis vs tight control that we impose when it’s our way or the highway.
 
I think by now you get the idea. At the risk of leaving you hanging, this topic is too big for one post. Stay tuned for Part II, where I talk about my antidotes to feeling powerless, and maybe even a Part III on Pride and Powerlessness (my version of Pride and Prejudice, it’s a reach I know) with Walter White from Breaking Bad. Oops, I forgot that scientists don’t binge Netflix. 
 
In the meantime, or for further in-depth study, I recommend the following resources.  
 
“The Nature of Personal Reality: Specific, Practical Techniques for Solving Everyday Problems and Enriching the Life You Know ”,  by Jane Roberts.
 
“Solve for Happy”, by Mo Gawdat. 
 
“The Illusion of Control”, Mo Gawdat, Talks at Google. 
https://www.youtube.com/watch?v=IsTNyr6bF-0

​Humans are wired for story. Your grant, whether you realize it or not, has a cast of characters including a hero, villain, supporting characters, plots and subplots. If you think about your grant in these terms when you write, the ideas will flow better and your proposal will be easier for outside readers (code for reviewer) to understand. 
Before I explain further, I have a confession to make. I review grants for a large government institution that funds human health-related research. I confess this because things that bug, annoy, peeve, confuse, or irritate me as I’m reading a grant might have the same impact on reviewers reading your grants. Reviewing grants is a great learning experience, and I’m here to share what I’m learning.
Today I’d like to talk about the rogue character. As mentioned above, your grant, just like a novel, has a cast of characters. Unlike a novel, however, you don’t have an unlimited amount of space and time to introduce your characters. You have one, dare I say specific, page to introduce your main characters. For the reader/reviewer, even those close to your field, getting a grip on your characters is a little like going to a family reunion where you don’t know most of the people. You’re “hanging on for dear life” to remember the name of your second cousin twice removed, who you were just introduced to a few minutes ago and is now heading towards you with his significant other. 
Let’s look at an example. To maintain anonymity, I’ll stick with the reunion analogy. I was minding my own business, merrily reading a proposal, and taking notes to keep the relatives straight. I already met the problem, the drunk uncle, whose behavior has gotten out of hand. He needs an intervention. Along comes the young whippersnapper nephew, who has a special relationship with the uncle and is going to facilitate these interventions. The uncle has had this problem for a while, so he’ll need at least 3 different types of interventions. Now that I’ve met everyone, and I know the interventions, I’m settling in to see how the nephew is going to pull this off.  All of a sudden, in walks Janet. Huh? Wait a minute, who in tarnation is Janet? Nobody knows her. Maybe she’s a “reunion crasher” just pretending to be a relative. I go back through the story/proposal to make sure I didn’t miss anything, and low and behold there she is. Her name is on a roster of relatives, but I don’t know who she is or why she’s there. Turns out that Janet is going to play a major role in the first intervention, but since I don’t even know how she’s related, I’m a bit perplexed. In addition to being perplexed, the flow of the story is broken, and now I need a coke and some potato chips.
Needless to say, Janet’s arrival would have been a lot less confusing if I would have known ahead of time that she was coming. Maybe the author of this story thought it would take up too much space to tell me about Janet ahead of time, or maybe the author thought I was a mind reader. Reviewers get that a lot. However, just like the author of a good novel, the onus is on you as writer to properly set the stage for each of your characters. 
I hope this analogy hasn’t been too much of a stretch, but sometimes it’s more fun to talk about books and relatives than signal transduction pathways. If a molecule/pathway/chemical, etc is a major part of an aim, the reviewer should be introduced and know the context prior to the aim itself. Otherwise, you run the risk of confusing your reviewer. In the world of grants, confusion = no. And on that happy note, I’m going back to the story. Turns out the drunk uncle was an American spy in Russia during the cold war. Might explain the vodka.
 

​The beginner’s eye, not to be confused with Bette Davis eyes, is looking at things as if you’ve never seen them before.  What if you reviewed your last several months’ worth of experiments as if you’ve never seen them before – no hypothesis, no preconceived notions, just a clean slate and a basic understanding of your science (hey that sounds like a reviewer!). 
 
Beginner’s eye is critical in science. Consider your favorite hypothesis. I intentionally use the word favorite, because we get an idea about what is going on and start to build on it. As we build, we limit our analysis to the context of our working assumptions. Or maybe that’s just me. 
For example, I recently had an interesting observation about a protein I’m working with. I got enough data to form a hypothesis, and then recently found something that contradicts the hypothesis. Do I explain it away, or take a closer look? The contradiction kept popping up, and I now feel compelled to take a closer look. I plan to revisit my recent work, as best possible, with a fresh eye and see what comes up.
 
Of course, there are ways to help keep our mental tendencies for bias on the straight and narrow. The whole “rigor and responsibility” thing for NIH grants is geared towards this, even though it was developed for public accountability and not for scientists. Nevertheless, as scientists we can and should take these elements to heart to improve our work. Consistent use of positive and negative controls (ok I’m really going back to the basics here), blinded analysis, sufficient replicates, etc all help subdue the “demon bias”. Getting a fresh look from a colleague unfamiliar with your work can help too. Besides making for better science, you’ll probably uncover some potential objections from reviewers that you might not have otherwise noticed.
 
Although keeping bias out of work is always a good thing, the main benefit to the beginner eye is seeing something you haven’t before. As Mrs. Potts from Beauty and the Beast says, or more accurately sings, “There may be something there that wasn’t there before.” For those of you who aren’t Disney fans, try this quote from Shuryu Suzuki, 
 
"In the beginner's mind there are many possibilities, but in the expert's there are few."
 
This quote is worth sitting with for a moment. Think about all of the mental constraints that you’ve built up based on past experiences. No, I’m not just talking about science anymore. There are entire books about the implications of this idea, so I’ll leave it for you to think about. Let me instead suggest a treatment. Note I said treatment because there is no cure. We all interpret life through the bias of our experiences, but awareness of this bias helps. I mentioned taking a fresh look at old data, but you can practice taking a fresh look at life. Consider the water coming from your shower head as something you’ve never seen before, or the cold closed box of your refrigerator. Wonder at the usefulness of a door knob. Try this for even five or ten minutes, and you’ll be amazed at the world around you.