Alternative medicine is my fault

My boot camp instructor’s name is Keith and he’s about as hard-assed as they come. Love him. He reminds me of Jack Nicholson’s character in A Few Good Men. “You want me on that wall…you NEED me on that wall.”


Today as our class was grunting and sweating out jumping lunges and hill sprints, he told the class of an experiment he did on himself eliminating gluten from his diet for a month. Bottom line: he lost 9 pounds after a few days, and put that weight back on after two days of reintroducing gluten back into his diet. I’m with you dear reader, besides a handful of people with Celiac disease, I think the gluten free graze is a lot of BS. But Keith is not a fool. He knows he did not loose muscle or fat in 48 hours, that what he experiencing was shifts in water weight.  And he monitors his food and his weight very carefully.

Feh, you say, one anecdote, no controls, gluten diet stuff is still BS, not science.  Yeah, but it dawned me after class watching everyone come up to him with questions about what he ate that Keith is a master of outreach, by that I mean the part of science where epistemology happens.  As a scientist, I sorta feel we have the lock on epistemology, how we know what we know and create knowledge, but as we discussed on a PubStyle Science, the world is more complicated than the scientific method.  A critical part of creating knowledge happens when disinterested observers become convinced of one side of an argument.  That’s what I saw happening at boot camp, people who don’t care about randomized controlled trials were becoming convinced.  Hell, even me.

Point is, scientists and doctors can look down their noses at alternative medicine and old wives’ tales about what to eat, but it is our own fault for being so damn slow to examine issues that people care about.  Clinical research moves too damn slowly, and many people turn their noses up at the medical establishment in return.  

There is increasing attention to the need to accelerate medical research, but most efforts are misguided because they are intertwined with a capitalistic urge to develop new pharmaceuticals.  Yes, we need better drugs for horrible diseases.  But the Pharmaceutical Era has reached it’s peak and we could accelerate research if we started to think about anti-pharmaceutical approaches.  The gluten thing is a good example.  Testing a new drug requires much bureaucracy to protect people from harm.  More on this in another post, but what I call anti-pharmacy, eliminating compounds from consumption might move quicker.  “Don’t eat gluten for a month” is arguably inherently safer proposition than “take this drug for a month.” 

Another place where I see the general public doing an end run around the medical establishment is with pot.  I was recently in Colorado and visited a marijuana dispensary for the first time in my life.  (Purely for research purposes, I assure you!)  It was a store that had a history of operating in the medical marijuana space, and the staff explained in great detail the different medical benefits of different strains of pot.  This strain for arthritis, this strain for cancer.  Yes, yes, more untested BS, I’m with you, I’m with you.  But these folks know that different strains have different concentrations of different active ingredients, and the fact is that while controlled trials are years/decades away, people are experimenting on themselves.  While I agree that 90% of the claims will eventually be confirmed BS, I’d be willing to bet that there are scientifically confirmable truths in there somewhere.  There is no doubt that different chemical components will be found to have different effects and different toxicities.  It’s not the fault that people believe this stuff now, IMHO, it’s our fault in the medical community that we move so damn slow to test their hypotheses.  

Submitting a grant: is perfection too much to ask?

Does your grant have to be perfect to be funded?  @Drugmonkeyblog posted a thoughtful bunch of words that addresses this question, and a little back-and-forth on twitter was summarized by The Mistress of the Animals @pottytheron here.  I’m motivated to kill more electrons on the issue because honestly, DM and PT and I really I think agree on the important point, and I want the message to be clear:  submit your damn grant this cycle.


Silver?  Gold?  What the hell do these things mean?  @Pottytheron is spot on, there is no objective measure, only the inherently arbitrary opinions of study section.  We agree on the point that any grant submitted has a good chance of rejection for whatever reason.  And the *critical* part of academic success is to keep submitting.  Like shots on goal, you have to keep trying to win.

When I said, “silver proposals do not get fundable scores,” our apparent disagreement, I suggest, was the perception that I was referring to how “great” the science is.  Is this grant your “best” science?  I agree with DM, that question is not the most important one.  I super agree it’s not worth a grant cycle trying to improve the scientific concept of your grant.  We agree completely I think that too much time spent with tunnel vision on how brilliant your science is has diminishing returns.  What I mean by a “flawless” grant one that is holistic, that is, that treats each and every section (the budget, your biosketch, lay abstract, etc) with equal diligence.

A senior huge-ass deal PI told me once when I was a post-doc that grant proposals should be “round like a ball of wax,” and for years I could not figure out what the hell he meant.  I think his words though are key to understanding the paradox here– yes, I agree that a grant does not have to be perfect, and most importantly you should not spend an inordinate amount of time trying to make it so.  But at the same time, the grant must be large error-free.

Here is the rest of a post I had started earlier on the topic of writing a “perfect grant.”  What I point out are a few fatal flaws that have tanked grants of mine and those I’ve reviewed.


Wait a minute, Smarty Pants…how can I, a not-quite-perfect person manage to put together a perfect grant proposal?  Damned if I know, to be honest.  But there were a few pitfalls I wanted to broadcast to perhaps prevent one of you from falling into similar holes.

Review the work of your admin.  At least two grants in my stack last week were painfully trashed because of the same mistake on their face page:  the mechanism was incorrectly filled out.  Specifically, two grant that were otherwise perfectly fine independent investigator grants had “career development” mechanism listed on their face page, clearly in error. The grants staff thought hard about whether it would be acceptable to correct this error for the PI.

Focus your grant on your strongest suit.  On the twitter, I made the comment that it was not a good idea to put in a grant on a topic that is not your strongest suit.  I was recently on study section where PIs got tepid scores, in part perhaps because their grant focus was different from their most recently published papers.  Odesseyblog in fact has an outstanding post describing his success in just such a subject matter switch.  Indeed has a super post on his mid-career research change.  Reading his post I think only underscores my point that such transitions should be undertaken with care.  OB says that he already had an extremely successful research enterprise in one area so sure.  If you already have stable grant funding for one project, and if you results are pouring in to suggest that you are mining a good data vein, then sure.  By all means, branch out.  (This is what the NIH intended the R21 mechanism to be for, in my understanding.)  The struggle I witnessed reviewing grants were PIs that were *not* yet firmly successful in one subject  area.  They came across as diffuse, unfocused.  If your main lab effort is *not* fully funded, your proposals, I suggest, should hit different facets of a singular focus, and not be shots into different areas completely, where you have no track record, hoping to get lucky.

Don’t bring coals to Newcastle.  No matter how brilliant you think your ideas are, be very very cautious about trying to “improve” a well-known area.  Specifically, I am referring in my experience to well-studied genes and molecular pathways.  As a junior investigator, I felt I had some great data on a well-studied gene, and felt that adding a “new angle” on an old pathway would be greeted with enthusiasm.  I was wrong.  This is a dicey one because new angles on old pathways *can* be huge breakthroughs, clearly.  My mistake was that as a small lab investigator, I thought that my moderate amount of interesting new data would be enough to pique the interest of those in the field.  In a well-established field/gene/pathway, novel aspects typically need to be accompanied by overwhelmingly strong data, preferably using a novel technology.  I overestimated the impact a few interesting experiments could have on jaded reviewers, and I’ve seen others do the same.  The bar for getting interest is much lower if you have a previously unknown, or under studied pathway.

Take a leap forward.  Success in an application can in the big scheme be viewed as a careful balance between innovation and feasibility.  It must be clear to reviewers that you are able to accomplish what you set out to do.  Publications are key.  Preliminary data, invaluable.  Yes, paradoxically, if your entire grant is completely feasible, then it risks being labeled “incremental,” a death sentence.  The best grants have a leap forward in there somewhere.  Reviewers want to see that if the grant is funded, the work will bring a quantum leap forward…not just tie up some lose ends.

Yes, most of these points are arguable.  These guidelines are successfully broken by senior scientists on a regular basis.  Careful though… like old F. Scott said, “Let me tell you about the very rich.  They are different from you and me.” The points above are directed at junior level investigators, and are delivered with the understanding that I am really only describing my personal experiences.  As “advice” take it with a grain of salt and a healthy dose of skepticism.   Nullius in verba, after all.


Lessons from a study section

First, some news: I was told last week that my promotion to full professor was unanimously approved by the faculty council (yay, me)!!! The promotion still has to be approved by the dean, but it seems likely. It felt really nice in itself as a validation of years of work…but also, my Division chief told me that my letters of support were glowing, and that meant a lot because the people who wrote those letters were leaders in my field. As I told my chief, their glowing letters said as much about them as people as about me, but still it felt good. Celebrations have been made, champagne has been drunk. I have to watch it though…a good friend has noted that I already have increased the pompous greybeard pontificating. So, apologies in advance if I come across a little preachy, but here we go.


I just finished two days of conference calls as an ad hoc reviewer for a Department of Defense cancer grant program, and the experience was, as always, eye-opening. Our job was to screen hundreds of preliminary applications to see who would get an invitation to submit a full application. These preliminary applications were short: two pages of science, two pages of biosketch, and a page of statements regarding the relevance to the military population. Shorter than a full application, sure, but there were so many of them…my pile alone consisted of 85 applications. It is often said that being involved with the grant review process is important for young faculty to understand how the process works, and I couldn’t agree more. Even experienced scientists fell into holes–they received bad scores for reasons that seemed avoidable. Based on actual fails, here are my take-aways:

Take the career development plan seriously. This kills me a little inside, because this is grantsmanship pure and simple. There is a nugget of honest concern for the trainee and how they are being mentored and supported, and this needs to come across in the application. We screened a number of career development awards, and many grants were dinged because the Career Development Plan section was not sufficiently detailed or seriously considered. It doesn’t fly to spend a paragraph saying basically that your “career development” consists of working in the lab. A list of faculty for a mentorship committee and a schedule for meeting with them. A list of didactic courses that you will take. Defined journal clubs and lab meeting times. These are the elements of a serious career development plan.

Several applicants listed mentors at another institution. While this is not formally a problem, several reviewers, including myself brought this up as a concern. Sure with technology, mentorship can occur long distance, and if this is the case, spell this out in detail. Otherwise, identify a mentor at your own institution.

Educate yourself on clinical needs. There were two grants I crushed because while the cell biology was strong, it was clear that the PI had serious lack of understanding of the disease that they claimed their research was poised to benefit. As an MD that does basic science research, I’ve taken pains to establish my basic lab bona fides, and I’m sorry, but it was too painful to read interpretations of current clinical care that were frankly mistaken. Please please please discuss your grant with someone that is familiar with the disease you are addressing.
Two sections asked applicants to explain how their research would benefit military personnel and/or their families. Many grants were received devastating scores simply because applicants failed to address military benefit specifically.

Clarity is king. Don’t make your reviewers work to understand you. Not only do your reviewers have to read and understand your grant, they have to turn around and explain it to the larger group. Help them. Clarity is an art, sure, so if you are unsure, have other PIs read your grant. You don’t have to “keep it simple,” in fact, I would argue against 100% simple…in my opinion, a great grants, or any science presentation, starts simple, and end simple, but reveals complexity (reality) in the middle.

Keep applying.  Let me say what others might be reluctant to:  the process is fallible and there is no question that some applications get dinged by “bad luck.” We like to pretend that grants are reviewed objectively and that the scores represent some kind of God’s-eye evaluation of its merits, but who gets assigned to read your application, how rushed they were in reading it, and whether the grant is discussed early or late in the day all make an impact. There is a reviewer spectrum sweet spot–too little knowledge of the topic area and the reviewer can’t really appreciate it, or advocate for it to the panel. To close a working knowledge of the area, and small problems can become a topic of extended discussion, something that nearly always drags down scores.

The cold truth is that reviewers are looking for any excuse to destroy your grant. Some may seize on the randomness in the system to call the entire grant process a crap-shoot, but it’s not true. Yes, the competition is fierce. Reviewers want to like your grant, but you have to help them. You will be punished if you don’t take each and every section of the proposal seriously. Your application has to be flawless.

Next time: hints on how to write a flawless proposal.

Facebook Research is like Tuskegee Experiment? Not.

Let’s try this again..

I agree with Dr. Isis that comparing the Facebook research study with the Tuskegee experiment is bananas.  I understand people being upset by the lack of informed consent, but an IRB in this case would consider the degree of potential harm that could be done, e.g. dying of tuberculosis versus reading a sad text on your timeline.  That is what would be considered “minimal risk,” and in some cases informed consent is not considered absolutely necessary.  Facebook manipulates us all the time so I’m not sure this has done any more harm that the usual soul destroying that goes on.  Certainly human subjects issues are worth discussing..

Reflections on loving small science in the cold room

Sorry for the delay, dear readers.  Lately, I’ve been feeling like Howard the Duck.  “Trapped in a world he never made!”  A brief chat with a colleague stirred up my ambivalent feelings about Big Science:  awe mixed with skepticism, and spurred this made me contemplative about my own start in lab…


Saw a colleague yesterday headed off to an NIH study section convened on some kind of crazy idea to sequence single neurons from all parts of the brain.  After a briefly swinging my…knowledge base…a little bit, shook my head at the idea, “Wow, you neuro guys are crazy ambitious!”  It made me think about the contrast between modern biomedical research, and the kind of science I fell in love with.

I’ve loved learning about science for as long as I can remember, but it first dawned on me that I liked life in the lab while a college student labeling Eppendorf tubes in a cold room on 168th street. Years earlier, my 6th grade teacher Mr. Petro-Roy let me take home some beat up astronomy books he was using as bases for a ball game. I’ll never forget what he said when he saw I was assigned to his class, “how did I get blessed with you?!”  Important encouragement for a poor kid with no confidence.  In 8th grade, my science teacher, Mr. Vreeland, would have the class packed up and ready to go out the door a few minutes before the bell every day, and somehow it became our ritual that I would try and stump him with a question.  I loved that.  He seemed to too.  About 10 years ago, I heard that Mr. Vreeland had died.  I get misty thinking about him.

As a college student, I sneered a little bit at professors that admitted they got poor grades in the subjects they were lecturing on.  With irony, I confess now I am one of those teachers.  When I got to college, I had gotten in to Wesleyan University by the skin of my teeth and was a January Freshman (my roommate, with a wicked grin, for years introduced me as such).   I took Genetics along with as many other classes as I could handle and was so stoked to be finally out of a mind-numbing job and a tense home situation.  I took too many courses, and tried to cut corners by taking the Genetics lecture without the drosophila lab portion, which was listed in the syllabus as optional.  The midterm was incomprehensible, and I confronted my professor during office hours.  He told me most of the questions I struggled with were taken directly from work done in the lab, and he was astonished that anyone in class was not also taking the lab.  I got a “C” and was devastated.  Around the same time, I went to the Science Library and tried to read journals with the word “genetics” in their title.  The technical jargon was impossible to understand and in no way resembled the science I thought I loved.  So I concluded after my first semester that I was not cut out for genetics and needed a new plan.

My best friend told me he always imagined I’d be a doctor, so I figured I’d try that.  I made spending money for college doing temporary clerical work and on fateful week I spent at the Muscular Dystrophy Association helping to unpack and sort grant applications.  The head of the office on a tour of the stacks of grants asked me what I wanted to do when I grew up…”Be a doctor, I think.”  Well, to get into medical school these days, you need some research background.  He picked up the phone and arranged an interview with William Johnson a doctor doing research in Tay Sachs disease.  His goofy energy was infectious…”what’s on the docket for today?” he would ask every morning.

In his small lab, I labeled tubes, I ran gels I barely understood.  The time flew by and for a change, I felt that I was playing a small part of a worthy, scrappy effort.  Once in medical school I realized that this is what I wanted to do with my life.

Grand projects are wonderful.  They are stimulus for the economy and they energize the public for the ambitions of science.  In my neck of the woods, The Human Genome Project has unquestionably been a boon to life science and biomedical research.  But it’s critically important that Big Science is funded over and beyond a stable budget for regular science.  If Big Science like BRAINI is going to be funded by stealing money from within the current NIH and NSF budgets, then I am violently opposed.

Younger scientists need protection from the ambitions of their elders.

The practical application of science to cure diseases for example is wonderful, but a cure for any disease would generate millions if not billions of dollars in profits in our current medical care system. IMHO if the research is “translational,” maybe it should be supported by staggering profits of the pharmaceutical industry.

Anyone interested in science, in working to fight a disease, to help other people and join a team of scrappy geeks, let’s pay it forward.  Certainly, I wouldn’t be where I am now without little selfless acts.


Stupid atheist tricks at MIT

I was going to keep my mouth shut on the atheism thing, but an essay the other day in the NYTimes, by MIT’s Alan Lightman (Our Lonely Home in Nature) both amused and pissed me off a little.

I’m supposed to side with the scientists when they go all anti-religion, but this dude went one step beyond and dismissed my own world view in a dangerous way.  Thankfully, he did it in a way that made me laugh.


I applaud Lightman’s humanistic message that we humans need to look after each other.  I could not agree more with atheists like him and Richard Dawkins that don’t believe we should depend on being rescued from our follies by a magic God.   It’s been a few years since Sam Harris’ the End of Faith announced, “F- you and your stupid god.”  OK, I’m paraphrasing a bit there, the book was a vigorous atheist response to the religious fanaticism of the 9/11 World Trade Center attacks.  It’s an important book, great for discussion, but these atheist diatribes rub me the wrong way for two reasons.  Their apparent lack of irony in holding righteous and fundamentalist world views, and their lack of compassion for people who find comfort in religion.  The hypocrisy of a rational humanism without compassion for most of humanity seems to me a shaky foundation.

My view on how people use religion is informed by my experiences with patients on our transplant and leukemia service.  WhenI’m on the wards, the phrase, “there are no atheists in fox holes,” often comes to my mind.  I see good people, regular Joes and Janes, who have been kidnapped by disease and thrown into a world of illness and death they are completely unprepared for.  Good for Christopher Hitchens who can face death with areligious rationality.  Good for Richard Dawkins who can contemplate the horrors of the known and the abyss of the unknown with a calculus textbook and the complete works of Shakespeare for comfort and guidance.  But, for the um… “handful” of people that weren’t educated at Oxford or MIT, a concept of God is a fucking useful tool for understanding and communicating about the universe.  It pisses me off when the intellectual 1% look down their noses at the struggles of their fellow men and women trying to make sense of their world.

I smiled when, in the first pages of Dawkin’s “The God Delusion,” he says he isn’t arguing against the God of Einstein and Spinoza because theirs is an esoteric view held by an insignificant minority.  Ha!!  That minority is me!!  And the nature-based religion I hold dear is the view that Lightman takes a swipe at in his piece.  Briefly, the foundation of Spinoza’s view is that there is no separation between the creator and the created.  This division is the foundation of the Abrahamic religions, but serves a mostly political purpose, and erasing this line brings the religious and secular worlds into harmony.  Spinoza believed that studying the world was the way to get closer to God.  “Nature is God,” is an oversimplification, but comes close.  Which brings me to what was humorous and mildly offensive about the “Our Lonely Home in Nature” essay.

The first thing that made me smirk was the arrogance in the guise of humility.  The Lightman piece describes his near-death experience in the Aegean Sea.  He and his wife lost sight of land and the experience of nearly getting caught in a strong wind changed his life.  He realized that, “there was no compassionate overseer or oceanic consciousness…”  Sure, many of us have had the realization that, hey, I could die here.  I have sympathy there.  Life is fragile, for sure.  What made me chuckle was the light bulb over this guy’s head, thinking, if the universe doesn’t care about me personally…then the universe doesn’t care about anyone.  Heh.  If I’m not the center of the universe, then the universe is an ass!!  That made me laugh.

The smile was wiped off my face by Lightman’s core argument that, “Nature, in fact, is mindless.”  Ok, hold up, that view is deeply stupid.  My childhood was infused with science fiction and I’m still fascinated by the question of whether there is intelligent life in the universe besides ours.  Think about non-human consciousness for a minute.  If there are other life forms out there…you think they will look like Tasha Yar*?  Doubtful.  One could argue that the greatest challenge in our search for extraterrestrial life is our lack of imagination regarding what constitutes life and intelligence.  Beyond star-gazing, the “nature is not intelligent,” view is dangerous for life here on earth.  Lightman advocates looking with our own limited intelligence and profound ignorance at the infinite complexity of Nature and concluding that there is no mind there because we don’t recognize ourselves in it.  Do I recognize myself in my fellow humans?  Sometimes.  Not always.  If someone is different from me, if someone doesn’t care about me, does that make them mindless?  No.  Lightman has taken secularism to an extreme that undermines not only Western religion, but also core principles of Eastern religions (e.g. there is no real separation between you and the universe) and condones a close-minded outlook that shuts out our fellow humans if they don’t look like us.


* Thanks to DrugMonkey for pointing out that Tasha Yar was, in fact, human.  I agree, Kira Nerys would be better example here..

How we fix the NIH

 I was on the beach in Florida with a business school prof friend of mine a couple of weeks ago and he blew my mind.  I like big ideas about how to change things for the better.

He’s always up to something interesting.  When I asked him, “what are you working on?”  he surprised me.  “Fixing the NIH grant system,” he told me.  What!?!  He gets paid as a consultant to jump in to an area he may not be familiar with, do some research, and then be the answer man.  Someone from the NIH was in a executive managment course he teaches and described the grant “problem.”  I love this guy because he approaches complex problems like such a boy scout, with an earnest optimism that any situation can be improved. Whether it be how to get our 6th grade basketball team to play better offense, or how to fix the national debt, he’ll say, “here’s what you do..” and roll out a Four Point Plan.  It’s funny…at the same time, I can’t help but play the devil’s advocate and bring up all the complexities and possible roadblocks.  But this is an important topic, so let me step out of the way and tell you what he said …

His primary recommendation was to crowd-source solutions to revamping grant review.  This is his entry for what he proposes to be an open competition for proposals on how to fix the grant review process.  His basic idea is simple, but would be revolutionary.  He proposes that projects should be categorized and evaluated in four separate research categories, based on how the work relates to existing paradigms, and that NIH funds should be evenly split amongst these bins.  This concept of research diversification is taken from the business world, and it’s designed to speed progress and limit risk by spreading support for knowledge generation across classes of research. A key element of this plan is that competition for funds be within these groups so we fund the best of each type. Based on research he did with NIH scientists, the categories he proposes, are:

1.  Pre-hypothesis or exploratory studies.  These are experiments and projects that may not claim to have a paradigm or hypothesis but are designed to gather new information.  

2.  Replication studies.  We had a discussion about this one because I don’t think anyone in science really sets out to do work replicating the work of someone else.  My friend told me that respondents to his questionnaires told him otherwise.  In any event, in a way, this is the most intriguing category to me because it addresses the crisis of reproducibility in science while at the same time giving validity to scientists who are technically adept and hard working but who may not want to compete in other areas.  no one I know in science would admit that that We had a discussion about this

3. Paradigm extending studies. This is where most NIH-funded work currently fits.  Many bemoan this “safe” way of funding research, and one great strength of this system is to limit the amount of resources that go into “incremental” work.

4. Research that may develop a new paradigm.  This is the type of work that gets the most press and that everyone vocally supports.  Fresh thinking, new ideas, etc.  It’s an intriguing and common-sense ideal to compartmentalize this type of work, to recognise that paradigm breaking is high risk and that not all resources should be put in this basket.


A final important point of this scheme is that if it is adopted across institutes (?!) it would facilitate consolidation of bureaucracy.  By imposing a constant framework like this one, it would allow cross-institute comparisons.  And lastly, he proposes to grade the success of grantees with a new objective measure of knowledge generation.  The belief being that papers and patents are not a sufficient index of how well the money was spent.  How should we measure how much useful knowledge is generated by a grant?  That’s the big question, and he says let’s open that up to crowd-sourcing.

What do I think?   I have mixed feelings about shaking up the grant system just at the point when I think I’ve learned the game.  But, it’s clear grantsmanship is a game, and that we owe it to eveyone involved to make it more transparently about funding the best research.  The more I thought about this system, the more I can see its benefits.  The primary road blocks I see to implementing this system are lack of political will, and getting study sections organized to deal with this restructuring.  Study section culture is rigid and I’m not sure whether study sections would subclassify the grants they get or whether new study sections would be needed.  I’m really curious about what my colleagues think of this scheme.