Good News: Lancet Article Author Cooks Data on Vaccine/Autism Link Updated and Bumped: Lancet Retracts Wakefield’s 1998 Paper

(See important update, below)

The Times of London yesterday ran a story that Jenny McCarthy needs to read (h/t HotAir.com).  The article details an investigation of the results of the 1998 paper in the Lancet medical journal which shows a link between thimerosal in MMR vaccines and autism.  The investigation concludes the author, Andrew Wakefield, manipulated data to show the link.

Confidential medical documents and interviews with witnesses have established that Andrew Wakefield manipulated patients’ data, which triggered fears that the MMR triple vaccine to protect against measles, mumps and rubella was linked to the condition.

The research … claimed that the families of eight out of 12 children attending a routine clinic at the hospital had blamed MMR for their autism, and said that problems came on within days of the jab. The team also claimed to have discovered a new inflammatory bowel disease underlying the children’s conditions.

However, our investigation … reveals that: In most of the 12 cases, the children’s ailments as described in The Lancet were different from their hospital and GP records. Although the research paper claimed that problems came on within days of the jab, in only one case did medical records suggest this was true, and in many of the cases medical concerns had been raised before the children were vaccinated. Hospital pathologists, looking for inflammatory bowel disease, reported in the majority of cases that the gut was normal. This was then reviewed and the Lancet paper showed them as abnormal.

How convincing was Dr. Wakefield’s article?  Vaccination rates in the UK dropped from 98% to below 80%.  Some 1350 cases of measles have been confirmed in the UK, a 2400% increase over the number of confirmed cases in 1998.

Besides the obvious implications of manipulated data, no one seemed too concerned that Dr. Wakefield’s sample in the 1998 paper included only 12 children.  Time after time after time, studies have tried to replicate Dr. Wakefield’s results.  Not surprisingly (anymore), no one was able to.  Yet, that doesn’t stop parents from receiving news time warning about vaccines, the CDC from needing to issue a statement on the safety of thimerosal, the HHS from issuing money from the vaccine injury fund (!), and major presidential candidates from telling town hall attendees that there is a “strong link” between thimerosal and autism.

I don’t even think this qualifies for an Ig Nobel award.  It’s just infuriating.

Update (2/2/10): Today, the Lancet Medical Journal officially retracted Dr. Wakefield’s original 1998 paper.  The retraction was the final domino to fall in officially discrediting the specious claim linking thimerosal and autism.  How long will it take to rid the vaccine-autism link from the minds of worried parents?  That’s a different question.  Hopefully, though, doctors can now use this to help persuade overly-worried parents that vaccines are indeed safe.

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Meth and mirror images: errors in Nick Reding’s “Methland”

I recently picked up Nick Reding’s book Methland, which is about the blight of a small Iowa town due to methamphetamine use. I was interested in it because I had heard about it from NPR; I was interested in what Reding had to say about the chemistry of meth synthesis. What I found was pretty amusing.

I should pause to say that Reding was not focused on the chemistry at all — rather, his thesis was that meth was a mere symptom of the devastating effects of global economic forces on a small Iowa town. It’s well written and pretty gripping stuff.

I’m sure I’m not the only chemist who can get distracted by chemical explanations that’s just obviously wrong. But some of the explanations were just terribly, terribly wrong:

“Mirror imaging is a process whereby a chemical’s molecular structure is reversed, moving, for example, electrons from the bottom of a certain ring to the top, and vice versa. Pseudoephedrine, ephedrine, and methamphetamine are already near mirror images of one another. To make meth from ephedrine, it is necessary to remove a single oxygen atom from the outer electron ring. Thus ephedrine and methamphetamine not only look the same under a mass spectrometer, but both dilate the alveoli in the lungs and shrink blood vessels in the nose-hence ephedrine’s use as a decongestant while raising blood pressure and releasing adrenaline. The key difference is that meth, unlike ephedrine, prompts wide-scale releases of the neurotransmitters dopamine and epinephrine.

What the 1997 tests at the University of North Texas showed was that, at least in lab animals, mirror-image pseudoephedrine was equally as effective as regular pseudoephedrine as a decongestant. Unlike regular pseudo, however, the mirror-image version didn’t cause any side effects to the central nervous system, such as high blood pressure and a racing heart: the common “buzz” that one associates with cold medicine. Better yet for Warner-Lambert, mirror-image pseudoephedrine could only be synthesized into mirror-image methamphetamine, which, according to the Oregonian, had no stimulant effects and could not then be made into regular meth.” (quote thanks to Mike the Mad Biologist.)

Where to begin? First of all, “mirror imaging” is not a term; the word you’re looking for is, of course, enantiomers. The explanation about electrons is not correct; you can’t move electrons willy-nilly around rings. The comparison of ephedrine and methamphetamine as mirror images is wrong — they’re not even structural isomers. To make meth from ephedrine, you don’t “remove a single oxygen atom from the outer electron ring” (that sounds like something you do on the planet Zefu), you remove an oxygen and a hydrogen from a side chain by reduction. Ephedrine and methamphetamine most certainly DO NOT look the same under a mass spectrometer; I imagine it’s quite easy to distinguish the peaks from one another. Did Reding’s editor basically make a pass on the science stuff?

Reding’s book relies heavily on a series of articles on the meth epidemic written by Steve Suo of the Portland Oregonian. (If you look in Suo’s articles, you’ll see that Reding basically reworded the somewhat-more-correct chemistry explanation from Suo’s article.) Reding and Suo’s larger point  is that (-)-pseudoephedrine does not generate CNS-active methamphetamine, and that Warner-Lambert (and subsequently, Pfizer) were not interested enough in the larger public health issues to spend the money to push (-)-psuedoephedrine through the FDA approval process when the enantiomer they had was already quite lucrative.

So now that we’ve had a laugh about bad chemistry explanations, a question for everyone: how easy is it to get (-)-pseudoephedrine? The companies in India contacted by Suo said that they could supply ton quantities, no problem. I’m skeptical, but not that skeptical. Anyone out there know about this?

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How ethical are organic chemists?

In a recent commentary in the Journal of Organic Chemistry the editor-in-chief, C. Dale Poulter, frets about the shenanigans of some authors.^[JOC]

In 2008, 15 manuscripts were deactivated because the authors were unable to provide original copies of reports for high-resolution mass spectra or combustion analyses. By June of 2009, 13 of these manuscripts had been published in other journals. In seven publications, the inconsistent data were left unchanged, were removed, or were replaced with another set of inconsistent data or data obtained by another analytical technique was substituted.

…it is deeply disturbing that about a third of those authors chose to ignore the problems pointed out by JOC and submitted their manuscripts to other journals without adequately resolving the issues surrounding the data they originally reported. The responsibility for this behavior clearly rests on the senior authors, who are setting a horrible example for their young colleagues.

I thought it would be informative to assess what percentage this is compared to the total output of JOC. There are 1900 articles, more or less, published in JOC in any given year from my best estimates using ChemFeeds. Seven out of 1900 is ~0.4% of authors displaying truthiness. These hooligans would seem to represent a vanishingly small percentage, smaller than I would expect from other human endeavors. Although they can not be excused their misdemeanors, the numbers as a whole are comforting.

Link to commentary: Reporting Analytical Data

Mitch

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Federal Funding for Embryonic Stem Cell Research – Part 2

Thought I’d revisit my previous post on federal funding for embryonic stem cell research (FFESCR).

When we last left the situation, President Obama had signed an executive order allowing scientists to apply for FFESCR for more than just the 21 lines grandfathered in by President Bush’s 2001 executive order.  The NIH had 3 months to rewrite the rules governing FFESCR.  That was 9 March 2009.

Two days later, on 11 March 2009, President Obama signed HR 1105, the Omnibus Appropriations Act for the rest of fiscal year 2009.  Usually a non-newsworthy event.  However, section 509 contains what is known as the Dickey-Wicker amendment – an ammendment that has been in every appropriations bill since FY1997 – which states, in part:

None of the funds made available in this Act may be used for … research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death…

So two days after President Obama opened up FFESCR, he promptly closed FFESCR for the rest of the fiscal year (FY2009 ends 30 September 2009).  Oops.  That’s development 1.

Read more »

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Obama to Open Federal Funding for Embryonic Stem Cell Research

President Obama will announce tomorrowMonday that he is reversing President Bush’s ban on federal funding for embryonic stem cell research (AP, Bloomberg). With the announcement, President Obama will become the second American President to allow the use of federal funding for embryonic stem cell research. The first, of course, was President Bush. Bush’s 2001 announcement declared that federal funding would be available for the 21 lines created before the announcement, but no others.  The ban – and President Obama’s lifting of the ban – does not change the policy for privately-funded research.

One of the President’s advisors is quoted as saying Obama plans to “use sound, scientific practice and evidence, instead of dogma” to guide his policy, rebuking the previous administration.

The announcement indicates the NIH will have 3 months to write new rules governing the research.

The announcement comes three years after Japanese researchers have shown they can transform skin cells into cells with embryonic stem cell properties.  Last February, those results were confirmed by scientists at UCLA.  With the announcement, researchers can apply for funds for stem cell lines outside the original 21 just like they would apply for any other research grant.

Adult stem cells are currently used in the treatment of some 75 diseases.  With the current success of adult stem cells and the ability to turn cells into embryonic stem cells, I wonder if opening up funding is really necessary.

What do you think?

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Hot news on an old story

Some stories never seem to end. The hexacyclinol story is one of them. Is it over now?

I assume most readers will be familiar with the controversy about the two proposed structures of hexacyclinol, the original one (1) and a revised one (2), and about a total synthesis of 1 by James LaClair that was challenged by Rychnovsky and Porco on the basis of calculations and a synthesis of 2. The debate has been extensively covered in the blogosphere, e.g. in C&EN and by Derek Lowe.

Proposed structures of hexacyclinol

There is some new evidence now. An Italian group have simulated the 1H and 13C NMR spectra of both structures using DFT calculations (Org. Lett. ASAP). The calculated spectra seem to point to 2 as the correct structure. In addition, 1 cannot have the same spectra as 2 according to the calculations. The authors summarize: “The structure of hexacyclinol is confirmed to be 2. Furthermore, if 1 had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of 2 as to guarantee their distinction.” This seems to exclude LaClair’s claim that structure 1, which is the target of his total synthesis, happens to have the same spectral data as 2. The authors of the paper are of course reluctant to draw the obvious conclusion.

Update: This piece of news has been covered in Derek Lowe’s blog. There has been quite a discussion, with James LaClair participating in person! It has also appeared in The Chem Blog.

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Ethics of Conference Proceedings

Laws of Scientific Writing
First Law: Never plagiarize someone else’s work.
Second Law: Never plagiarize your own work.
Third Law: You must write papers that never conflict with the First or Second Law.

I pour myself a heavy glass of French Bordeaux. 

Presenting in your specialty’s conferences is a great experience. Often you get to travel far, present to an audience that actually cares about your topic, and be the shiny new penny of your sub-sub-sub-field. However there is one horrible trial you have to endure after the conference, the writing of your contribution to the conference proceedings.

For noble setiments of honesty, integrity, and righteous justice have no place.

In 90% of cases, the talk you present at the conference is already the meat of a paper you already published. Honestly, why present work that could potentially get scooped? I understand there are circumstances where you want to announce a breakthrough or solicit feedback from peers before publication, but these have to be the minority of circumstances.

Procrastination keeps me pure, but the deadline approaches.

So I’m left with the unethical quandary of writing two peer-reviewed papers on the exact same topic, one of which is already published. I asked guidance by people older than myself. The post-docs described how bad they felt their first time, but how it gets easier the more times they have done it. I’m left wondering if conference proceedings are a gateway publication.

I can’t watch what I’m doing. My fingers apply pressure to ctrl, c, and v in an unsettling rhythm.

I edit the text of my first paper with the help of Maz. “Films” are now “layers”, “solutions” are now “metal-organic precursors”, and “nanometers” are now “micrograms per centimeter squared”. Uglier images are selected instead of pretty ones. Excel graphs are re-worked. My beautiful prose are slaughtered into stumpy fragments. I still feel guilty, but the task had to get done. I can’t spend all my research time writing papers on already published work. There are immediate research endeavors that demand my attention.

As I finish writing, I stare into the bottle of wine and let the bitter notes of weighted apathy corrupt my soul.

Mitch

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Porn at the NSF?

For those of you who dont know, Chuck Grassley, ranking member of the Finance Committee on the Senate is doing an investigation into the National Science Foundation. Why? Well, because people have been spending time looking at porn instead of doing what they’re suppose to do (look through our grant proposals perhaps?)

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Chuck Grassley knows it when he sees it.

The “it,” of course, is pornography. And Grassley has seen it deep in a demurely titled section of a report from the National Science Foundation — a report that says NSF employees have been spending significant amounts of company time on smut sites and in other explicit pursuits….

In one particularly egregious case, the report says one NSF “senior official” was discovered to have spent as much as 20 percent of his working hours over a two-year interval “viewing sexually explicit images and engaging in sexually explicit online ‘chats’ with various women.”

Investigators calculated the value of the time lost at more than $58,000 — for that employee alone.

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I dont think this spells good news for people trying to get grants right now. Amongst my friends and I, we can already imagine the responses to grants.

Prof. So and So,

We are unable to fund your proposal because….it costs money to investigate people looking into porn at work.

Sincerely,

The NSF and the Senate

For more, here’s the link: Grassley launches porn inquiry into the NSF

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A Word on Research Misconduct

Dig out your dictionary and look up the word “hyperbole” (I know, it might be a while since you’ve last had English class)—exaggerated statement or claims not intended to be taken seriously.  I tend to hyperbolize a bit when I replay an incident that happened at the bar or in class, which I attribute to the fact that I’m a terrible storyteller.  I think we all do it to a certain extent.  I know I’ve once said something to the effect of, “It was the greatest movie, ever…in the history of humans.”  A hyperbole at its finest.

While most common vernacular is riddled with hyperboles, I’d argue that the majority of intellectual study makes an effort to stay away from gross exaggerations (with history being the exception).  In particular, science is the observation and study of the physical world, and it leaves no room for hyperboles.  Just facts.  For example, if you mix an aqueous solution of silver nitrate with an aqueous solution of sodium chloride it is a fact that a precipitate will form.  There are no equivocations about scientific facts.  Though, science sometimes falls short when making assumptions that connect two or more facts into one coherent theory or proposal.  Still, these assumptions, en route to a new theory, are usually reasonable if not simplistic (i.e. Occam’s razor).

What about bad data?  Of course, there are ways to make our raw data more “natural” without exaggerating.  In the event that we have to plot data points, for example, as scientists we can exclude data that “doesn’t belong.”  We call these anomalies “outliers” and there is statistical rationale as to why a stray might be “bounced” from the data set without any bias to the result.  But even in these cases, the data point is often so far away from the others that including it might be a detriment to a fact about Mother Nature.

What irritates me to no extent is a term I refer to as “hyperbolized research.”  We have all seen these situations before: yields that are bumped a good 5 to 10 to 50%, data that is fit just right, patent procedures that are not reproducible.  Why are these practices tolerated?  Contemporary science is themed “publish or perish,” which essentially means that if you are not producing enough results (nevermind quality) you will soon be unemployed.  I recall hearing stories about early 20^th century scientists who studied science without the proverbial gun to their respective heads and still made great findings.  A lot of these experiments were groundbreaking, marvelous and truly beautiful.

It’s no surprise that this issue of “publish or perish” rears its ugly head in science.  Society is incredibly fast-paced, and science is certainly trying to keep up.  But, it’s really hard to do so with a tiny, bankrupt research group (where most if not all members are teaching) versus a behemoth firm with hundreds of years of experience and millions of dollars of materials to use. 

So, what do groups do to keep pace (or at least appease the boss)?  “How did you do with that reaction you couldn’t get to work last week?”  “Um…I got 98% yield with 95% ee.”  “Great, let’s write up a manuscript and submit to JACS.”  I’ve heard stories of “big name” research groups who’s members purposely inflate their yields to keep “the man” happy.  In these cases, researchers keep two sets of lab notebooks: the real one (usually under lock and key with the actual experimental results) and the boss’ one (usually kept in the open, so the boss can see how his researcher got a 90% yield on chemistry that is next to impossible to reproduce).  The bottom line is that papers get published, lectures are given and proposals are funded—criminality is rewarded.  How is this right?  Furthermore, how is it fair to another researcher who needs to repeat the results?

Have we not learned anything from the Bell Lab incident?  For those not familiar, Hendrik Schön was a groundbreaking physicist working for Bell Labs in the late 1990’s.  He was purportedly on par to win a Nobel Prize with his creation of an “organic molecular transistor.”  The papers describing this work were met with criticism in the scientific community and at some point (c. 2001), Bell Labs launched an internal investigatory committee to examine Schön’s work.  Their final report ultimately alleged 24 accounts of misconduct that were essentially fit into three categories: “Substitution of data,” “unrealistic precision of data,” “Results that contradict known physics.”  In the end, he was ultimately stripped of his doctoral degree.  But think about the repercussions of not investigating Schön’s findings.  Had Schön’s work not been policed, potentially millions of dollars would’ve been invested into falsified research.  While I’m aware that Bell Labs was recently closed, without insinuating anything, it makes me wonder if this Schön incident had any weight in the lab’s termination.

Rex Dalton covered the aftermath of this incident along with several other examples of research misconduct (Nature 2002, 420, 728-729).  He ultimately offered up the following observation:

“Science may be self-correcting, but sometimes it is a painfully slow process.”

Perhaps he’s right.  Sure, several papers are going to be questioned in the future.  And of those papers, a few might be blatant lies.  How much time is it going to take to correct these mistakes?  According to Corey: “Occasionally, blatantly wrong science is published, and to the credit of synthetic chemistry, the corrections usually come quickly and cleanly.”  Case in point?  The hexacyclinol incident that was excellently covered by C&EN and by a couple of fellow bloggers: Derek Lowe and Paul Docherty.  In this case, there was a rapid turn around (possibly due to public interest).  However, this case might be the exception.  It could be years before a questionable project is proven incorrect.

I know…you want me to provide a solution.  Maybe there isn’t an immediate, reasonable answer.  But, alas, here’s what I’ve uncovered: there are a few wonderful articles in J. Chem. Ed. about scientific misconduct, which both hover around the LBNL and Bell Lab incidents (see: J. Chem. Ed. 2002, 79, 1391; ibid. 2005, 82, 1521).  The authors’ messages (albeit bluntly or implied) were that ethics and empathy should be at the forefront in the early years of scientific training.  Some people cannot discern between right and wrong and teachers should do their jobs by teaching students about the rights and responsibilities of being a scientist.  While I did not receive formal training on scientific misconduct, I was given a lambasting for bordering on plagiarism my freshman year of college.   I learned my lesson early—you and your lab partner need to keep separate lab notebooks.  Perhaps this experience has formed me into the scientist that I am today (I’m anal-retentive about my lab notebook). 

I guess there is a remaining question still looming.  What sparked this rant about “doing the right thing”?  I’ve been repeating experiments for the past couple of months that were reported to be exceptionally clean (requiring no chromatography) and high yielding.  Most of these reactions have tanked—miserably—even with exceptional preparation and precision.  So, I’m painstakingly re-optimizing experimental procedures so someone else doesn’t have to.  It’s taking a while—much longer than it reasonably should.  But, hey, “sometimes (correcting science) is a painfully slow process.” 

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The Interface of Rose Bowls and Priestly Medals

Few equate chemistry with (American) football.  You could imagine my surprise to see that this year’s chemistry SURP program featured a guest lecturer that would cover the symbiotic relationship between ethics and athletics.  My freshman year of college, I had a philosophy professor that taught Aristotle’s Nicomachean ethics through a football analogy, but that’s the closest I’ve ever made a connection between scholarly aptitude and a rugged manly sport.  After getting “special permission” from the department to attend (I’m definitely not a SURP student), I got the rare opportunity to sit in the same room with a prominent sports figure—the head coach of our University’s football team.

Those who know me will probably know which coach I’m talking about, but for the sake of anonymity, I’ll simply refer to him as “Coach.”  Arriving a few minutes late, “Coach” darted through the door and up to the head of the classroom avoiding eye contact.  Truthfully, I saw no difference between his social manner and most other profs (no smiling, reasonably polite yet focused).  Rather than stand in a traditional lecturing position, Coach elected to sit at eye level with the 20 of us (some of whom were there to bombard him with football questions).  He started the discussion by saying, “I’m not really sure what I’m supposed to talk about, but this’ll be pretty informal.  I figure I’ll talk about ethics from my perspective then answer any questions you guys have, except about the football team.”  That was a pretty reasonable request because if I were hypothetically in a room with Terry Francona, he probably wouldn’t want me to ask why he hadn’t benched Manny Ramirez weeks ago.

The crux of Coach’s discussion was two-fold and actually quite simple: (a) goal setting is paramount to excellence and (b) you have to learn to overcome anything that gets in the way of preventing you from reaching your goals.  He offered up this story:

“I asked one of my wide receivers, ‘what’s your goal for the year.’  And, he says, ‘Coach, I want to catch 50 passes this season.’  That’s not a goal.  That’s an end result.  His goal should be to push himself to become a better player so that you are able to catch 50 passes…Now, if you mix distractions into the equation, you’ve introduced another hurdle to cross for you to reach your goal.”

At one point, Coach drew on King’s street sweeper quotation.  For those of you who are not familiar here it is:

“If you are called to be a street sweeper, sweep streets even as Michelangelo painted, or Beethoven composed music, or Shakespeare wrote poetry. Sweep streets so well that all the hosts of heaven and earth will pause to say, ‘Here lived a great street sweeper who did his job well.’”

Coach’s overall message?  Give it everything you have and you can sleep easy at night knowing you did your best.  “It” in his case is defined as hard work on the football field.

That night I tried to distill away the football and civil rights references to understand how I could apply Coach’s lessons to my job/education as a chemist.  I asked myself, “should I focus on making sure I have 25 papers before I leave grad school (I know, it’s a dream) or should I spend more time on developing my skills to be the best chemist I can be so that I can give my best at trying to get 25 papers before graduate school.”  Ultimately I arrived at the later option. 

I realize that while I do give an honest effort on most days, there’s always room for improvement.  I argue that the blogging, literature searching and even podcasts I listen to are making me become a smarter scientist.  But, do I really need to be listening to the new Tantric album while I’m trying to think my way through a reaction, for example?  Should I eliminate my distractions (including occasional, social interaction) and maintain focus at all times?  When do you call it a day?  8 hours?  13?  20?  When is the job truly done?  How do you correctly balance work and family/personal time?  Perhaps I don’t have a good objective answer to any of these questions.  But I’ll tell you that my lab bench and desk are now the cleanest and distraction-free they’ve been in a while.  Let’s see how long this lasts.

P.S.  I definitely plan on seeing the new X-Files movie this weekend (I own an “Asian Collectors Edition” of seasons 1-9).  It appears to have bad reviews, but I’m a diehard fan, so I’ll go see it anyway.  How about you?

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