Return to AACR: Every Time I Think I’m Out, They Pull Me Back In

The 2012 AACR Annual Meeting starts on Friday, March 31st in Chicago, IL.  Guess who’s been “elected” to represent my company at a “mini-symposia”?  I have been scrambling to prepare materials, slides, and everything has to go past our marketing and legal teams.  At least two conference calls a day for the last five days. My company has OCD about logos… you can’t invert the colors, you can’t size them larger than such and such, etc.

Sorry for the lapse in video and blog entries, but the concept of “free time” is elusive of late.  I’ll try to bring back some photos or stories.  I think the big idea this year is going to be circulating tumor cells, and if I can find the time, I’ll put together an entry on them. The other hot topic, and one I’ll probably work into my own 10 minute session, will be long non-coding RNAs (lncRNAs).

This is the video from last year’s annual meeting… I haven’t seen one from this year.

The Story of Chad Kerksick and the OU – IRB

Wow!  Just wow!  I’ve been reading the background on the story from last November’s Huffington Post article on University of Oklahoma Assistant Professor Chad Kerksick.  As I mentioned in the previous post, I did some work with his lab a few years ago, and it was my first encounter with muscle punches or muscle cores in exercise physiology.  They were a nice group, lots of laughter and smiles and good questions and everybody seemed to be friends with everyone else.  As I page through the Institutional Review Board investigative findings, it paints a very different picture.  One of Dr. Kerksick’s grad students/study managers pulled a “whistle-blower” on his research practices with regards to the way he enrolled volunteers, performed biopsies of muscle and fat tissue, subsequently handled the material and even how he documented the results.

I might have a slightly different perspective on this than the average person.  I’ve mentioned before that what most people would find shocking in a research lab is how young everyone is.  Most research in academic labs is done by 20-26 year olds (look at the picture above!) and rarely will you find anyone over 35 in the lab proper.  This is different from medical centers and institutes as well as pharma and biotechs where the research staff tend to be older and better trained.

Imagine a company run entirely by one CEO and an army of interns, and you have an idea of what the academic research lab is like.  The “CEO” or principal investigator, in this case, is an exercise physiologist, and if my brief exposure is any guide, a good one.  He studies exercise, body-building and athletes.  He fulfills the image of the jock-scientist, and his group are mostly weight-lifters, student athletes and future sports medicine folks… not your classic molecular biology or medical group.

A needle biopsy device

They paid volunteers to exercise on a treadmill and then collected a sample of muscle tissue from the thigh using a hollow needle, larger than a syringe needle, or alternately, a sample  of fat/adipose tissue was taken from the abdomen.  The volunteers received a lidocaine shot to prevent local pain, but the tissue is certainly traumatized, resulting in bruising and some light bleeding.  I’m sure it’s a very low-risk procedure, but still makes me a bit queasy to imagine what is essentially minor invasive surgery being done in a gym area on a sweaty student by another student.  My own misgivings aside, this is not unlike what is going on at medical schools and med tech programs around the world.  It’s probably about as risky as having your ears pierced or a tattoo added.

On to the accusations.  The review came about as the result of video and research records submitted by one of Chad’s grad students, Patrick Dib.  Patrick, going by statements Chad made in response, has been the instigator of other, similar investigations at USC and UCLA.  I’m very suspicious that I’m not getting the full story on his background, and I’m having a hard time making sense of the “he said, she said” but three things are clear:

1.  Chad Kerksick didn’t adhere to the highest standards of human research in terms of record keeping and minimizing human risk or suffering.  He was sloppy and irresponsible in supervising his grad students, probably as the result of all that laughter and all those smiles.  People were probably TOO chummy to really bring the axe down on misconduct.  “Hindsight is 20/20”.

2.  The kind of things the Institutional Review Board found were typical of many labs at primarily undergraduate institutions.  It’s like any other audit; if you look hard enough, you’ll find something.  Some criticisms included leaving lidocaine in an unlocked drawer in a locked room, or submitting his own muscle tissue to a study (which I didn’t know wasn’t allowed either… I’ve done it myself).

3.  The story in the local media and the HuffPo doesn’t really convey the magnitude of infractions committed.  Emails with jokes like “bring me Dibs head in a box, or at least his thumbs” are represented as serious death threats.  Muscle cores sound very scary, but are routine in this field of study and have been performed hundreds of times without adverse event.

The resolution to the story:  Chad received a 1 year leave of absence, agreed to leave OU during that time, and received 18 months salary as part of an arbitration.  His existing research has been brought to a halt by the IRB.

One note:  the most serious allegations were data tampering, which I don’t think was ever substantiated, and forcing students to submit to fat biopsies, which Kerksick insists was part of the training.  I find his explanation makes sense and I’m inclined to give him the benefit of the doubt.  Medical techs and ER techs often work on each other or themselves as practice, and it sounds like that’s what happened here: the procedures were part of education, not research.  I also can’t speak to his private funding sources.

What I would like to be the message from Chad’s story is that IRB’s (the institutional review board that governs human research) really need to start conducting regular audits with the same scrutiny they use in investigations of incidents.  It protects the researcher and the institution from these kinds of “shocking revelations”

For the rest of the story and further reading:

Read the IRB decision here.

Read Kerksick’s responses.

News9 story.

I heart Abbie Smith (ERV)

Update: There are/were TWO Abbie Smith’s at OU (which would be a good name for a band, BTW). I met the Exercise Physiologist Abbie Smith in 2007, and I follow the blog of the brunette Abbie Smith, ERV. That explains a LOT of things that were bugging me, like hair color and research fields. Perhaps I should just say “I heart ERV”, because she (brunette Abbie) is awesome.

I met Abbie Smith at University of Oklahoma in Norman, OK back in 2007. She was a young grad student in the Kerksick lab* and I was there to help them kick-start a molecular biology/real-time PCR program for their work in exercise physiology. She impressed me then, and she impresses me now. The fact that she’s taken up virology, science advocacy, and blogging is icing on the cake. Her blog is here, called ERV. I highly recommend you check it out. She has a quirky, dry humor that I love and her passion for her topic shows through her writing.

Here she is, recently debating Dr. Steve Kern on creationism being taught in the public schools at Oklahoma City Community College:

You have to love the energy, the enthusiasm, and the down-to-earth discussion of why creationism/evolution discussion matters.

*As an aside, Chad Kerksick was recently the subject of a news report by the Huffington Post on his use of grad students as medical guinea pigs. As I recall, many of the grad students submitted “muscle cores”, which are small tubular chunks of muscle tissue removed from the thigh using a device very similar to a large-bore syringe needle. I’m sure it’s quite unpleasant and leaves some bruising, but I’m not sure I understand how that was a violation of an ethical code (UPDATE:  more in separate post!). Researchers are often used for control samples. For example, I submitted 40 mL of blood almost every week for months as a control sample in immune profiling. The con was it made me a little woozy for a while and I hate needles. The plus was a small donor fee ($40) and the fact that I now know more about my immune profile (I walk around with a subclinical monocytosis), I could detect when I was about to get sick, and it helped out the progress of our study. I don’t know enough about Chad’s situation to condemn or condone, but he was a very nice guy in my interactions with him.

Assessing the ‘true’ effect of active antidepressant therapy v. placebo

I’ve just read this article in The British Journal of Psychiatry (2011) 199: 501-507 .    It proposes an explanation for why so many reviews fail to find a clinically relevant difference between antidepressants and placebo:  the way the data is analyzed.  The vast majority of studies use a statistical model called ANCOVA (analysis of covariance), which assumes a linear relationship between two variables.  Let’s say on one axis we put a score for how improved a patient’s depression is.  On the other axis we might put how severe the person’s depression was to begin with.  That would allow us to evaluate if there is an interdependent relationship between those two factors: they are “covariant”.

However, the problem highlighted in this paper is that depression and response to antidepressants may not be well represented with a smooth line.  People may not exist along a continuous curve of depression, but rather fall into distinct groupings and to draw a line connecting those groups ruins the validity of the ANCOVA analysis.  Instead, we might analyze the data by category:  people who respond to drug, people who don’t respond to drug, and people who respond a little, then in each category measure how many people have serious depression, major depression, and minor depression, as measured on a depressive symptoms scale.  They did this using something called the “mixture model” that I was unfamiliar with.

The authors point to another paper I don’t have access to that suggests that the clinical significant effects are buried in the very minor improvements seen in some categories of patients.  I suppose the best analogy I can come up with is evaluating a special fertilizer used to enhance the growth of garden crops.  We apply that fertilizer to our garden but also the lawn, the patio and the driveway.   Let’s say a total of 600 square meters are fertilized, where the garden is only 100 square meters.  We produce 30 kg of crops versus 15 kg the previous year, unfertilized.  You could report this as generating 15 kg increase per 100 sq m (Effectiveness Index = 0.15 kg/m2), or as 15 kg increase per 600 sq m (Effectiveness Index = 0.025 kg/m2).  If you are trying to figure whether this fertilizer is cost effective, the difference between analyzing only the garden and the entire fertilized area is significant.

Likewise, depression is often being over-treated as a matter of course.  That sounds deplorable, but it’s a very blunt instrument and sometimes necessary to treat more people than truly respond.  NNT is the “number needed to treat”, and we use it as a way of measuring how many non-responders have to be treated to get one truly effective response.  The authors of this paper produce values of 6 for response and 8 for remission.  That means you need to treat 6 people who don’t respond fully in order to get one clinically significant response, and 8 people have to be treated to get a remission of depression.  Not inspiring, I know, but actually much better than most previous studies.  I out of 8 people on antidepressants are getting enough of a benefit out of the drugs to live a more-or-less normal life.  One in 6 are at least getting measurable relief.  The other 5, the ones who are suffering side effects with no significant relief, are the ones that concern me most on this topic.

Final point, because I didn’t really cover it.  The authors found in the data a “bimodal response profile” in most cases (there were a few exceptions).  That means if we separate the patient set into two groups, they are much more distinct in terms of response to drug.

On the left here you should see Figure 1 from the paper.  The total population looks relatively flat, but when subdivided, two populations clearly emerge (bimodal distribution).

I’m very interested in this because it was my initial assumption/bias that this would be the case.  I assume that we’re broadcasting this drug to everyone during clinical trials, regardless of whether we know they will respond, and I would fully expect that a drug that changes serotonin biology (SSRIs) would only be effective in patients with an underlying serotonin problem.  I’m always very careful when I find data to support my preconceptions, so I’m trying to scrutinize this analysis as carefully as possible to avoid getting carried away with confirmation bias.

A big part of my own research has been into how to randomize cancer patients on a responder/non-responder profile of “biomarkers“, so this type of bimodal distribution is very significant to me.


Some Foods Contain Nicotine… But Not Much

One fact frequently used by proponents of e-cigarettes is that regulating their favorite product because it contains nicotine means we should also regulate foods that contain nicotine.  Yes, many foods we eat produce measurable levels of nicotine.  Tomatoes, potatoes, cauliflower, and green peppers are known to contain small amounts, and black tea is sometimes suggested to contain some, although recent tests don’t confirm this.

Does this nicotine affect us?  Are we, like Homer Simpson, creating addictive tomato-tobacco hybrids (Tomacco)?  The short answer is no.  The dose makes the poison, and in this case the dose of nicotine you receive from a cup of these vegetables barely registers when compared on the same graph with the nicotine content of a single cigarette.  The figure below uses figures produced in a letter to the editor of the NEJM.  Cooked vegetables, especially boiled, will probably have lower values, but the amount is only really significant in relation to the specificity of clinical tests designed to detect nicotine (and cotinine, its metabolite) levels in the blood.

What this figure also highlights is the potential harm from the abundant nicotine found in e-cigarette juice.  The cartridges are intended to be used many, many times so that the delivered dose is not much different than a single smoking session with a real cigarette, but it would be a simple thing to forget and over-consume from the cartridge, resulting in increased total nicotine intake.

I’ve covered it before, and frankly I have more important topics to deal with, but I personally think there’s not enough evidence to conclude that e-cigarettes are as safe as the FDA regulated nicotine replacement therapies designed to help people quit.  As always, I recommend anyone with questions about their health consult an actual physician.  I’m just some guy on the Internet.

March of Progress in Cancer Treatment

I came across this today, and I thought it might give some people hope for the future.  The source is: Cancer Research UK, Survival Statistics for the most common cancers.

What really strikes me is the number of cancers where 5 year survival is over 50%.  Pancreatic, Lung and Esophagus cancer are still very deadly, though.

Now take a look at where we’ve come from since 1971:

You can see that many cancers have radically improved in 10 year survival.  There’s still much room for improvement, but I take a lot of comfort in the progress we’ve made and are continuing to make.

My postdoc was at a cancer research center that shared a building with a cancer treatment clinic.  Every day I’d walk past the waiting room and the chemo chairs and see someone’s mother, grandmother, father, brother, sister awaiting treatment.  It was great motivation to take my job seriously.  F–k Cancer, Support Cancer Research!

Humor: The Methodology Section Translator

This is hilariously accurate.  I think people forget that most university research is done by 20-25 year olds… Normal grad students who just want to get their degrees.  I always try to remember that when reading a paper with surprising findings.  My own estimate, I’d guess that 60%+ of the retracted papers and unreplicated findings aren’t some vast conspiracy or collusion with Big Pharma… they’re some poor grad student who didn’t document well, or after the 8 gazillionth time running a gel to find a band of interest, finally broke down and just Photoshopped the fracking thing into the TIFF.

By c0nc0rdance Posted in Humor

Menin Doesn’t Satisfy the Challenge to the Discovery Institute

“The MEN1 gene, mutations in which are responsible for multiple endocrine neoplasia type 1 (MEN1), encodes a 610-amino acid protein, denoted menin. The amino acid sequence of this putative tumor suppressor offers no clue to the function or subcellular location of the protein.”
–Proc Natl Acad Sci U S A. 1998 February 17; 95(4): 1630–1634.

I got a request to test the Menin gene today to see if it meets the criteria of the challenge to the Discovery Institute to locate a gene with no homology to other genes: in other words, a gene that appears to have been created by non-natural processes.  This is the mirror of their challenge to produce an observed instance of “macroevolutionary change” which is based on false premises… I’ll save that for a later post.

What about Menin?  Well, in 1998 we didn’t have any homologous proteins… but a lot has changed since that young person’s textbook was printed.  Below I’ll put a screen shot from Homologene .  For the sake of brevity, I’m only including the first part of the protein sequence.

Sorry for the graphics quality.  Each of those letters represents an amino acid in the protein.  Notice that even the invertebrates (fruit fly, mosquito) have a menin homolog, although there’s an increase in differences the further away we travel from the common ancestor of each pair.  Chimp and Human menin sequences are identical across the full length.

So, no, this doesn’t meet the challenge.  If you want to read more about Menin, a tumor suppressor protein where variations are tied to a variety of diseases, go here.

My Mission Statement (yes, really)

I know, I know… mission statements are for corporate drones, but honestly I wanted to make it clear why I’m continuing in making videos and running a blog, both to you and to myself. Consider this a contract, of sorts: I promise to keep evaluating scientific claims if you promise to watch and respond thoughtfully.