Third year med student brilliantly teaches Integrity 101 to professors at Duke . . . and to all of us

I wish my field had something like the Cancer Letter.

Not sure how much this story has been chronicled outside of coverage in the Cancer Letter. Maybe the story has been widely disseminated and I just missed it before.

It is a truly impressive example of integrity. In a nutshell:

1. Duke third year medical student opts to do required third year research project in the lab of a rising star at Duke, Anil Potti.  Potti was collaborating with and working under the wing of a another, very prominent Duke faculty member running a large genomics program, Joseph Nevins.

2. Clinical trials were being designed and run--enrolling terminally ill cancer patients--on the basis of Potti's work.

3. The medical student becomes concerned about the research--based on reviewers' comments on a submitted manuscript--and acquires a sophisticated knowledge of the complex topic (analyzing large datasets from genetic studies and identifying markers of tumor susceptibility to specific therapies). His knowledge of the research rapidly advances to the point where he feels comfortable challenging the way the research is being conducted.

4. The student has enough confidence--and courage--to take his concerns up first with Potti and then, up to the next level, with Nevins, and then with the medical school leadership at Duke.

5. Remember, this is a third year medical student doing a required one year research project. He is planning to apply for a competitive residency program and not to go into research.  Potti is pressuring the student to get the manuscript out; if not to the journal that is asking questions, then to another one.  He has nothing to gain here by making waves and the paper would greatly bolster his chances of landing his desired residency.

6. The student next kicks his concerns up to Duke's associate dean for medical education and its director of student affairs. The former suggests that he reiterate his concerns to Nevins. The student then (March, 2008) writes a nuanced, clear memo of his research concerns. The Cancer Letter states, "According to top-tier biostatisticians who were asked to review these documents, his understanding of biostatistics was extraordinary for a med student—or even for someone with specialized training."  Impressive, no?

7.  Nevins "implored" the student not to take his concerns any further, according to the Cancer Letter, "because he did not want Duke or any other entity looking closely at the data underlying the clinical trials [that were ongoing and based on Potti's results]."

8. The Cancer Letter says:

Dr. Nevins validated many of Brad Perez’s [the student's] concerns by referring to the serious issues raised regarding Dr. Potti’s lab as “being somewhere along the spectrum between sloppy research and a difference of opinion to research fraud,” and that Dr. Nevins confirmed that he would “go back through each and every dataset that we have posted in relation to various publications to ensure that there are no errors.”

9. The student, having taken his concerns to Potti's sponsor (Nevins) and high up the chain at Duke then moves on.

And get this,

• 10. He declines to resubmit his first author paper despite co-authorship with and reassurances from prominent Duke faculty members that all was above board and any errors would be fixed
• 11. The student asks to have his name taken off every other paper from the laboratory--there are a number--on which he is listed as a coauthor.
• 12. The student returns a merit award he received based on the research in question and turns down an opportunity to present at a major meeting
• 13. He decides to repeat his third year of medical school rather than present or publish any results based on the flawed work in the Potti lab 
• (and all this despite an upcoming application to a competitive residency program)

Epilogue:   The student wrote his letter of concern in April, 2008. According to the Cancer Letter, Duke administrators--aware of the letter--met in October 2008 to discuss Potti. Meanwhile, outside experts began to raise concerns. Nevins continued to defend the work and the ongoing clinical trials. Duke allowed the trials to continue.

In 2010 there was a slew of retractions of Potti's work--Lancet Oncology, Nature Medicine, NEJM, etc.--Potti left Duke, and the clinical trials were, late that year, finally halted. In March, 2011, Nevins admits "nonrandom data corruption."  The Cancer Letter has discovered that Duke--where Nevins still works--misrepresented its knowledge of the medical student's concerns and put out a false timeline regarding when they became aware of potential problems. Duke is currently being sued by participants in the cancelled trials.

Yet more from the NEJM

Just finished writing this post when I see yet another Perspective article in the New England Journal regarding the ACA.

The Perspective article details the enormous problems for Obamacare that  a win for the plaintiffs in the Supreme Court case King v. Burwell would entail. It is clearly important to proponents of the Affordable Care Act that the plaintiff's case be weak and that the defense prevails. Indeed, the strength of the plaintiff's case is of such great consequence for Obamacare that you would think that the editors would want to see that it was covered fairly.

Here is the sentence regarding the argument at the heart of the case: "The case hinges on enigmatic statutory language that seems to link the amount of tax credits to a health plan purchased 'through an Exchange established by the State.' According to the plaintiffs in King, that language means that consumers who buy insurance through federally run exchanges don't qualify for subsidies"

The authors cannot get around the fact that the law states that only participants in exchanges established by state governments are entitled to subsidies (contrary to how the subsidies are currently being distributed).  When the authors say that the wording "seems" to link eligibility for tax credits to buying insurance through a state--rather than the federal--exchange, what they mean is that the law does make that link: they just can't bring themselves to state so plainly, hence the weak attempt to introduce uncertainty.

Of greater interest, the NEJM editors also let the word "enigmatic" slip by. Surely they could have at least provided some hint that the rationale here is not at all enigmatic. Perhaps the best way to understand the rationale is listen to Jonathon Gruber, a key architect of Obamacare, plainly lay the rationale out (lately proponents of the bill have--for obvious reasons--tried to make Gruber's role disappear). Anyone paying attention to the ACA litigation--including the NEJM editors--must be aware of the relevant Gruber videos: they received a lot of attention when they were uncovered. The linkage of subsidies to state exchanges is logical, not mysterious: the purpose is to strongly incentivize states to set up exchanges. Relevant discussions and links to the pertinent Gruber recordings can be readily found through Googling: here is one and another and a third.

Dear NEJM: please think about the balance between functioning as a journal of political advocacy and your general credibility.

The Lancet: much, much worse

(Continued from prior post:  The politicalization of two major medical journals: bad and much, much worse)

In contrast to the NEJM, the Lancet has long evidenced obvious biases. This has done much to severely damage its credibility. The Journal is run for Elsevier by Jon Horton, who seems to be a man of the European left. His editorial judgments have landed the journal in trouble before. For example, he published two politically-motivated studies from a group at Hopkins purporting to look at deaths in Iraq attributable to US military actions. These studies were later found to be seriously flawed and biased by politically-motivated funding.

Worse, though, is Horton's turning what should be a prestigious journal of clinical medicine into a platform for obnoxious anti-Israel propaganda. Recently, as just one example, he discredited himself and his journal by publishing a letter in the middle of the most recent Gaza war authored by a group of viciously anti-Israel activists. Among others, the authors included two who have worked with the former Ku Klux Klan member and current neo-Nazi David Duke and also a maoist, pro-Hamas, strident anti-Israel activist. Later, as the antisemitism underlying the letter became more evident, Horton claimed to be sorry for publishing it. He has yet to remove it from the Lancet's website.

The Lancet reflects poorly on Elsevier and, arguably, on the British medical establishment. Elsevier needs to rethink its staffing of the journal.

The politicalization of two major medical journals: bad and much, much worse

Bad:  
The New England Journal of Medicine purports to take no position, pro or con, on Obamacare. The Editor-in-Chief and Executive Editor have come out in favor, yet, somehow, despite their biases--they claim--the Journal itself has not staked out a position. This is risible.  I subscribe to and very much like the NEJM, but ever since the Affordable Care Act (ACA) was first proposed, the Journal has been flogging Perspectives and other articles written by advocates as if it were a journal of politics and political policy: routinely publishing articles that could just as easily be found on the Op-Ed pages of newspapers or in any number of--primarily left-leaning--political/policy journals. Yes, they have published articles written by skeptics here and there (I can recall only one right now), but basically the Journal has been pushing Obamacare since the get-go: it's not subtle.

No forum for pro-ACA writings would be complete without an essay or two from the egregious Jonathon Gruber. The NEJM's conflict of interest policies has spared the Journal criticism for not disclosing Gruber's financial links to the ACA: if readers took the time and looked closely enough, they could find the NEJM's mandated disclosure (there has typically been no disclosure elsewhere he has been published or quoted). However, I doubt that even NEJM readers who found the disclosures knew at the time of the magnitude of Gruber's financial interests in the ACA. These amounted to millions of dollars: $400,000 from the feds alone.  Would the Journal let a consultant being paid millions of dollars by Amgen write a perspective advocating for more Epogen use?  If so, would a hard-to-notice financial disclosure statement be adequate, or would perhaps a disclosure need to be included in the text?

One final question: now that we know that Gruber has intentionally obfuscated important facts about Obamacare and has attempted to deceive the Congress and US electorate on key policy points, does the NEJM need to go back and look at his articles?  I bet they would have a second look at, say, a clinical trial that was published by an investigator later have found to have published fraudulent manuscripts.

I really like the Journal. It has been painful to see the Journal become so politicized during the ongoing debate surrounding Obamacare. The claim cited above that the Journal has not taken a position is belied by the articles that make it into its pages.

Continued in next post: Much, much worse

NPR covers funding woes (updated)

I've been on a bit of a hiatus due to a spike in the number of work-related responsibilities and outside matters demanding my time and attention. For example, my wife--the ever-patient Mrs. Grantslave--and I were distracted the last few weeks preparing to ship our oldest child off to college. This bittersweet (for the parents) life-cycle event has now come and gone. I won't drop any clichés about time passing quickly as one gets older, but it does.

I've been linking to reports and editorials concerning biomedical funding issues, and, in this regard, I wanted to be sure to link to this NPR report. It's of interest, first, because of NPR's stature as a national news organization and its influential audience, and, second, because it's well-reported. I was pleasantly surprised, for example, that the report includes a quotation that directs attention towards the large degree of culpability of the biomedical research establishment itself--including the NIH, universities and other major research institutions--for the current gloomy funding environment:

It seemed like great fortune when the NIH budget soared more than a decade ago. "Unfortunately, a lot of research institutions and medical schools were hogs to the trough," Burke says. "They hired a lot of people and built a lot of buildings with the expectation that that would continue. And when that flattened off, and started losing money to inflation, the institutions were essentially bloated."

There was nothing on soft money salaries and how they greatly magnify the impact of funding constraints and the overall level of gloom, but have a look for yourself: the NPR story is a nice, concise introduction for lay people to the current NIH funding situation.

UPDATE:  I see now that this story is part of a series by NPR's Richard Harris on the ugly NIH funding environment. The title of the next installment is kind of depressing: When Scientists Give Up. Not sure I want to listen or read the transcript, but the first episode was promising enough that I guess I'll eventually get around to reading the whole series.

Addendum: The disappointing Physician-Scientist Workforce Working Group Report

This comment (written by "William S.") from the discussion of the Physician-Scientist Workforce report on the NIH Rock Talk blog is worth posting because it seconds the point I made in the post immediately prior to this one and perhaps better fleshes out my critique:

From the perspective of the trainee, there are really only two issues relevant to this discussion: career opportunities – (i.e. will I be able to find an appropriate research position when my training is finished?), and career longevity – (i.e. is there a reasonable chance I will still have my lab in 10+ years?). If the answer to either of these questions is no, then attempting to encourage physicians to pursue research careers, through whatever mechanism, is not only misguided but disingenuous. . . . .

If, for whatever reason, the NIH and/or other powers that be feel that current numbers are inadequate for sustaining a robust biomedical work force (and I agree with this assessment) then the focus should not be the individual, but rather system wide, institutional, issues that deter and demoralize highly motivated physicians from choosing this career path. These individuals are generally quite smart and can see the landscape as well as (or perhaps better than) the PSW working group.

The disappointing Physician-Scientist Workforce Working Group Report

Did the authors of the recommended actions in the Physician-Scientist Workforce Working Group Report read the rest of the report?

The report: was released last month. First, some excerpts:

This set of facts about physician-scientists was interesting:

• Over the last 25 years, 37 percent of Nobel Laureates in Physiology or Medicine had an MD degree. 
• Over the Lasker Awards’ last 30 years, 41 percent of the Basic Awards and 65 percent of the Clinical Awards have gone to MDs. 
• 69 percent of NIH Institute Directors have an MD degree. 
• 60 percent of the National Academy of Sciences Class IV (Biomedical Sciences) members have an MD degree. 
• 70 percent of the chief scientific officers at the top 10 pharmaceutical companies have an MD degree.

A key focus of the Working Group was determining why the supply of physician-scientists is falling. The uncertainty of grant funding was, not surprisingly, a top concern cited by the students, junior faculty and medical school deans interviewed.  Here is a sample of excerpts from the body of the report:

• Qualitative research undertaken by and on behalf of the PSW-WG indicated that the uncertainty of funding is by far the biggest concern of young physician-scientist faculty; its importance cannot be overestimated. (page 40; emphasis mine here and below)

• The uncertainty of research funding was the major challenge to a career in research articulated by both dual degree students and single degree students interested in pursuing a research career. By far, the largest concern from students interested in research is the issue of funding and the uncertainty of the funding. Job stability is very concerning to those who wish to pursue careers with research components. (page 80) 

• The [MP/Ph.D.] students admired successful physician-scientists, who are able to continue getting funded for research. . . . On the other hand, these students described the older physician-scientists who are running a lab, being a mentor, and an academic teacher/advisor, as looking tired. Each student in the focus group verbalized that the uncertainty of research funding was the major challenge to a career in research. Financing a career in research and the perceived politics of government funding makes each one nervous about being able to sustain a career as a physician-scientist. (page 91) 

• Most [MD] students respected and admired those who are physician-scientists, but they were not particularly interested in navigating the grant funding process. . . . “And it is almost like being, to me, how artists have to go out and get gigs and do that whole thing. I feel like researchers have to like go out and find grants, find funding, find people who believe in them, and it just seems really, really tedious.” From a student who has aspirations to do research: “I think the funding environment now is something that is pretty scary."  

• [Medical school deans] identified the most important factors that they believe influence students’ career decisions. The stability of research funding and ability to sustain a career as a physician-scientist was frequently mentioned as an important factor, since students are observing their professors losing research funding and complaining bitterly about it. (page 111) 

• Most [young faculty] expressed fear and frustration about the possibility of not being able to continue their research  careers if they are not able to secure an R award. They expressed the fear that they have invested so much of their adult life preparing to do scientific research and it could all be ended by not being successful with an R award. They have sacrificed both a lucrative clinical salary, as well as precious time in the hopes of being able to continue to build a research career. (page 117)

Within the body of the report can be found all the key concerns that deter qualified individuals from embarking on a career as a physician-scientist and that threaten the morale of those already engaged in such a career. This leads one to wonder, then, whether whoever devised the list of recommended actions actually read the report.

Trainees contemplating embarking on a career as a physician-scientist and those (like myself) who have already committed to such a career are worried about the overall stability--short-, medium- and long-term--of careers in biomedical science. Incredibly, the recommendations listed at the conclusion of the report are entirely comprised of the standard fare of training programs, fellowships, new investigator privileges etc that we have seen discussed, tested and/or implemented ad nauseum up to now. As before, these all would serve to continue to front-load the pipeline and do not concern what was clearly the chief concern identified: the highly uncertain stability and desirability of physician-scientist positions downstream.

Trainees are not dumb: the report shows that they are not only thinking a year or two or three ahead. They are looking ahead to what happens after that first K award or after they get their first R01: when they are no longer young investigators; perhaps when they have kids, a mortgage, college tuition to pay. The fact that the authors of the recommendations, ignoring the findings presented in the report, think that they can alleviate the shortage of physician-scientists by luring young investigators with goodies up front and hoping that they will forget about increasing pressures, stress and instability downstream is astonishing.

Tacky

Some non-physicians think physicians are overpaid. This physician disagrees, but does think that a number of specialties are way overpaid (I'm looking at you radiology, dermatology and some others--you know who you are).

After walking through a university parking lot while on a visit recently, I had these thoughts:
1. If you are in a highly paid specialty, there is no need to drive to work in a late model Ferrari. This is in bad taste in a time of great concern about health care costs.
2. Even if you feel that you need that Ferrari and need to drive it to work, you do not necessarily need vanity license plates that announce you paid for the vehicle by billing for your grossly over-compensated medical service.
3. All of the above is doubly true if you work for an academic medical center.

Part of a dying breed

The DrugMonkey blog is laden with the type of practical, career advice that I wish I had been given early on. I was thinking recently about a post from last year:

So noob, you put in one grant, it didn't get funded and you feel mopey? . . . .
It is not about what anyone else or the "typical" person has done. It is about doing whatever you possibly can do until that Notice of Grant Award arrives.
My stock advice right now is that you need to have at least one proposal going in to the NIH for each standard receipt date. If you aren't hitting it at least that hard, before you have a major award, you aren't trying. If you think you can't get out one per round.... you don't really understand your job yet. Your job is to propose studies until someone decides to give your lab some support.
My other stock advice is take a look at the payline and assume those odds apply to you. Yes, special snoflake, you.
If the payline is 10%, then you need to expect that you will have to submit at least 10 apps to have a fighting chance. Apply the noob-discount and you are probably better off hitting twice that number. It is no guarantee and sure, the PI just down the hall struck it lucky with her first Asst Prof submission to the NIH. But these are the kinds of numbers you need to start with.
Once you get rolling, one new grant and one revised grant per round should be doable. They are a month apart and a revision should be way easier. After the first few, you can start taking advantage of cutting and pasting a lot of the grant text together to get a start on the next one.

And also, in the same vein, this:

In the face of budgets which allow the funding of only a subset (a third? quarter?) of the grants which are excellent and interesting and impactful and all that jazz, review becomes variable. Meaning the difference between making it into a fundable score and just missing a fundable score takes on the appearance of chance. The only way to beat such odds is to give yourself more chances at the game. This means writing and submitting multiple applications (on different topics, of course).

And I was castigating myself: "how come I'm not doing this? I obviously need to submit more applications; why can't I find the time?"

And then it occurred to me: I was thinking this while I was writing a medical clearance letter on behalf of a patient.  And just before that, I was reading about an unusual case I saw in clinic on UpToDate. And I have my half day clinic the day after tomorrow, which, if you include associated documentation, follow-up, reading and responding to patient queries, really takes up a full day. And the month before, I was on the hospital consult service, which breaks up the day and eats up time. On top of that, I have the same responsibilities as DrugMonkey and most of his audience: stay up to date on the science literature, run a lab, write papers and, oh yes, write grant applications.

Another thing about DrugMonkey is that, as far as I can tell, he does not have kids at home. The thing about having kids is that when they're not driving you crazy--which, fortunately, tends to be more than 50% of the time--you want to spend time with them; and your spouse, also. In fact, now that I think about it, by virtue of being single, divorced or old enough to have adult kids, many (most?) of the investigators I know who are thriving in the current environment do not have kids at home.  Hmmm.

Medical students are smart. They can put two and two together: soft money salaries + historically low NIH grant success rates=job insecurity and potential for high stress.  "Fixes" for the system thus far proposed generally involve pumping more physicians into the system through training grants and lower barriers for initial R01 grant awards. Proposed measures seem to never involve increasing downstream job security. Our society idolizes youth. This includes the NIH: trainees and new investigators are loved.  Once you've been sucked into the system and you're trying to get your grants renewed, you're on your own buddy. Think the PhDs reviewing your grant applications or tenure file give a fig that you are a physician-scientist? Think again. Physicians in training--and this goes for MD-PhD students also--aren't blind: they see what is happening.

There: I've solved the puzzle of why medical students are less inclined than ever to do what I do for a living: of why predictions that physician-scientists are a "endangered species" are coming true.

Annals of ineptitude: NIH grant planning edition

Still clearing my desktop.

The April 4th issue of Science has a ten page section up front regarding the current travails of U.S. grant-funded researchers: "Chasing the Money".

The NIH funding situation has been getting progressively worse over the past few years. Meanwhile, over the years, the NIH has kept coming up with new schemes to direct funds to new investigators in order to pump fresh blood into the system.

Now, read the following excerpt from the lead article:

• The agency makes it easier for new investigators to get funding, for example, but it doesn't know how they fare 5 years out, when their first big grant is up for renewal. "We want to make sure we're not setting them up for failure," says Sally Rockey, NIH's deputy director for extramural research. The agency plans to start tracking these people, to gauge whether they're headed for dire straits.

Now read it again.

Note the words "plans to start." Plans. To. Start. Plans to start. Now? Now?(!) 

Two things: 1) when starting a program, it's good to think through the outcomes beforehand. Especially when your enticing people into a career and investing heavily in them. Especially when their livelihood while pursuing that career is dependent on your organization. Similarly, it's good to try to ascertain results/outcomes in as timely a fashion as possible. 2) Sally Rockey and her colleagues should read "Chasing the Money" in the April 4th edition of Science as well as the many other articles out there about the current funding environment. They might learn something. Why would these new investigators not be headed for dire straits?

File this away under the NIH subsection of government ineptitude. 

Clearing my desktop part 2. Medicine-the ABIM piles on

Two recent articles of interest concern medicine, and specifically how burdens unrelated to patient care continue to accumulate in a cruel fashion.  I want to highlight one quotation from each article. These quotations perfectly echo my sentiments about one particular new aggravation .

The first article can be found here.  The following quotation is in regard to one new initrusion that I and many, many of my colleagues find outrageous. The American Board of Internal Medicine (ABIM) continues to ratchet up the monetary and time burden of recertification with no evidence that anyone, aside from the ABIM itself, will benefit: 

• doctors also face board recertification in the various medical specialties that has become time-consuming, expensive, imposing and a convenient method for our specialty societies and boards to make money."

The second article--also dealing with new cruelties inflicted on physicians who would rather just be providing patient care--is here.  And here is the quotation: 

• Almost comically, the response of medical leadership—their solution— is to call for more physician testing. In fact, the American Board of Internal Medicine (ABIM)—in its own act of hostage-taking—has decided that in addition to being tested every ten years, doctors must comply with new, costly, "two year milestones." For many physicians, if they don't comply be the end of this month, the ABIM will advertise the doctor's "lack of compliance" on their website. 

Physicians would not be up in arms about these dictates from the ABIM if there were any shred of solid evidence that they improved patient outcomes. But there isn't. There is just yet more intrusion on the schedule, budget and sanity of physicians; yet more paperwork.

Clearing my desktop part 1. Science-the broken research funding system.

I have not written here for a while. Some of the key problems with the biomedical research enterprise that I have been thinking about of late have been described by prominent scientists in widely-circulated articles. What I would have written--at least regarding the descriptions of the problems, if not the solutions--would have been redundant.

Here is an example of one of these articles (in the op-ed section of the Wall Street Journal). Regarding the authors' description of the problems with grant review, I can only say "amen."  (The article, unfortunately, may be behind the Journal's paywall.)

Here is another example. Again, regarding the overview provided and the descriptions of the problems with the current system of research funding: "amen."

Whew, another three sentences written . . . I deserve a little break

Pro . . .cras. . .tin. . .ation

I do a lot of interesting reading while I'm in the midst of grant writing. The number of sentences I can write before "needing" a break is inversely proportional to the time remaining before the deadline, starting at about three and increasing exponentially beginning a few days before the deadline. If not for grant and manuscript writing, my knowledge of history, philosophy, Consumer Reports ratings of refrigerators, the 10 best places to retire, the 10 worse things to say on a first date, the Freedom-class littoral combat ship and Amazon.com's selection of V-neck undershirts would be infinitely smaller.

Recently, I ironically found myself reading this on my iPad, having stumbled upon this article while lounging on the living room couch, surfing the net and diligently avoiding completing a grant application due the next day. The article, "Why Writers Are the Worse Procrastinators," was strangely reassuring. I'm a professional writer in a way. Here I have been beating myself up about my chronic procrastination, but it turns out that, if you're a writer, it just comes with the territory.

Much of my training occurred before the advent of online grant submission. Evidence that a lot of my colleagues were fellow procrastinators? Scientists and administrative assistants waiting eagerly by the FedEx pickup box to ensure pickup 5 PM on the day before major grant deadlines. Common knowledge in the local biomedical science community about where to take FedEx packages for the very last after-hours drop-off (I seem to remember that it was at the airport FedEx office). True story: when I was in training, my lab's Principal Investigator missed the last FedEx and UPS pickups the day before a major NIH grant was due. I remember the frantic copying and stapling: even more panicked than usual the day before grants were due. The PI's solution: buy a ticket for a transcontinental  flight that very night to Washington DC, put a postdoctoral fellow on the plane with the application (and all 14 copies, or whatever it was back then) in hand, and send him off to hand-deliver the application to the NIH.

A tip for those of you whose procrastination leads to self-flagellation and misery: read this essay on Structured Procrastination by John Perry, emeritus professor of philosophy at Stanford, and his follow-on book, The Art of Procrastination: A Guide to Effective Dawdling, Lollygagging and Postponing.  They're both witty, easy reads and, importantly, many people (including me) find that Perry's way of looking at procrastination makes a huge difference in how they think about their procrastination and themselves. My only slight concern is that maybe these writings have lulled me into too much complacency about my procrastination and have perhaps forestalled my eventual self-"cure."

For my benefit

This post is for my benefit.  You may want to skip over it.

Due to the current funding environment, my job is a bit more stressful than I originally anticipated.  I am what is know in the business as a "triple threat": researcher, clinician, teacher. "Triple threats" may be a dying breed; there is some debate about that.  I have a lot on my plate. I don't claim to be alone or exceptional in that regard.

Things I need to remember when I feel stressed or when I am stewing over some job-related issue (if I sound like Stuart Smalley, I didn't intend it) :

It's too easy to focus on the "minus" column and overlook the pluses.

I am at home in two different worlds: I can function in a basic research environment as well as any PhD, and I can walk into a hospital or medical clinic and be mistaken for a pure clinician. MD-PhDs are plentiful at top medical schools. It is easy to forget that being both a fully qualified MD and a PhD-level researcher might be seen as impressive outside the medical school campus.  At least my parents are impressed.

Being a physician is a pretty big responsibility. Hey, some people do it full time and even make a career of it. I guess I should keep this in mind when I compare myself to straight basic research PhDs.

I can help diagnose and treat people who are ill. I am privileged to be able to do so. This also greatly helps in framing research questions.

David Brooks says " . . .  I tell kids if you have a great career and a crappy marriage, you will be miserable. If you have a crappy career and a great marriage, you’ll be happy."  I have a good marriage (to the fetching Mrs. Grantslave). I should count myself lucky.

I don't think my kids are going to laying on a psychiatrist's couch when they're adults and complaining about me.  I've been fortunate to have had the desire and the  flexibility in scheduling to be an involved, not bad father.  When I'm very old, I think I would have regretted the time I didn't spend with my kids more than the one extra grant application I didn't have time to write.

I have made contributions to our encyclopedia of knowledge about how the body works. For some reason, this is satisfying.  I have to remind myself that this is something I very much wanted to do when I was a naive kid.

Every predoctoral trainee that has come through my laboratory--both graduate students and students spending a couple of years in the lab before going to medical school--has had solid first-author papers.  This has not been the case with other, bigger, better funded laboratories that I am familiar with.

I have used the public's money efficiently and always keep in mind that I am spending tax dollars taken from the earnings of the supermarket manager just barely in the middle class or the tow truck driver just scraping by or spending funds donated by the earnest, well-meaning walk-a-thon participant.

I just looked at the blog CaliforniaStemCellReport, so I have to throw this in:
I have never and would never personally fight for the passage of a state proposition that would force residents of my state to pay specifically for my research, willingly or not. I would not grossly exaggerate the potential for near-term benefits of my research in order to influence 55% the residents of my state to vote for a law that would also forcibly extract money (as bonds are paid off) from the other 45% who perhaps felt they had better uses for their money.  Public funding of biomedical research is essential. I am strongly in favor.  But  I wouldn't become a huckster in order to coerce funding targeted specifically to my laboratory, which of course I think is highly valuable and meritorious of funding.

Update to: Taking the "R" out of CIRM: is the stem cell agency acting lawfully?

David Jensen is a retired journalist who writes, pro bono, the California Stem Cell Report, a website that makes an important contribution to the monitoring of CIRM.  He is commendably even-handed; it's admirable that he takes time out of his active retirement to provide this service.

Mr. Jensen has written that he "expects to post an item dealing with the significant issues that our anonymous reader has raised."  I hope he finds the time to do this.  He is known at CIRM, so I imagine they'll be responsive to his queries. If he follows-up on this, I'll update this post accordingly.

"Academic bigotry"

Whenever I go to major scientific conferences, I'm always impressed by how well-represented Israel is. I have to stop and remind myself that Israel is tiny nation with a population of 8 million,  less than half of that of the greater Los Angeles metropolitan area. It's really amazing. Walk through the posters, go to the oral presentations: not only is Israel very well represented in quantity, but also quality. I don't like to generalize, but here goes: the Israeli scientists I meet are generally very talented and, equally important, they are nice, down to earth people. In terms of its contributions to science and medicine, including the number of Nobel prize winners who are connected in some way to Israel, the nation is pulling vastly more than its own weight, to the great benefit of all of us. Indeed, an immediate family member of mine who I feared would have been in a wheelchair years ago is still walking and active thanks to a medicine for MS developed in Israel.

I am fortunate to currently have a collaborator in Israel who has taken some of my findings and run with them, producing (so-far) exciting results that could, we hope, have a therapeutic application and help treat a major disease (although, as I have discussed previously, the odds of any particular therapeutic idea actually even making it as far as phase 1 trials--let alone into the clinic--are extremely low).

I don't know whether to be embarrassed or sickened or both by a small but vocal group of university faculty members--primarily in the humanities (which unsurprisingly is beset by a number of self-inflicted problems, including drastically falling numbers of undergraduates majoring in their area)--who, hopping from one trendy cause to the next, are now currently intent on badgering and trying to undermine the economy and safety of this small country surrounded by dysfunctional, violence-prone nations and by terrorist groups with truly genocidal intentions. They remain completely unable to provide a rational reason why, of all the nations in the world, they are singling out this one. Many people oppose the boycott idea on grounds that it is incompatible with academic freedom and the exchange of ideas. That is a valid reason, but there are other, more important and profound reasons to be disturbed by what these anti-Israel academics are up to. As Larry Summers put it, these boycott resolutions are  “anti-Semitic in their effect if not necessarily in their intent."

I wish my writing were anywhere near as crisp and lucid as Charles Krauthammer's:
". . . the ASA boycott has nothing to do with human rights. It’s an exercise in radical chic, giving marginalized academics a frisson of pretend anti-colonialism, seasoned with a dose of edgy anti-Semitism."

CIRM fought the California Legislature to keep the two-thirds vote requirement for funding non-stem-cell science. Said it was standing up for the will of the California voters.

The following points were made in my prior posts regarding CIRM:

• First, if CIRM asks to raise more money via a new bond issue, they should not restrict grant awards made with the new funding to stem cell research (i.e., the law should be revised; with the new funding initiative, CIRM should transition into CIBR: California Institute for Biomedical Research). This makes obvious sense in light of the fact that  federal restrictions on embryonic stem cell funding have been lifted. (For the record, it is not GrantSlave's intention here to advocate for a continuation of CIRM in any form, even if it were to transition to CIBR.).
• Second, CIRM is blatantly disregarding the intent of the law that brought it into being by funding non-stem-cell, non-regenerative medicine projects. Furthermore, there is no public record (that I have been able to find) that CIRM grant reviewers are deliberating whether these non-stem cell projects constitute "vital research opportunities" that merit funding despite being outside the intended scope of the law. The grant reviewers are legally required to vote on whether non-stem cell projects are "vital research opportunities" before these projects can be funded. A two-thirds super-majority is mandatory in order for funding to be approved.

In 2008, the California Senate passed SB 1565 amending the law underlying CIRM by a vote of 40-0. The bill won in the assembly 64-7. This bill would have made it easier to fund non-stem-cell science, something I advocated in my first post. It was vetoed by Governor Schwarzenegger and never saw the light of day again.

CIRM opposed SB 1565. They wanted to keep the two-thirds vote requirement for non-stem-cell research. They felt it was important. Here is what the CIRM leadership had to say (emphasis not mine--underlining and bolding from their letter):

•  ". . . the proposed amendment to Proposition 71 would send the wrong message to Californians and to the nation at large. It would also thwart the will of the more than seven million Californians who voted for Proposition 71 in order to address the federal funding gap for human embryonic stem cell research, a gap that continues to exist to this day. By removing the two-thirds vote requirement, the amendment would undermine the very purpose of Proposition 71 – to provide a priority for funding human embryonic stem cell research. . . . For all of these reasons . . . we are strongly opposed to the removal of the two-thirds vote requirement."

So, the will of the California people was to fund embryonic stem cell research? OK, the feds have lifted their restrictions, so we can excuse CIRM's funding of other, non-embyronic, stem cell research. This other stem-cell research is, after all, allowed in the underlying law. 

But what about all the funding of non-stem cell, non-regenerative medicine projects? What happened to standing up for the will of the more than 7 million Californians who voted for Prop 71? And what about this very important two-thirds vote requirement for funding non-stem-cell research? Is deliberating whether non-stem-cell projects are "vital research interests" no longer important? There no mention of such deliberations or the legally mandated votes in the detailed review summaries generated for funded grants: see, for example this summary of an awarded, non-stem cell grant. CIRM fought to keep the requirement for these two-thirds votes in place: is it not important to at least document for the public that they have occurred?  My guess is that they are not taking place: if they were, the discussions and outcomes would most likely be included in the review summaries.

(note: post revised for clarity)

Taking the "R" out of CIRM: is the stem cell agency acting lawfully?

The California Institute for Regenerative Medicine (CIRM) was brought into existence by the passage of Proposition 71. Note the word "Regenerative." It is essential to understanding the intent of Prop 71 and how it was sold to the voters. The name of the agency was not an afterthought: it was stipulated in the first sentence of the enabling constitutional amendment: "There is hereby established the California Institute for Regenerative Medicine."

Proposition 71 was meant to promote research using stem cells, most significantly human embryonic stem cells. Stem cells can be employed in biomedical research in different ways. The most exciting and most heavily-promoted potential application was (and is) using these cells to regrow or create replacement tissue for damaged organs or nerves: to "regenerate" these tissues. Here is how the argument that was put forward in favor of Prop 71 in the official voter information guide begins: "stem cells are unique cells that generate healthy new cells, tissues, and organs. Medical researchers believe stem cell research could lead to treatments and cures for many diseases and injuries . . . ."

Now let's look at the intent of Prop 71 as spelled out within the actual text of the law. From the Findings and Declarations: "the California Stem Cell Research and Cures Act will  . . . [establish] an institute which will issue bonds to support stem cell research, emphasizing pluripotent stem cell and progenitor cell research and other vital medical technologies, for the development of life-saving regenerative medical treatments and cures" (emphasis mine).

In short, the intent of Proposition 71 was crystal clear. Californians agreed to pay for stem cell research and especially the development of  "regenerative medical treatments and cures." Why, then, has CIRM awarded almost $100 million for relatively conventional, non-stem-cell cancer research? Is this because the stem cell program has so far failed to yield new therapies? Is CIRM is so eager to make good on its promises that it's willingly ignoring the intent of the law that created it?

You can find the words "stem cells" in the titles and the abstracts of the cancer research to which I'm referring, but don't be fooled. Cancer stem cells are not the stem cells or pluripotent/progenitor cells referred to in the law or in the advertising for Prop 71. Cancer stem cells can have some of the same characteristics and molecular properties as stem cells and they may perhaps arise from normal progenitor cells, but they are abnormal and, unlike stem cells, cannot form normal tissues: rather, they yield malignancies and are thought to underlie disease relapses. They have no use in regenerative medicine. Research into cancer stem cells is conventional in several senses. First, as has always been the case with cancer, the goal is to find therapies to kill the malignant cells or at least get them to stop dividing--for example by inhibiting enzymes called kinases or targeting proteins on their surface--while leaving normal cells as unperturbed as possible. This type of research is widespread in academia, pharma and biotech and has never been subject to federal restrictions. The NIH has been funding research involving cancer stem cells since at least 1999. Of note, Iriving Weissmann, a big proponent of Prop 71 and recipient of Prop 71 funds for cancer stem cell research (most recently a nearly $13 million award focused on leukemia), has been receiving NIH funding for research into cancer stem cell-related therapies since at least 2009.

Funding of cancer stem cell therapy is not aligned with the intent of the law and has never been subject to NIH restrictions. Adult stem cells, stem cells, progenitor cells and pluripotent cells--the cell types that are are the focus of the law--are defined in Article 3. Cancer stem cells do not fall under any of these categories.

Now delving further into the letter of the law: consistent with law's intent, the section describing how research funding is to be awarded stipulates that "a high priority shall be placed on funding pluripotent stem cell and progenitor cell research that cannot, or is unlikely to, receive timely or sufficient federal funding, unencumbered by limitations that would impede the research. In this regard, other research categories funded by the National Institutes of Health shall not be funded by the institute." Cancer stem cell research is not pluripotent stem cell or progenitor cell research, there are no restrictions on cancer stem cell funding, and the NIH has funded many grants looking at cancer stem cells in one way or another.

A provision of the law allows non stem-cell research to be funded  "if at least two-thirds of a quorum of the members of the Scientific and Medical Research Funding Working Group recommend to the ICOC that such a research proposal is a vital research opportunity." The Review Summaries from the Scientific and Medical Research Funding Working Group are available online (e.g., see here). There is no indication that consideration was given to the fact that the projects are outside the intended scope of the law nor is there reasoning provided why they should nevertheless be funded as "vital research opportunities."  Of equal importance, there is no indication that the required separate votes were taken and resulted in the stipulated two-thirds super-majorities.

In the latest funding announcement from CIRM, half of the awarded applications and approximately half of the $60 million in awarded funds went to such non-stem cell (cancer stem cell) projects. Other projects within the intended research scope of the law were passed over.

CIRM, perhaps feeling pressure to live up to its initial hype, seems to be disregarding the intent of Prop 71 (as spelled out within the law itself).

Unless the required votes are being taken recommending the cancer stem cell projects as "vital research opportunities," CIRM may be operating unlawfully. I am unable to find any mention of these votes and the required two-thirds outcomes in the publicly-available documents on the CIRM website. I do not understand how, if these procedures are not being followed, CIRM can be said to be acting in a lawful manner.

Should CIRM be backing away from the riskier, much less further advanced stem cell research it was created to advance in favor of cancer research? Should we expect CIRM to adhere at least to the letter of the law if not the intent?

UPDATE: more on the two-thirds vote requirement in my next post.

ANOTHER UPDATE: David Jensen may look into these issues.

CIRM, the stem cell bandwagon, and the hard sell

Biomedical science moves from one hot fashion to the next. A new technology emerges, investigators jump on the bandwagon and pitch it to the general public as the next great thing: a way to cure this, that or the other disease. I don't think the public understands just how extremely difficult it is to advance even the best ideas to a point where they have any hope of being transformed into a therapy, let alone the enormous difficulty of developing a therapeutic agent. We work with immensely complex systems (cells, tissues, the entire body) and, frequently, do not even have a halfway decent blueprint of the systems we're trying to manipulate.

Back when I started, the flavor of the month was gene therapy. Later, antisense, siRNA and genomics all had their moment in the spotlight. The beautiful thing is that these approaches sometimes pay off: it just takes a lot of time and slow, painful, grinding research. Often, they don't. Monoclonal antibodies were the hot new thing for drug development in the early 1980s, making the covers of Newsweek and Fortune in 1985. They faded from the public limelight, but investigators and biotech companies kept plugging away and, in 1997, important new therapies for cancer and autoimmune diseases based on humanized monoclonal antibodies began to emerge. It has been exciting and gratifying to watch the steady roll-out of important antibody-based therapies. Gene therapy, on the other hand: well, that's been a different story.

Which brings me to to stem cells. In 2001, the Bush administration severely limited research using human-embryo-derived stem cells. In response, in 2004, a group of activists sold California voters on the promise of the sexy new technology of "regenerative" medicine. California voters--perhaps a bit too trusting--jumped on the bandwagon, passing proposition 71 to fund the research. Scientists were heavily involved in making the pitch, most notably scientists who would directly benefit from this source of new grant funds (though they didn't make any great efforts--not any effort at all really--to point this out). Oh, by the way, how many lines of text in print advertisements or in scripts for TV and radio commercials did the proponents devote to conveying how challenging it would be to actually develop therapies? Or informing the lay public that stem cell-based therapies might not pan out at all?  Here's one hint: a central topic of one of the first stem-cell planning meetings held at my institution after Prop 71 passed was how to dampen down the very expectations that the campaign had raised way, way too high.

In 2009, restrictions on federal funding of human embryonic stem cell funding were dropped. Also, new sources of stem cells not involving human embryos have been developed. The California agency doling out the stem cell research funds (CIRM, California Institute for Regenerative Medicine), has finite access to borrowed money and will award its last grants in 2017.

The good news is that the federal restrictions are gone: now stem cell researchers can compete on equal footing with researchers taking other approaches to finding cures. Since their approach is so promising, they should feel confident that their proposals will fare well in the grant application review scrum. Oh, wait, surprise! They are already making noises about wanting the good people of California--already some of the most highly taxed in the nation--to sell  more bonds to support more research. Whose research? Theirs of course! Why compete for funding with investigators trying to cure cancer, nerve injury, diabetes etc with different approaches when you can pitch your story right to the well-meaning voters, going through an agency that is rife with conflicts of interest? If the stem cell folks decide to go ahead and ask the people of California for more money for research, will the proposition they write be more at aimed at curing diseases (in which case research using the most promising approaches, whether stem cell-based or not, will be considered for funding) or will it be equally aimed at funding their own labs and thus promoting their own careers (including salaries)?

My car's gas door

I was pulling out of the gas station yesterday and this scruffy looking guy drives up behind me in his old beater and starts energetically gesticulating. I didn't know what to make of this and thought he was probably angry at me for some inadvertent slight. He got out of his car and walked rapidly towards mine. Oh Oh.
Then he reaches toward my car and . . . shuts my gas cap cover--once again I accidentally left it open (not the cap; the door)--gives me a thumbs-up and walks back to his car.

I don't know why--maybe because I'm getting older--I forget to close the gas door every now and then. Some kind person always alerts me or, more often, runs up to my car and closes it themselves. It's almost always someone driving an older or fairly downscale car. I have never once left a gas station with the door open. It's a small thing, but anything that provides a reason for optimism is good.