over at ScienceBlogs.

I admit I got a little excited when I saw a Twitt RT’d earlier today from Noah Gray.

Soon to be in press: Strong evidence supporting the neurogenesis-depression hypothesis, from @jsnsndr: http://j.mp/qn6fyD

I’m sort of vaguely aware and following a literature that is trying to establish a causal link between depression and alterations in hippocampal neurogenesis, proliferation and general plasticity based on creating new, functioning cells.

This is generally a non-human literature, typically in mouse models and….highly correlative.

With respect to this latter, the state of the art for a long time has been to treat markers of neurogenesis (there are many stages and concepts here which I’ll glomp under one heading. Follow the link in the tweet to the Functional Neurogenesis blog for all your background reading) as dependent variables to be reported. Not manipulated. This is, perhaps obviously, the case for any post-mortem human brain analysis but also for many animal models to date. In essence, you do some thing to the animal and then look at the markers afterward. Then you report whether neurogenesis is up, down or unchanged. So far so good. But this approach doesn’t quite get at the question of causality which is important if we think that altering the effects on neurogenesis (say by a drug or behavioral therapy*) would have a beneficial effect on the affective disorder itself. It could, after all, be a result of depression with no causal role.

There is also a question of whether a given animal model is a valid representation of a human affective disorder. Here we can think about issues of predictability- does it matter, for example, what the mouse model looks like if the ability to predict what anti-depression, anti-anxiety or anti-mania drugs will work (ultimately) in the clinic is high? Of course not…if your goal is drug development.

If you goal is understanding the neurobiological underpinnings of the human disease, well, you want to be careful.

My take on the current state of the nonhuman models of depression is that we are not yet at the point where we have high confidence in calling any model “depression”. They are models, they have various points of high correspondence to human illness but they also have limitations. They are, in cases, highly predictive of drugs which will ultimately prove useful in the clinical setting.

So I confess that when I see a scientist (Noah Gray is, after all, a scientist by training even if he currently inhabits an Editor job) tweet “strong evidence”, well, I’m looking for some coolio stuff.

Following the link to the post on Functional Neurogenesis, I found the post title to include the word “confirmed”! yay, let’s read!!!!

So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice).

“in mice”. Fuck.

Okay, so let’s scratch the “strong evidence” and the “neurogenesis-depression hypothesis confirmed stuff” for now.

Pretty cool paper, by the sounds of it. Again, from my distinctly nonspecialist position, this is the next step. Manipulations of the neurogenesis processes as independent variables to provide stronger evidence that there is a causal relationship. Between these processes and a behavioral or physiological phenotype. I can’t really say where this all fits into the “first demonstration” or “best demonstration” or “critical demonstration” picture so as to give you a valance for exactly how cool it is. But I do recognize that these approaches are the next place the field needs to go to better establish that the neurogenesis-depression hypothesis could be “confirmed”.

Me, until the state of animal models are better and more convincingly established, I want to see data in human subjects before I am willing to concede either “confirmation” or “strong evidence”.

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ps. Do take a read over the Functional Neurogenesis blog. It is really quite good and this area of neuroscience is fun. Many of you may still labor under the old belief that the adult brain doesn’t grow new neurons and can’t repair itself. It’s no liver, but the brain does have some capacity to generate new neurons.

Well, well, well. Hard on the heels of my interpretation of OER head Sally Rockey’s comment about R21s having lower success rates as “Kill the R21“, what should appear but a note from NHLBI (thanks to PiT for making me aware).

The R21 grant mechanism is intended to encourage exploratory and developmental research by providing two years of support for the early and conceptual stages of research project development. The NIH has standardized the Exploratory/Developmental Grant (R21) application characteristics, requirements, preparation, and review procedures in order to accommodate investigator-initiated (unsolicited) grant applications.

The R21 grant is meant to facilitate the award of larger regular research project grant (R01) applications by providing investigators with limited funds and time to pursue initial studies to obtain preliminary data for larger, more fully developed research projects. However, the NHLBI has determined that this grant mechanism is not having the effect or the impact on its research grant portfolio in the manner for which it was originally intended.

Consequently, the NHLBI will no longer accept investigator-initiated R21 applications in response to the NIH’s Parent Funding Opportunity Announcement (FOA), NIH Exploratory Developmental Research Grant Program (Parent R21). Investigator-initiated R21 applications will not be accepted for review and funding beyond Fiscal Year 2012. Therefore, the last receipt dates for NHLBI investigator-initiated R21 grant applications are October 16, 2011 for new applications and November 16, 2011 for resubmission (amended) applications.

No additional word as to why they think it is not having the intended effect.

Nor, of course, what they might have considered as alternative strategies to get the allegedly intended effect. ’cause you see where I’m going here, right?

If you have a desired goal, and the thing you thought would accomplish that goal isn’t getting the job done, you might want to fix or replace it. Otherwise someone might conclude you aren’t really interested in the goal in the first place. Or that you are perhaps no longer interested in a goal that you previously had established.

As you know, Dear Reader, I am of the opinion that there is nothing structurally wrong with the idea of the R21, in fact I think it is a great idea. The problem is that study sections are not, and perhaps never were, able to get their collective heads into the game.

This is not entirely the fault of study section members. If there was one single meta-review issue (having to do with the process of review rather than the actual review of proposals) that ate up the most time in my collective experiences on sections to date it is the intent of the R21 mechanism. Reviewers are capable of altering their behavior and many, if not most, are trying hard to do the job they think they have been set. The trouble is, the NIH is very loathe to address certain (not all, which is what makes it odd) issues. Such as what in the hell the R21 is for. Exploratory? Developmental? High risk/High reward? JuniorMint Starter Grant? Are they serious about the no-preliminary-data thing? how can they be when the “best” grants all have supporting evidence…? Etc.

It is my belief that the NIH should have stepped in a long time ago and fixed the review of R21s. Perhaps by putting them in their own sections. Perhaps by eliminating Preliminary Data. Perhaps by a series of reviewer instructions. Or, maybe, by prioritizing any R01 that arose from a successful R21 interval? Or maybe, just maybe, merely by pointing out all along the way how R21 scores were shaking out, telling study sections they weren’t (obviously) doing the intended job of treating it like a different mechanism from the R01 and urging them to do better. It is also my prediction that the NIH could fix a lot of the bad study section behavior just by shining a bright light upon it.

Throwing up their hands and closing out the mechanism is no solution.

Nor is it a solution, I would venture, to replace the R21 with some other mechanism without fixing the root problems. Take note of the long failed history of the R29/FIRST, NI checkbox, ESI focus, etc attempts to help out the junior investigators. It has quite obviously been an issue with the NIH since at least the 80s, going by their attempts at structural fixes. None of that kept study sections from beating up the junior faculty to an unfair degree. Why didn’t they try to fix the behavior of study sections first?

It’s funny. I was just being regaled by a Program type in a somewhat different context about how great the ARRA experience was. Two years, up and out! Try it out and cut it off if it isn’t working! Let’s not jump into these 5 year plans that slog along fruitlessly in the second half. I’m paraphrasing but this was the essence. This kind of thinking should shift Program my way….towards favoring even more R21 awards.

Not towards killing the mechanism off.

RIP, R21, RIP.

GertyZ has a new post up at Balanced Instability which discusses the joys of Indirect Costs in the context of major grant awards, for our purposes we’ll focus on the NIH grant.
This is not a mere inconvenient detail of little direct importance to the PI, nor is it merely a topic for “Do it to Julia!” type solutions to the
A Twitt-scussion blew up [PP, avert your eyes, everyone else: @GertyZ, @profgears, @DoctorZen, @namnezia, @biochemmebelle, @multi_cellular, @salsb] which focused on the disposition of equipment when a PI left one University to take up a job at another. As we’ve discussed on several occasions, the NIH grant is awarded to the University or other Institution, not the PI who is named in (and in most cases wrote) the application. That means the starting position is quite simple:

The. University. Owns. EVERYTHING. Up to them to set policy RT @saban_lab but if you move will they hold on to that “stuff”?

Read the rest of this entry »

Hitting your marks

July 10, 2011

I am not a very scheduled person. No doubt to my detriment in many areas of life. I don’t make ’em, and I have a hard time sticking to externally imposed ones.

But I have almost always hit my grant deadlines.

In the generic, investigator-initiated grant submission to the NIH, schedule is not all that critical. If you miss a deadline, you just have to wait another 4 months. There are plenty of people who would actually advise you to miss a deadline if your grant is less than perfect.

I’ve always erred on the side of getting the application closed out and submitted. Some of this may be in recognition of my own procrastination. Submitting grant applications is hugely important in my job and maybe I figure that if I let myself skip a deadline that I will never make one again. Or maybe I see myself as someone who is a closer. As being good at getting the application finished and out the door at crunch time. Perhaps I take pride in that…

I’ve fielded questions now and again about PIs that are horrible at this. That seen to habitually fail to meet their grant deadlines. By this, I mean they’ve told their lab and/or admins that they are planning to submit..and the lab could seemingly make good use of another grant, pronto…and yet the proposal never gets submitted. I had a few queries during this recent submission round. The details vary but it all boils down to the same binary issue- you are either giving yourself a chance to win funding or you are not.

The most I can usually do is shrug my ignorance. I don’t understand this phenotype at all. Increasingly, I see trainees, and even techs and admins, that *know* that this is a problem. They are more cognizant these days that grants are hard to come by, that money is tight and safety nets are weak or nonexistent. So they start to worry..about their job, their science and even the personal well being or mental health of the PI.

I mutter platitudes. Maybe the PI got busy with kids or spouse or family. A divorce? Maybe she has other irons in the fire due to collaborative grant writing. Maybe he decided writing papers was critical. Maybe her read of summary statements finally got through to her that revising was a nonstarter. maybe some other proposal recently got scored in the fundable range?

None of these explain the repeat offender, of course.

But I have little else to offer.

Strategically, DearReader, there is a prescriptive lesson herein. Don’t do it. Don’t get a reputation with your lab or admins as a chronic misser-of-grant-deadlines. It makes them really nervous about your competence…and the lab’s medium-term prospects.

You don’t want your people losing confidence in you.

Kill the R21!!!!

July 9, 2011

The NIH’s R21 grant mechanism is called Exploratory/Developmental. It is limited* to $275K in direct costs, to be split across 2 years however the PI sees fit. It cannot be competitively renewed.

Sally Rockey, head of Extramural research at the NIH, has just Twitted, and then blogged, advice that applicants not try for the R21 because success rates are higher for R01s.

Ding, dong the R21 is dead.

This seems like a very bad move on the part of the NIH. But clearly, with a statement like this coming from the top applicants should pay heed. And stop writing R21s.

No biggie, right? The R01s are superior because the project can be proposed for 5 years, and competitively renewed after that. More importantly, there doesn’t seem to be any easier review of R21 vs R01s. These “Exploratory” and/or “Developmental” proposals are being sent back for revision and beat up for lack of preliminary data. Scores are being (to appearances) benchmarked against R01 applications.

And almost unbelievably, Program appears to be passing these over when using their discretion about funding priority and portfolio balance.

In theory, peer review should love these things. They are low risk! And we know the demand for ever increasing amounts of preliminary data for R01 applications is mostly about scientific “risk” and “feasibility”.

Program should likewise be pleased to take a low cost look at an idea before jumping in with 5 years of funding.

At about half the cost, the NIH could boost it’s R-grant funding stats by picking up 2 R21s for the price if one R01.

I have no idea what the NIH is thinking on this, but they have this 180 degrees wrong. They should be encouraging the funding of even more R21s.

In fact, I think there should be a boost given to the funding of any new R01 proposals that follow from a reasonably successful R21 award. (Where successful need not only mean papers but include the generation of solid preliminary data, models, systems, etc.) Among other benefits this would reduce the current reality that PIs generate substantial preliminary data for their next proposal(s) on the dime of their current projects**.

For this to work, the NIH would have to get real about making study sections review the R21 properly…but they should do that anyway. Rockey’s position should not be to pass along the bad news but to FIX THE PROBLEM, imnsho. If they made these unrevisable and banned preliminary data, that would work wonders.

Can anyone point to any decent reasons why the NIH would rather get rid of the R21?
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*currently. Previously it was limited to $100K per year for up to 3 years. There may be the occasional use via RFA that has these older parameters.

*technically illegal, btw.

A news bit by J. Mervis in Science reports a case in which a professor is suing her institution for reneging on financial commitments made during her recruitment.

Before making a final decision, Suter managed to bump up her start-up package by negotiating for another $100,000 from a pot of state money for computational biology. Then, satisfied that she had done the best she could, she accepted the job in June 2006, packed up, and headed west, primed to take the next step in her academic career.
Within weeks of her arrival, however, she found herself instead hurtling down an academic rabbit hole, as her start-up funds were diverted and her research plans delayed. Last summer, after exhausting other options, Suter hit bottom: She sued the university and six UTSA administrators and professors. She claims in her suit that the university failed to honor its commitment to support her research in a timely fashion and that two other male faculty members who arrived after her received money earmarked for her start-up package.

Good. I hope she wins.

Universities need to receive a little brush-back pitching on this issue. And it goes far, far beyond sex-discrimination that appears to be the part of this that is likely to get traction.

If I’ve said it once, I’ve said it a dozen times. If there is one singular issue, one, that dominates newly-hired Assistant Professor dissatisfaction with their new workplace it is the University reneging on promises apparently made during negotiations.

This why I tell all of those on the job market that they need to get *everything* in writing and not just from the Chair of the Department either. It has to be signed by the Dean or Vice Provost or ViceWhatnot that has the ultimate authority.

Otherwise, things have a way of magically disappearing on you. That lab space? Oh, that’s actually “shared space”. Nice big pool of cash? Did we mention we’re going to subtract your office furniture from that? and you have to pay for your phone line…and internet! Even worse are the crocodile tears expressed by the Chair when he has to report “well, the Dean didn’t go for it. He promised me! What can I do, my hands are tied..

Look, it doesn’t happen everywhere. Sometimes (most of the time?) everything works out great. But when push comes to shove, the University knows that they have you over a barrel and there really isn’t much you can do about it.

And we all know that in this day and age this stuff has major consequences. A few extra 10s of thousands of dollars can mean the difference between being able to generate the data to secure that NIH grant or not. It can be the difference between successful launch and dismal failure.

It is the responsibility of the candidate to make a deal for herself that is going to maximize her chances of making it to tenure and beyond. She may be fielding multiple offers and is taking each University at their word that they will provide what they are promising. It is likewise the minimum responsibility of the University to actually follow through.

I hope Suter wins her case. And that other Universities pay attention and stop reneging on their promises.