Phenomenal science powers!

So you toil for 4+ years in graduate school, 4+ years as a post-doc, land your first academic gig. Now you get to do all this awesome science, right? Well, sorta…

Oy! 10,000 years in the cave of graduate school will give you SUCH a crook in the neck!

Oy! 10,000 years in the cave of graduate school will give you SUCH a crook in the neck!

Proposal gambit – Update 1

Last week I posted about my strategy for a proposal I’m just submitting. Pretty simple really, just using a publication in a post-publication peer review journal (F1000 Research) as the crucial piece of my preliminary data in my grant. Here’s an update on the process.

So, if you’re going to predicate an R01 submission on having a citation to a paper with a crucial set of preliminary data in it… don’t leave it until the last minute. I submitted my paper to F1000 Research on Thursday (one week prior to the submission date for my grant). They responded very quickly – next day, with requests for some minor changes and to send the figures separately (I had included them in the document). No problems, but then the weekend came up and I ended up getting everything back to them on Sunday evening. Fine. Monday came and went and I didn’t have a link. Also on Monday I was surprised because I was erroneously told that I had to have the absolute final version of my grant to our grants and contracts office that day. With no citation. I scrambled to make myself an arXiv account so that I could get it out that way (a good thing in any case). But turns out it was incorrect and I could still make minor modifications after that.

So yesterday (Tuesday) I pinged F1000 Research, politely and with acknowledgment that this was a short turnaround time, and mentioned that I wanted to put the citation in the grant. They replied on Wednesday morning apologizing for the delay (nice, but there was no delay- I was really trying to push things fast) and saying that the formatted version should be ready in a couple of days and GIVING ME A DOI for the paper! Perfect. That’s what I really needed to include in the grant.

So today the updated grant was actually submitted- a whole day early, probably a first. Now it’s just a matter of settling in until June when it will be reviewed. Of course, I still need to get my paper reviewed, but I think that won’t be a huge problem.

Overall this process is going swimmingly. And I’ve been really pleased with my interactions with F1000 Research so far.

Proposal gambit

I am currently (this minute… well, not THIS minute, but just a minute ago, and in a minute) in the throes of revising a resubmission of a previously submitted R01 proposal to NIH. This proposal generally covers novel methods to build protein-sequence-based classifiers for problematic functional classes- that is, groups of proteins that have a shared function but either are very divergent in their sequence (meaning that they can’t be associated by traditional sequence similarity approaches) or have a lot of similar sequences with divergent functions (and the function that’s interesting can’t be easily disambiguated).

I got good feedback from reviewers on the previous version (though I did not get discussed- for those who aren’t familiar with the process, to get a score- and thus a chance at funding- your grant has to be in the top 50% of the grants that the review panel reads, then it moves on to actual discussion in the panel and scoring). Their main complaint was that I had not described the novel method I was proposing in sufficient detail, and so they were intrigued but couldn’t assess if this would really work or not. The format of NIH R01-level grants (12 pages for the research part) means that to provide details of methods you really need to have published your preliminary results. Also- if it’s published it really lends weight to the fact that you can do it and get it through peer review (or pay your way into a publication in an fly-by-night journal).

So anyway. I’ve put this resubmission off since last year and I’m not getting any younger and I don’t have a publication to reference on the method in the proposal yet. So here’s my gambit. I’ve been working on the paper that will provide preliminary data and it was really nearly finished it just needed a good push to get it finalized, which came in the form of this grant. My plan is to finish up the last couple of details on the paper and submit it to F1000 Research because it offers online publication immediately with subsequent peer review. I’ve been intrigued by this emerging model recently and wanted to try it anyway. But this allows me to reference the online version very soon after I upload it (maybe tomorrow) and include it as a bona fide citation for my grant. The idea is that by the time it’s reviewed (3 months hence) it will have passed peer review and will be an actual citation.

But it’s a gambit. It’s possible that the paper will still be under review or will have received harsh reviews by the time the reviewers look at it. It’s also possible that since I won’t have a traditional journal citation in text for the proposal- I’ll need to supply a URL to my online version- that the reviewers will just frown on this whole idea and it might even piss them off making them think I’m trying to get away with something (which I totally am, though it’s not unethical or against the rules in any way that I can see). However, I’m pretty sure that this is a lot more common on the CS side (preprint servers, and the like) so I’m betting on that flying.

Anyway, I’ll have an update in 3+ months on how this worked out for me. I actually have high hopes for this proposal- which does scare me a little. But I’m totally used to dealing with rejection, as I’ve mentioned before on numerous occasions. Wish me luck!

A Fine Trip Spoiled

I had a dream the other night that inspired this comic. My dream was about waiting for a connecting flight. I decided to take it easy and do something fun, then realized that my flight was leaving soon and I was nowhere near the gate. Then I got on a train and realized I was going the wrong direction. Anyway, I woke up to the realization that I’d relaxed and done fun stuff most of the weekend (I did work some in the evenings) and that I had an unfinished grant that was still due this week. As it turned out I finished up my grant quite nicely despite the slacking off- or maybe even because of the slacking off. But it gave me the inspiration for this comic.

You see, writing and submitting a grant proposal is a lot like planning for a vacation that you’ll probably never get to take. The work you’re proposing should be fun and interesting (otherwise, why are you trying to get money to do it, right?) but your chances are pretty slim that you’ll ever get to do it- at least in the form that you propose it. I’ve started to think of the grant process as a long game (see this post from one DrugMonkey)- one where the act of writing a single grant is mainly just positioning for the next grant you’ll write down the line. Writing grants give you opportunity to come up with ideas, to consolidate your thoughts, and think through the science that you want to do and how you want to do it. The process can push you to publish your work so that you can cite it as preliminary data. And it can forge long-lasting collaborations that go beyond failed proposals (though funded proposals certainly help to cement these relationships in a much more sure way).

I think “A Fine Trip Spoiled” may be the title of my autobiography when I get rich and famous.

GrantWritingTravel_2

Dealing with Academic Rejection

Funny, it feels like I’ve written about exactly this topic before…

I got rejected today, academically speaking*. Again. I was actually pretty surprised at how

"Not Discussed", again

“Not Discussed”, again

nonplussed I was about the whole thing. I’ve gotten mostly immune to the being rejected- at least for grant proposals and paper submissions. It certainly could be a function of my current mid-career, fairly stable status as a scientist. That tends to lend you a lot of buffer to deal with the frequent, inevitable, and variably-sized rejections that come as part of the job. However, I’ve also got a few ideas about advice to deal with rejection (some of which I’ve shared previously).

Upon rejection:

  1. Take a deep, full breath: No, it won’t help materially- but it’ll help you feel better about things. Also look at beautiful flowers, treat yourself to a donut, listen to a favorite song, give yourself something positive. Take a break and give yourself a little distance.
  2. Put things in perspective: Run down Maslow’s hierarchy of needs. How you doing on there? I’ll bet you’ve got the bottom layers of the pyramid totally covered. You’re all over that. And it’s unlikely that this one rejection will cause you to slip on this pyramid thing.
  3. Recognize your privilege: In a global (and likely local) perspective you are extremely privileged just to be at this level of the game. You are a researcher/academic/student and get to do interesting, fun, rewarding, and challenging stuff every day. And somebody pays you to do that.
  4. Remember: science is ALL about failure. If you’re not failing, you’re not doing it right. Learn from your failures and rejections. Yes, reviewers didn’t get you. But that means that you need to do a better job of grabbing their attention and convincing them the next time.
  5. Recognize the reality: You are dealing with peer review, which is arbitrary and capricious. Given the abysmal levels of research funding and the numbers of papers being submitted to journals it is the case that many good proposals get rejected. The system works, but only poorly and only sometimes. And when everyone is scraping for money it gets worse.
  6. Evaluate: How do YOU feel about the proposal/submission: forget what the reviewers said, forget the rejection and try to put yourself in the role of reviewer.
    This is YOU on the steps of the NIH in 6 months! Winning!

    This is YOU on the steps of the NIH in 6 months! Winning!

    Would YOU be impressed? Would YOU fund you? If the answer is ‘no’ or ‘maybe’ then you need to reevaluate and figure out how to make it into something that you WOULD or decide if it’s something you should let go.

  7. Make plans: Take what you know and plan the next step. What needs to be done and what’s a reasonable timeline to accomplish this. This step can be really helpful in terms of helping you feel better about the rejection. Instead of wallowing in the rejection you’re taking ACTION. And that can’t be a bad thing. It may be helpful to have a writing/training montage to go along with this since that makes things more fun and go much faster. Let me suggest as the theme to Rocky as a start.

I’m not saying you (or I) can do all of these in a short time. This process can take time- and sometimes distance. And, yes, I do realize that some of this advice is a little in the vein of the famous Stuart Smalley. But, gosh darn it, you ARE smart enough.

stuart_smalley

*For those interested, I submitted an R01 proposal to the NIH last February. It was reviewed at the NIH study section on Monday and Tuesday. The results of this review were updated in the NIH submission/tracking system, eRA commons, just this morning. I won’t know why the proposal was ‘not discussed’ for probably a week or so, when they post the summary of reviewers’ written comments. But for now I know that it was not discussed at the section and thus will not be funded.

At this point I’ve submitted something like 8 R01-level proposals as a PI or co-PI. I’ve been ‘Not Discussed’ on 7 of those. On the eight I got a score, but it was pretty much the lowest score you can get. Given that NIH pay lines are something around 10% I figure that one of the next 2 proposals I submit will be funded. Right? But I’ve been successful with internal funding, collaborations, and working on large center projects that have come to the lab- so I really can’t complain.

New biosketch format for NIH

Just got word of this from the Twitters- the NIH is announcing rollout of a new biosketch format for grant applications. I thought I’d summarize the information about it here to make things easy.

  1. Starting for grants that would be funded in 2016 (so anything you apply for in 2015 will have this, essentially)
  2. Will be a five page limit (as opposed to 2 page for current format)
  3. Will NOT include a ‘bare’ list of 15 publications
  4. Now includes a new list of up to 5 of your “contributions to science”, which can include up to 4 citations each (your own presumably). So that’s a total of 20 citations you can have.
  5. You will be able to include a link to your full citation list in an online database (NIH resources sciENcv or My Bibliography are mentioned but could be others I guess)
  6. Here’s a template that includes an example new biosketch
  7. More information can be found in the announcement here from the NIH on Salley Rockey’s blog
  8. As it’s being rolled out the requirement for the new format will be stated in the RFA – SO LOOK FOR THIS IN ALL RFAs from here out. Two pilots already have it RFA-CA-13-501 and  RFA-CA-13-502

The upsides: In my opinion the addition of the contributions to science will be the biggest one and should allow you to really highlight your publications (or lack thereof) in appropriate context. Plus space for moar buzzwords!

The downsides: It’s gonna be a pain to write (like a mini grant in there) and reviewers won’t read this one either.

Goodbye to two good friends

(Note: this post isn’t nearly as sad as it might seem from the title or the introduction below)

Yesterday I lost two close friends. We had been friends for five years, though our relationships had extended a tumultuous 10 or so months before that. Given that we still have unfinished business I expect our friendships to straggle on a little longer. But really, it’s over. My friends have helped me grow in a number of important ways- become more mature, deal with different personalities, forced me to communicate more clearly and to take criticism in a constructive light. The friendships both challenged me in different ways and supported me through a fragile time in my life. I will miss both of these friends for some different reasons- and some of the same reasons.

Like many friendships they have ended because of what other people thought about them. A small number of people had comments on our friendship- some of the comments, upon reflection, were probably well-placed, others certainly were not. But that outside influence is what really broke us apart. I hope that we can become friends again in the future- but we both will have changed so much in the intervening time that we may well be unrecognizable to each other. Still it would be nice to continue this friendship.

Bye Bye

Farewell Systems Biology of Enteropathogens and Systems Virology Centers – you will be missed but not forgotten.

Here are a few mementos of our time together….

  1. Ansong C, Schrimpe-Rutledge AC, MitchellH, Chauhan S,Jones MB, Kim Y-M, McAteerK, Deatherage B, Dubois JL, Brewer HM, Frank BC, McDermottJE, Metz TO, Peterson SN, Motin VL, Adkins JN. A multi-omic systems approach to elucidating Yersinia virulence mechanisms.Molecular Biosystems 2012. In press.
  2. McDermott JE, Corley C, Rasmussen AL, Diamond DL, Katze MG, Waters KM: Using network analysis to identify therapeutic targets from global proteomics dataBMC systems biology 2012, 6:28.
  3. Yoon H, Ansong C, McDermott JE, Gritsenko M, Smith RD, Heffron F, Adkins JN: Systems analysis of multiple regulator perturbations allows discovery of virulence factors in SalmonellaBMC systems biology 2011, 5:100.
  4. Niemann GS, Brown RN, Gustin JK, Stufkens A, Shaikh-Kidwai AS, Li J, McDermott JE, Brewer HM, Schepmoes A, Smith RD et alDiscovery of novel secreted virulence factors from Salmonella enterica serovar Typhimurium by proteomic analysis of culture supernatantsInfect Immun 2011, 79(1):33-43.
  5. McDermott JE, Yoon H, Nakayasu ES, Metz TO, Hyduke DR, Kidwai AS, Palsson BO, Adkins JN, Heffron F: Technologies and approaches to elucidate and model the virulence program of salmonellaFront Microbiol 2011, 2:121.
  6. McDermott JE, Shankaran H, Eisfeld AJ, Belisle SE, Neumann G, Li C, McWeeney SK, Sabourin CL, Kawaoka Y, Katze MG et alConserved host response to highly pathogenic avian influenza virus infection in human cell culture, mouse and macaque model systemsBMC systems biology 2011, 5(1):190.
  7. McDermott JE, Corrigan A, Peterson E, Oehmen C, Niemann G, Cambronne ED, Sharp D, Adkins JN, Samudrala R, Heffron F: Computational prediction of type III and IV secreted effectors in gram-negative bacteriaInfect Immun 2011, 79(1):23-32.
  8. McDermott JE, Archuleta M, Thrall BD, Adkins JN, Waters KM: Controlling the response: predictive modeling of a highly central, pathogen-targeted core response module in macrophage activationPLoS ONE 2011, 6(2):e14673.
  9. Aderem A, Adkins JN, Ansong C, Galagan J, Kaiser S, Korth MJ, Law GL, McDermott JG, Proll SC, Rosenberger C et alA systems biology approach to infectious disease research: innovating the pathogen-host research paradigmMBio 2011, 2(1):e00325-00310.
  10. Buchko GW, Niemann G, Baker ES, Belov ME, Heffron F, Adkins JN, McDermott JE (2011). A multi-pronged search for a common structural motif in the secretion signal of Salmonella enterica serovar Typhimurium type III effector proteinsMolecular Biosystems. 6(12):2448-58.
  11. Lawrence PK, Kittichotirat W, Bumgarner RE, McDermott JE, Herndon DR, Knowles DP, Srikumaran S: Genome sequences of Mannheimia haemolytica serotype A2: ovine and bovine isolatesJ Bacteriol 2010, 192(4):1167-1168
  12. Yoon H, McDermott JE, Porwollik S, McClelland M, Heffron F: Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar TyphimuriumPLoS Pathog 2009, 5(2):e1000306.
  13. *Taylor RC, Singhal M, Weller J, Khoshnevis S, Shi L, McDermott J: A network inference workflow applied to virulence-related processes in Salmonella typhimuriumAnnals of the New York Academy of Sciences 2009, 1158:143-158.
  14. *Shi L, Chowdhury SM, Smallwood HS, Yoon H, Mottaz-Brewer HM, Norbeck AD, McDermott JE, Clauss TRW, Heffron F, Smith RD, and Adkins JN. Proteomic Investigation of the Time Course Responses of RAW 264.7 Macrophages to Salmonella Infection. Infection and Immunity 2009, 77(8):3227-33.
  15. *Shi L, Ansong C, Smallwood H, Rommereim L, McDermott JE, Brewer HM, Norbeck AD, Taylor RC, Gustin JK, Heffron F, Smith RD, Adkins JN. Proteome of Salmonella Enterica Serotype Typhimurium Grown in a Low Mg/pH Medium. J Proteomics Bioinform. 2009; 2:388-397.
  16. *Samudrala R, Heffron F, McDermott JE: Accurate prediction of secreted substrates and identification of a conserved putative secretion signal for type III secretion systemsPLoS Pathog 2009, 5(4):e1000375.
  17. *McDermott JE, Taylor RC, Yoon H, Heffron F: Bottlenecks and hubs in inferred networks are important for virulence in Salmonella typhimuriumJ Comput Biol 2009, 16(2):169-180.
  18. *Ansong C, Yoon H, Norbeck AD, Gustin JK, McDermott JE, Mottaz HM, Rue J, Adkins JN, Heffron F, Smith RD: Proteomics Analysis of the Causative Agent of Typhoid FeverJ Proteome Res 2008.

*these were really from slightly before our time- but I’ll count them there anyway

A 12 step program for writing grant proposals

Recent experience talking here (interested, non-Science types, there’s a short explanation to give context at the end).

  1. Boundless, unfounded optimism: Yes! You’ve just had the greatest idea EVER! Sure it’s lacking a few details, but the reviewers are gonna love it! The whole idea is there, it just needs a little writing and you’ll be done. This time, for sure you’ll be able to knock it out quick and without much effort since it’s such a great idea. Just great.
  2. Period of procrastination: Since it’ll be so easy you don’t have to worry about it right now. Sit back and relax since you’ve still got loooooooooads of time before this baby is due. Maybe talk with some people about how you’ll need to start working on it sometime, and about how great it is, but that you’re not worried about it now because it’s not due anytime soon.
  3. Panic: HOLY SH*T! What day is it? How did that happen?! Can it be that the due date is actually that close? It’s impossible- better check the calendar and the call a few more times. Gulp.
  4. Outline stage: What were those great ideas you had early on? Oh yeah- put those down on paper. Wow. Somehow they seemed a lot grander in your head. They look a little thin on paper actually. Are you sure that’s all? Maybe you forgot that one cool part.
  5. Cut-and-paste: Take text from wherever you can, manuscripts, other proposals, your grocery lists, and put it down in the sections that kinda make sense. It makes you feel a lot better to have something on paper and you can fill it in later, right?
  6. Sculpting: Now take all that great raw material you have and make it look like Michaelangelo’s David. Hmmmm…. that’s not quite right- it looks more like Frankenstein’s monster’s ugly cousin. Well, keep sculpting- the more sculpting the better. Put hours into that transition between Aims 2 and 3. It’s super important that you phrase it perfectly so you can rip it all apart in step 8.
  7. Imposter’s syndrome: “What am I even doing here?” You’ve got the simplest idea coupled with the most contrived, Rube Golbergian implementation. Nothing really fits together into a coherent picture. And it has no point. You wouldn’t even believe this crap if you were the reviewer.
  8. Demolition derby:  A flash of inspiration and you see how all the pieces fit together. Unfortunately it requires ripping everything apart and rearranging your aims, renumbering your figures, and stitching it all back together to make it look like you meant it to go that way the whole time. Oh, and you’ve got a little under 24 hours to accomplish this.
  9. Amazing period of focus and productivity: Where did that come from and why has it been hiding for so long?! You just knocked out 5 pages of text in 3 hours and it looks great. It would have been REALLY nice to be at this point a wee bit earlier in the process.
  10. Rose colored glasses: Yes. It’s finished and it’s perfectly wonderful! There could be some blemishes, or some outright holes. It doesn’t matter now ’cause you can’t do a damn thing about it. Too late. So it’s all wonderful and the best idea ever!
  11. Last minute scramble: Generally it involves either figure or citation formatting- formatting of some sort. And it’s absolutely incomprehensible why it’s screwing up now. Why won’t EndNote work the way it was designed to? You’ve got 2 hours before your grant administrator has a friggin’ stroke and you can’t get X to work correctly (where ‘X’ is some formerly inconsequential software feature that just wants attention- but you can’t ignore it at this point)
  12. Now where did that focus and productivity go? It’s off. Submitted safely at the funding agency. A warm sense of accomplishment in your belly. The drive to do more still rattling around in your bones. OK- now that you found that amazing kernel of productivity that you didn’t remember existed it should be easy to get all that stuff done that you put off during your proposal process. If only you weren’t so tired. And apathetic. *Sigh*

Here’s a little background for those of you not so “fortunate” to be tied to the whims and whimsey of academic funding (and, importantly, are still reading this). Academic researchers (and those in national labs, like me) have to, for the most part, fund the research they do by applying for grants from funding agencies. These are governmental agencies like the National Institutes of Health (NIH), National Science Foundation (NSF), the Department of Energy (DOE), and others, or non-governmental funding agencies (private philanthropic funds, the Gates Foundation, etc.) and they issue ‘calls’ for proposals that specify the kinds of research they’re looking for. There are deadlines associated with these calls and some recur on a regular basis but others are single-shot. After you submit your proposal the agency will review it for merit using criteria generally outlined in the call. NIH does this with an established peer review process. If you are so lucky to be funded then you get to do what you propose- and live for a little longer in the academic research game. Yay!

The 5 stages of reading reviews

In many parts of our lives we have to receive criticism. Sometimes directly, from someone like a boss telling us we screwed up, and sometimes indirectly, in the form of written reviews from anonymous reviewers. In science, reception of criticism, ingestion, and self-improvement as a result are a part of the gig. A BIG part of the gig. We submit papers that get reviewed (that is, criticized) by at least two peer reviewers. We submit grant proposals that get shot down. We present ideas that rub somebody the wrong way- so they tell us in public ways. I’ve had a lot of experience at this. A lot.

Today I found that the renewal of a collaborator’s 30 year old NIH R01 (it’s been renewed 6 times before) that I wrangled myself a co-PI spot on was not discussed in study section. This happens when it gets scored poorly by reviewers and so doesn’t move to the stage of open discussion when the group of reviewers meets. It means that the grant will not be funded and generally that it didn’t make the top 50% of proposals for that round. It stinks.

Here’s how I often react (riffing off of the 5 stages of grief):

  1. Denial. When I first get a poor grant review I often think, “hmmm… that’s weird, there must have been some kind of mistake. I’ll talk to the program officer and get this all cleared up right away”. Loosely translated this means, “my proposal is so good there’s no possible way it could have been not discussed in study section so the only reasonable explanation is that there was a terrible, and highly unlikely, clerical error.” Yeah. Right.
  2. Anger. “Those STUPID nitwits! How could they be sooooo stupid as to not see the brilliance of my obviously brilliant study? What total imbeciles. It’s a good thing that it’s all their fault.”
  3. Bargaining. “OK. You know what, I’ll do better. I’ll do better and write better and experiment better and this will all go away. It has to, right?”
  4. Depression. “I’m a failure and nobody likes me. Also, I can’t do science and I’m an imposter. Everyone else is way smarter than I am. Holy crap what am I going to do with myself now?”
  5. Acceptance. “Right. So I see the points that I need to fix. And I recognize the points that the reviewers just didn’t get. Since they didn’t get them it means that I didn’t communicate them well enough. I can fix this.”

Of course, getting through these to stage 5 is the goal. That’s where the rubber meets the road. How do I take what someone else has criticized me on, strip away the emotional attachment (they’re no attacking me), triage the good from the bad (face it, sometimes reviewers are not paying attention), and apply what you’ve learned to improve what you’ve produced. This process, and the uncomfortable stages that accompany it, has led me to write papers, improved the papers I’ve already written, spawned new ideas, and promoted self realization and betterment. Learning from how others see you is a critical and under-appreciated skill.

 

Finding your keys in a mass of high-throughput data

There is a common scientific allegory that is often used in criticism of discovery-based science. A person is looking around at night under a lamppost when a passerby asks, “What are you doing?”. “Looking for my keys” the person replies. “Oh, did you lose them here?” the concerned citizen. “No”, the person replies, “I lost them over there, but the light is much better here”.

cropped-night_tree_7.jpg

The argument as applied to science in a nutshell is that we commonly ask questions based on where the ‘light is good’- that is, where we have the technology to be able to answer the question, rather than asking a better question in the first place. This recent piece covering several critiques of cancer genomics projects is a good example, and uses the analogy liberally throughout- referencing its use in the original articles covered.

One indictment of the large-scale NCI project, The Cancer Genome Atlas (TCGA) is as follows:

The Cancer Genome Atlas, an ambitious effort to chart and catalog all the significant mutations that every important cancer can possibly accrue. But these efforts have largely ended up finding more of the same. The Cancer Genome Atlas is a very significant repository, but it may end up accumulating data that’s irrelevant for actually understanding or curing cancer.

Here’s my fundamental problem with the metaphor, and it’s use as a criticism of scientific endeavors such as the TCGA. The problem is this: we don’t know where the keys are a priori, the light is brightest under the lamppost, we would be stupid NOT to look there first. The indictment comes post-hoc, and so benefits from knowing the answer (or at least having a good idea of the answer). Unraveling this anti-metaphor: we don’t know what causes cancer, genomics seems like a likely place to look and the we have the technology to do so, and if we started by looking elsewhere critics would be left wondering why didn’t we look in the obvious way. The fact that we didn’t find anything new with the TCGA (the jury is quite out on that point) is still a positive step forward in the understanding of cancer- it means that we’ve looked in genomics and haven’t found the answer. This can be used to drive the next round of investigation. If we hadn’t done it, we simply wouldn’t know, and that would prevent taking certain steps to move forward.

Of course, the value of the metaphor is that it can be used to urge caution in investigation. If we have a good notion that our keys are not under the light, then maybe we ought to be thinking about going to get our flashlights to look in the right area to start with. We should also be very careful that in funding the large projects to look where the light is, that we don’t sacrifice other projects that may end up yielding fruit. It is true that large projects tend to be over-hyped and the answers are promised (or all but) before they’ve even begun to be answered. Part of this is necessary salesmanship to be able to get these things off the ground at all, but overselling does not reflect well on anyone in the long run. Finally, the momentum of large projects or motivating ideas (“sequence all cancer genomes”) can be significant and may carry the ideas beyond what is useful. When we’ve figured out that the keys are not under the lamppost we had better figure out where to look next rather than combing over the same well-lit ground.

Part of this piece reflects very well on work that I’m involved with- proteomic and phosphoproteomic characterization of tumors from TCGA under the Clinical Proteomics Tumor Analysis Consortium (CPTAC):

“as Yaffe points out, the real action takes place at the level of proteins, in the intricacies of the signaling pathways involving hundreds of protein hubs whose perturbation is key to a cancer cell’s survival. When drugs kill cancer cells they don’t target genes, they directly target proteins”

So examining the signaling pathways that are involved in cancer directly, as opposed to looking at gene expression or modification as a proxy of activity, may indeed be the way to go to elucidate the causes of cancer. We believe that integrating this kind of information, which is closer to actual function, with the depth of knowledge provided by the TCGA will give significant insight into the biology of cancer and it’s underlying causes. But we’ve only started looking under that lamppost.

So, the next time you hear someone using this analogy as an indictment of a project or approach, ask yourself if they are using this argument post-hoc? That is, “they looked under the lamppost and didn’t find anything so their approach was flawed”. It wasn’t- it was likely the clearest, most logical step, that was most likely to yield fruit given a reasonable cost-benefit assessment.