How to put together (your life and) a K99/R00 proposal

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UPDATE: New forum for comments/discussion/etc. started Feb. 2010:
http://k99r00-land.motionforum.net/forum.htm

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UPDATE FOR NEW, SHORTER APPLICATIONS starting Jan/Feb 2010:

Everything below still applies, and here is an additional piece of advice to you all for where/how to focus in these shorter apps:

#1 priority: "The Candidate" and career plan section.

#2 priority: Your independent research aims and plans.

I know some folks on the study section reviewing these applications, and the most common pitfall applicants create for themselves is to not have well-developed career plans with OUTSIDE, INDEPENDENT collaborators and FOCUSED, well-developed R00-phase research plans.

Take the rough % page breakdown from before (~6 pages The Candidate, ~5-8 pages intro, ~3-4 pages mentored phase research, ~8-10 pages independent phase research) and apply it to a total of 12 pages, and work on making your narrative extremely tight, focused and direct.

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So you need to get any combination of the following:

• Your %@#& together
• Some research funding
• A more independent job

If you are like most people, you probably do not work in So-and-so Famous Lab and have So-and-so Famous graciously handing off fully-formed R01 proposals and setting up lunch meetings for you with collections of other Famous Faculty who can think of nothing better to do with their time than help you out with your life, who pick out just the right faculty position (or other job) for you, make a few phone calls and BINGO you’re in the club. YOU TOO can take matters into your own hands: even just the process of applying, revising and resubmitting for a K99/R00 Pathway to Independence award from the NIH will help you get that shit together, whether you get it funded or not.

I am going to try to create an informal guide, based on my own experience as an A2 awardee, on how best to approach this award and revise for success if you don’t make it on your first time around. The most important thing that I cannot stress enough is DON’T TAKE REJECTION PERSONALLY. Don’t let a bad score permanently destroy your motivation—read the critique, do everything in your power to address it and TRY AGAIN.

This award is still in the wild-west phase—its first cycle was early 2006, and it has been feeling itself out over the past few years while the first couple sets of awardees made it through their mentored K99 phases and transitioned into their R00 segments. Its advantages are many: up to 2 years of post-doc funding, 3 years of funding to start your own lab, the cache on your CV, the focus of direction that it forces upon you, etc. A few kinks are still being worked out—given the painful slowness of the turning of the NIH gears, it’s relatively common for the awardees to already have a tenure-track faculty position offer, or at least some other kind of job offer that involves them moving on. It is just not practical or possible for senior post-docs (towards whom the award is aimed) to sit around by the phone waiting to hear the good news for 6-9 months (for a first submission, which can stretch to 2 years over the revision period) rather than moving on with their lives. What this means for you: APPLY EARLY! Don’t wait until you are in your 3rd-4th year to get started if you can possibly help it. BUT if you do for whatever reason wait that long, APPLY ANYWAY.

Like all NIH funding these days, K99/R00 awards are extremely competitive. Apparently they took away the K01 option and rolled it into this, so this really is one of the only transitional funding opportunities around right now. Even the Burroughs-Wellcome Biomedical grant seems to have been cut out because they said “Hey, now there is an option for you guys so we’re stepping out." It is not easy to get a K99/R00 funded, even if your research is really freaking cool and you have a great mentor. Here, however, are some key details to how to get as close to funded as you possibly can.

General notes

1. Don’t be as ambitious as you think you need to be. Take the system (i.e. which cancer, which other disease, which organism) your lab works with and keep the fundamentals the same. Change the technology or angle to make it your own, rather than going out on a limb and starting with something totally different than what your mentor(s) have published experience in.
2. If you do need/want to move to a new disease or organism or what have you, keep the technologies/angle the same as your mentor(s). The key is to take a relatively straightforward next step, make it your own, and find some innovative (but conservative) thing to do with it.
3. Find an off-campus collaborator of your own. Someone who is well-known in the area but has little to no official affiliation with your mentor(s), and who has experience in whatever NEW feature of the work you are trying to make your own. Best thing is to meet them at a Gordon or similar research conference/retreat, where there is time to have a nice chat. Contact them politely and ask if they would be willing to collaborate with you on your exciting project. Ask if you can spend at least a month in their lab learning something they do (at your expense). The worst they can do is say no or not reply, so have a few lined up to try contacting.
4. Assemble an “informal mentorship committee” that consists of the off-campus collaborator, a junior faculty member on campus, a senior faculty member on campus, and your official advisor. Ask them to act as assessors on your progress. Offer to write drafts of support letters for these people, and make those drafts address the context of their involvement (e.g. “I am delighted to offer my support and advice to X as they prepare their transition towards independence… Based on my expertise in area blank, I am happy to work with X to assess their progress on topic-blah-blah both at the time of transition and as they begin their independent position…” etc.)

The proposal

The proposal for this award requires two major sections: The Candidate and the Research Plan. Both of these need to fit into 25 pages total, and the split should be somewhere between 5-6 pp The Candidate and 19-20 pp Research Plan. I am not going to spend much time on the strategic formatting of the research plan itself. There is an excellent series on R01 proposal strategies here, for which all the same principles and most of the details apply to writing your K99/R00 research plan. However, I will give some tips that address some issues that are more specific to the K99/R00.

1. The Candidate

• “Summary of research experience to date:” Be succinct. Do not tell your life story in flowery language, keep it straightforward but highlight any significant research experience or awards you have gotten along the way. Provide a short (2-3 sentences) description of each project’s goals and accomplishments.
  
  
• “Graduate project description:” Write up a sub-one-page description of your Ph.D. project, addressing the three main things (in this order for maximum clarity) that anybody cares about any given research project:
• What was the big picture point?
• What systems/technologies did you use (specific aim-style) to address that big picture point?
• How did your contribution turn out (advances you made, papers you got published, funding you won along the way)?
  
  Any more than that and the snooze factor kicks in. If you think you can’t describe the big picture about your project because it was so complex or obscure or specific, then you just need to learn how to communicate better. Everything can be described in this simple of a format, and if you can’t do it, that illustrates that the problem lies with your ability to describe your work, not the work or the readers.
  
  
• “Current research training project:” 1-2 sentences outlining the purpose of your current (i.e. last couple of years of post-doc) work (if you are currently funded for it, make sure you stick to describing the work you have money for and not whatever other random stuff you’ve been doing instead!)
  
  
• “Current project description:” Similar to graduate description, sub-1 page explaining the big picture, and specific aims of your current project.
  
  
• “Discussion of current research and training program:” This is not redundant with current project description, it expands on it. This is a more thorough characterization of the type of “training” you have been getting from your environment, e.g. new techniques, new biological systems, new analytical or statistical methods; and why they are important to your development as a scientist. You also get to walk through what advances you have made towards those specific aims you listed in d. and any papers that have come out of it.
  
  
• “Career goals and objectives, a.k.a. Scientific biography:” This is a weird one. This part is like that college entrance essay you have to write to make yourself try to stand out. You want to avoid sounding too forced or too boring, and don’t write too much. Generally keep it less than 4 paragraphs, don’t be too reflective just try to give your “mission statement” in a digestible chunk.
  
  
• “Career development/Training activities during the award period:” DO NOT BLOW THIS PART OFF. Don’t just give some stock language about the courses your university offers in finding faculty positions or some crap. Here is where you have the opportunity to stand out, since most people just use boilerplate language. A few suggestions for looking more creative:
• Describe your informal committee. Use bullet points to list them, and give a short paragraph about how you will meet with them once every six months or something (you don’t actually have to do the meetings, but try).
• Describe a visit to your outside collaborator’s lab, what aspects of your mentored phase specific aim(s) you will address with their help.
• Suggest a specific small research meeting or outside course you will attend to learn more about some aspect of your mentored phase specific aim(s). Example: plan to attend a Cold Spring Harbor course, or if you are proposing proteomics, suggest attending the Seattle Proteome Center’s informatics course, provide a link to the course.
  
  
• “Training in the responsible conduct of research:” This can just be boilerplate.

2. Statements by the Sponsor, Co-Sponsor, Consultant(s) and Contributor(s)

• DO NOT BLOW THIS OFF EITHER! The mentor/sponsor statement is extremely important. If you don’t trust your mentor to write a good one, you need to write it for them and get them to sign off on it. The focus needs to be about what they believe your potential to be based on your previous work/behavior in the lab, and a big part of it needs to be spent on what opportunities they will provide you to learn new things, what their expertise offers you for training, how you get to take whatever you do with you, corroborations of support for outside activities like the ones you described in your career development/training activities section, etc.
• Who supports you is a bigger deal than you think. If you work for a younger, less-well-known PI, you will need a heavier hitter on your sponsorship committee. Find someone (preferably at your institution) who works in the area you are proposing who can serve as official “co-mentor” to you on this proposal. Do the same thing as for other support letters: offer to write a draft for their approval. Having an established vs. non-established name on here will make a difference between whether you get triaged or scored first time around, and you are not trapped if your PI is new—you just need to also get somebody more settled to sign on.
  
• These one or two statements should be included in the text, but you can attach other support statements (e.g. from your informal committee members) in the appendix or whatever.

3. Environmental blah blah: Boilerplate

4. Research Plan

Like I said, not going to spend much time here, just outline a few points specific to laying out the mentored vs. independent phases.

• Specific aims: Separate into mentored and independent phases. Do not try to have more than 1-2 aims for the mentored phase. Make the mentored phase aim(s) involve any characterization of new parts of your idea, system or techniques. Use the independent phase aims to expand on what you can establish in the mentored phase aim(s), but don’t be too ambitious even in that independent phase—stick to things that logically follow on from what you can do in 1-2 years of the mentored part.
• Background and significance should apply to the whole project, not to one phase or the other.
• MAKE SURE YOU HAVE SOME RELEVANT PRELIMINARY DATA. This requires having a mentor who lets you generate some probably on their dollar and time, so straighten that out with them beforehand.
• Give a timeline for the mentored phase. Suggest chunks of time that it should take you to address various parts of the mentored phase aim(s), and where you will do them (which mentor’s lab, on or off campus, etc.).
• Make sure you split mentored and independent phases fairly equally page-wise. It is easy to spend too much space on the mentored phase section, since that is the part you know exactly what you will do for the next year or so. But flesh out the independent phase fully and thoroughly—you can’t leave it hanging as if you’ll figure it all out when you get there, you have to have a plan for how you will set it up, what the pitfalls are, and what alternatives you have in mind for when things need to be adjusted.

Revisions

Revisions are almost surely going to happen to you. Use them as an opportunity to look flexible and ready to learn, and also to genuinely improve this package you have begun to put together. I learned more about my project, my ideas, myself, and how to write a grant from going through two rounds of revisions than I would have from getting it the first time around. These pointers here apply to any revisions, not just for this grant, but I figured I would give you details of what worked for me.

In order to make your revision as successful as possible, always always make changes from the last version very clear. Underline or what have you, don’t worry about it looking messy because at least they will be able to find it if it stands out. Write your Introduction to revised/resubmission (which goes at the beginning of any resubmission) with your reviewers’ energy and attention levels in mind:

• Start with an intro “Resume and response to summary statements” describing what good and bad things they had to say last time (quoting from the summary statement in italics or something like that), briefly outlining what you changed and what is new since last time
• Define what you have used in the main proposal text to highlight changes (did you underline, or italicize, or what?)
• Have sections with headings like “Specific response to Critique #1”
• In these, go through point by point the criticisms (quoting the reviewer) and how you address them (new data? New aim? Took out an aim? New description of pitfall and alternative?). Give page numbers in the new revised proposal for them to refer to.
• Keep it short and to the facts, no excuses or emotional descriptions of how important you thought something was, just DO WHAT THEY SAY.
• The less work they have to do to see that you clearly addressed all the critiques and fixed the issues the last reviewers had with your proposal, the better off you are. Use paragraph, heading, and font style changes to delineate each thing you want to draw their attention to, and they will have no choice but to admit you did everything that was asked of you and improved the proposal.

Wrap up

This probably isn’t a comprehensive document (even though it is this long), and it won’t guarantee you the funding or a job. BUT just the process of bringing something like this all the way through the system will get you ready to go on the job market, even if you don’t get the money. A well-scored (albeit unfunded) K99/R00 proposal (or even one that got any critiques at all) can serve as the foundation for your chalk talk, helping you get all those little ducks in a row that you never realized you needed to deal with to explain to other people why they should invest in your opportunity to run the project. You have to have your shit together to deserve an independent position, and the very application for this award is a training experience in and of itself that will prepare you for what lies ahead. It's scary how you don't realize this until you are through the grinder of having tried it.

Felicity, fearlessness and dumb luck in science

Thinking about notebooks made me remember how important it is to keep track of WHAT YOU DID rather than what you realize or think you realize was the best way later on. Also about the importance of not being afraid to try things that you don't know how to do, because then you don't know NOT to do the things that could make them actually work in a new way.

My own two stories of this from my Ph.D. work:

1. I needed to make bioreductive metal complexes of a drug I was working on. Everybody in the literature had been using Co(III) and it was not working very well for various reasons. I thought, "hell, why cobalt? I'm just gonna try whatever metal salts I can find in the cupboard" because I knew next to nothing about inorganic chemistry. Lo and behold, copper (II) not only made beautiful crystals (that showed via crystal structure just how perfect copper was for this compound) but also even had the intended biological effect. It was only because I was like, "Huh. Why not try it," that I went from mediocre Ph.D. progress to actual interesting advance that solved a problem people in the area had thought intractable for about 5 years.
   
   
2. One of the starting materials we needed for the compounds we worked on was a real pain in the ass to make. The reagents were nasty, the yield was bad, but the literature procedure was more straightforward than some and at least gave us SOMETHING. I toiled away at making it again and again for about two years, always having to make more because it would run out. Once I got an undergrad, I assigned him to churn out a few batches of this stuff. Whaddaya know but that guy gets 80% yield to my 30%! I was like, "DUDE what did you do that I did not do?" He couldn't find anything, we combed through his notebook, nothing. Finally I have him walk me through him setting up the reaction, he goes to add the catalyst, and uses a 5 ml syringe. Me: "Why are you using a 5 ml syringe to add 0.5 ml?" Him: "0.5 ml?......I was adding 5 ml......." This is why you should write EVERYTHING DOWNNNN especially when you first start and your detail muscles are not developed yet. Once we figured that out, everything in our lives went so much better, all because he screwed up and did it wrong in a good way (and I was able to extract out from him what the hell he did).

Another awesome story I was told by an eminent chemical biologist who will soon be my colleague: as a post-doc, she had been working and working on this idea that her PI had about something (that is now one of the classics of chemical biology). It hadn't been straightforward, and the molecular biologists in the lab (she was a synthetic chemist) were having all kinds of trouble with the assays. One day, one of them had to sacrifice an animal and use some particular parts, so she asked for just one organ to see if she could do anything with it. They gave her this organ, she put it on ice, and was like "Hmmm... now what do I do with this thing?" As a chemist having no idea how one normally processes an organ for its proteins, she just picked ye olde random (and not common) procedure from some random paper. Lo and behold, something very exciting was seen in the Western blot and her PI was super pumped. The biologists in the lab all made fun of her procedure and tried to do it more "normal" ways, but nobody else could make it work. Another lo and behold: the way she randomly picked as an inexperienced (but unafraid) chemist processed that organ was THE ONLY WAY to get this experiment to work. They subsequently figured out the mechanism for why and thusly learned more about the biology and the chemistry of the system.

This is one of the things I love about chemical biLOLogy--you get to screw around with stuff that you know is based on molecules, and so it should make SOME sense, and it doesn't matter at all if you understand what you are doing at the time. You can learn it as you go along, and the chemist's molecularly mechanistic perspective helps you go back and dissect your dumb luck to find the places you pinned the right tail on the wrong donkey spleen (or vice versa).

The Queen of TLDR

Speaks for itself. I'll try to work on concision (is that a word?).

Grad school: UK vs. USA

Even though I am from the midwest, and went to a small undergrads-only college thereabouts, I ended up going to graduate school in the United Kingdom (through having no shame about asking a random professor if I could do a summer project in his lab as an undergrad, surprising them there that I was not an idiot, and then being asked to come back for a Ph.D. when he found himself with an extra scholarship). Details of how that all happened aside, the differences between the systems affected my experience of graduate school immensely. For one, my thesis and Ph.D.-project papers are all written in the passive voice and use spellings like "tumour" and "aluminium." But more importantly, my experience was very structured and the department held me, my advisor, and themselves accountable for expediting my productivity and progress and keeping it to a 3-4 year limit--something that I have never, ever heard of for science Ph.D.s in the US.

I'm thinking about how to take advantage of some of the other, more advantageous, differences when I am a graduate advisor. I had a conversation with a future senior colleague about what that might be able to contribute to my mentorship at my second interview, and he was positive and encouraging--making a point to mention that constructive ideas would be at least welcomed in principle in the department. I'm still young enough to think optimistically about that.

Here are the key things that differ in general between typical grad programs (as I have perceived and experienced) in the respective countries:

USA

• Timeframe: 4, 5, 6, 7, 8 years?
  
• Projects: are chosen/developed after rotations, so you try out a few advisors and projects before you settle on something
  
• Funding: is plentiful, stipends are a living wage for the area (oh yes, you Ph.D. students may think you have it bad at ~$20-25K/yr but try living off half-the-poverty-line-level money (~$11K/yr at the time) in a city where everything is New York-level expensive)
• Classes: you spend the first year or two catching up on advanced study you missed out from enjoying the typical liberal arts focused undergraduate education
• Teaching responsibilities: are medium-high. You often have to participate in a good bit of teaching/TAing to support yourself (one of the sources of that plentiful funding)
• Departmental structure beyond classes: is minimal. Your committee and advisor decide the success of your progress, there's little truly formalized setup for goal-setting, there's almost no tracking and accountability about meeting those goals beyond what you decide to tell your committee and what they manage to remember about you.
• Endpoints: are absurdly subjective and vague. Since there's almost no formalized goal-setting or formalized accountability (of you or your committee/advisor), when you're "done" is decided in a different way for every person, leaving students at the mercy of decision-making that is often based on the advisor's needs in the lab, or the committee's political problems.
• Thesis: is a record only of the final, successful story and related significant issues.
• Defense: is mostly a formality, particularly the public part
  

UK

• Timeframe: 3 years mostly, 4 max.
• Projects: are assigned to you by the advisor who takes you into his/her lab (i.e. you get little choice at first, but it does mean you start working on it the day you show up)
  
• Funding: is SPARSE making spots harder to get, and the timeframe shorter
  
• Classes: aren't really worried about, since the UK undergraduate system gets people to approximately a Masters-level of focus
  
• Teaching responsibilities: are minimal. You have to do some TAing in labs, but really it mostly involves keeping the kids from setting things on fire with their bunsen burners.
  
• Departmental structure beyond classes: is more involved. HOWEVER you have no committee. The department head is often responsible for assessing quarterly reports and yearly checkups from each student, along with the advisor. This means you write up your progress every three months in thesis format. The 1st-year assessment involves writing a big review on your topic (thesis-intro-style), so you have essentially written a third of your thesis within the first year.
  
• Endpoints: are strictly defined by the 3-year timeframe. You can get one more year to write up if you need it, but you are normally not financially supported during that time. If nothing you did worked, despite your best efforts (or otherwise), you are still done after 3-4 years.
  
• Thesis: is a record of whatever you did that significantly contributed to the outcome of the 3 years. If it has to be a record of all the things you tried to do that didn't work, that's what it is.
• Defense: is pretty different. You submit your thesis to an internal and an external examiner. The internal is someone from the department who has nothing to do with your project and has never mentored you about it. The external is someone from anywhere, literally anywhere, who your advisor contacts to read your thesis. You meet with those two in a room for 2-3 hours where they can grill you about anything at all to do with your subject, whether it is related to your thesis or not. Usually the external is chosen carefully by your advisor as someone who would be interested in your research and sympathetic to its particulars. But sometimes they judge wrong and this person expects too much or too little which can screw you in various ways.

Personally, I thrived in the UK style environment, where the combination of my procrastinatory nature and my organizational OCD tendencies did well with the quarterly report thing. I also lucked out at having a mild-mannered, supportive advisor who let me do whatever I wanted, and a project that had enough backstory to provide a successful base of work and an opportunity for innovation. I ended up with three first author papers and a thesis that was just as solid as a 5-6 year USA thesis, as did most of my classmates. HOWEVER what I missed out on was that extra scientific maturity level and wherewithal that is gained by struggling through something for an extra two years. I had to develop those in my post-doc, and I was lucky to have supportive post-doc mentors (and an NRSA fellowship) to allow me that space to grow up.

Would I have "woken up" to my real potential, drive and obsession with this during my Ph.D. if I had gone to grad school in the US? Who knows. I do hope, though, that I can offer my grad students some structure by adapting the more frequent reporting and accountability aspects of my experience, which were so essential to getting me out the door with a full, published project in 2.9 years from my start date.

Science Baby Mama (with no kids)

Huh. I started reading and commenting on some blogs today since my cells need to hang out until tomorrow and my peptides need to lyophilize. I decided I would start my own blog a la FSP and see if I ever write in it. I'll try to keep a record of how things go as I start my first tenure-track faculty position at a major research university this fall. It can also be my public repository for my harebrained schemes.