Call for an accounting

I have my doubts about the efficacy of the growing welter of petitions for every possible cause, but at least we can express our concerns. There is now a petition to nvestigate psychiatric research misconduct at the University of Minnesota, my place of work, so I feel an obligation to bring it up.

Dan Markingson was mentally ill and committed suicide almost ten years ago. He was in bad shape and was committed for psychiatric care (he was suffering from violent delusions) when he was recruited into a study by AstraZeneca of anti-psychotic drugs. This was not a good idea; running an experimental clinical trial on patients at serious risk of doing physical harm to themselves and others is not recommended.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother’s throat, but had not threatened to harm himself—was a legitimate target for recruitment.

He was also signed on by his own consent: the consent of a committed mental patient with serious concerns about his competence, and against the wishes of his mother.

The petition does not assign blame, but only asks for an objective examination by external reviewers. You know there’s a problem when the university’s own bioethicists are supporting the call for investigation.

In 2009, the Minnesota state legislature passed “Dan’s Law,” which prohibits researchers from recruiting a patient under an involuntary commitment order into a psychiatric drug study. Media outlets such as Mother Jones, the St. Paul Pioneer Press, City Pages and Scientific American have published accounts of Dan’s story. His story was also featured in the documentary film, Off Label. In 2010, AstraZeneca, the sponsor of the study in which Dan died, settled federal fraud charges for $520 million, and a University of Minnesota psychiatrist was implicated. Last year, the Minnesota Board of Social Work found serious wrongdoing by the study coordinator for the research study in which Dan died.

More recently, evidence of fraud and serious privacy violations in psychiatric studies at the university have emerged. It is possible that other research subjects have died or suffered serious injuries, or that they have been mistreated in other ways. Bioethicists at the University of Minnesota itself have called for an external investigation, yet the university still refuses.

I signed it. I’d like to recommend that more people sign it.

Another scary aspect of this is the possible abuse of science. There’s some funny stuff going on in clinical trials…

A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, “The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the ‘right’ questions.

I’ve been reading Goldacre’s Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients. There really are grounds for more global concern.

What I taught today: molecular biology of bat wings

Hard to believe, I know, but this class actually hangs together and has a plan. A while back, we talked about the whole cis vs. trans debate, and on Monday we went through another prolonged exercise in epistatic analysis in which the students wondered why we don’t just do genetic engineering and sequence analysis to figure out how things work, so today we reviewed a primary research paper by Chris Cretekos (pdf) that teased apart the role of one regulatory element to one gene, Prx1, in modifying the length of limbs. It’s a cool paper, you should read it. It’s kind of hard to replicate the teaching experience in a blog post, though, because what I did most of the hour was ask questions and coax the students into explaining methods and figures and charts.

I’m afraid that what you’re going to have to do is apply for admission to UMM, register for classes, and take one of my upper level courses. I always have students read papers direct from the scientific literature, and then I torture them with questions until they extract meaning from them. It’s fun!

Although…it would also be cool to have a scientific-paper reading and analysis session at a conference, now wouldn’t it? Especially if it could be done over beer.

Yay! Another reservoir of sequestered carbon can now be released into the atmosphere!

Uh, that was a sarcastic “yay”. Japan is planning to extract natural gas from frozen methane hydrates in the deep ocean. It’s good for them in the short-term — they’ll be able to meet their natural gas needs for decades. But, oh boy, wait until everyone starts liberating yet another locked-up carbon source for energy.

I’m sweating already.

Good report on Federal wildlife torture from a surprising source

Sometimes, even Fox News gets one right [trigger warnings, as you might expect from the post title]:

The brutal approach by Wildlife Services is part of a culture of animal cruelty that has long persisted within an agency that uses taxpayer money to wage an unnecessary war on wildlife, according to two U.S. congressmen who have repeatedly called for a thorough investigation.

“This agency has become an outlet for people to abuse animals for no particular reason,” Rep. John Campbell, R-Calif., told FoxNews.com.

“It is completely out of control,” he said. “They need to be brought into the 21st century.”

The story covers an investigation that was spurred, in part, by revelations that USDA “Wildlife Services” employee Jamie P. Olson had posted photos of his dogs tearing trapped coyotes to pieces on Facebook. (Previously, on Pharyngula.) The issue’s been kept on the front burner by my colleague Camilla Fox at Project Coyote; she and her organization deserve your attention and support.

Brilliant! A positive story from the gamer community

This is very nice: a fellow hacked Donkey Kong for his daughter — he swapped the characters so that Pauline is rescuing Mario.

Donkey-Kong-Ellis-Edition

This would have been so easy for Nintendo to have done, it’s rather revealing that they didn’t.

Oh, and the gamer who did this generally got accolades from the community…but don’t read any youtube comments on the topic.

Reddit could be excellent

Rebecca Watson has a very good summary of her SXSW panel on Reddit. Reddit has an introspection problem (they don’t) and a criticism problem (they don’t accept it, even when they have a serious problem that needs correcting).

The panel then moved on to discussing where Reddit came from, how it differed from other forums and communities, and how its features have impacted both the internal community and the outside world.

On that last point, I talked a bit about how I think that Reddit’s shared values of “freedom of speech” and anonymity combine with the “karma” voting system to create an ideal environment for the proliferation and normalization of bigotry and hate. I showed screenshots that I grabbed from just the previous few days of posts on r/ShitRedditSays, with credit given and a brief detour for us to talk about whether the existence of a self-critical subreddit like SRS is cause for hope (my answer being “no,” because SRS is popularly seen by other Redditors not as a helpful part of Reddit but as a hateful, misguided, humorless, and occasionally dangerous outside threat, an idea that supports my forthcoming point that Redditors hate and resist criticism). I pointed out that the karma system resulted in bigoted ideas being not just tolerated but rewarded, sometimes by people thinking they were being edgy and ironic and sometimes by actual hate groups like Stormfront, a racist forum that encourages users to game Reddit so that their ideology is represented prominently.

Free speech is a good thing except when you fetishize it to such a degree that it gets elevated well above personal responsibility.

Also, I think the majority of Reddit users are basically good people; their success at promoting great causes (which Rebecca talks about) is testimony to that. However, by refusing to address reasonable limits on what ought to be said, they’ve privileged a tiny minority of trolls and wreckers and parasites who love to rampage and ruin the site’s reputation for others…and management vacillates over doing anything about it, because they seem to think they need to worship the 4chan version of ‘free speech’.

Seriously: does encouraging the existence of a “jailbait” forum that tramples over the civil rights of the targets of their surreptitious photography represent a net increase in civil liberty, or a net decrease? If that’s what you care about, this ideal of personal freedom, then handing it to abusers at the expense of the innocent is not advancing your goals at all. Unless your goal is just making cheap porn and trampling on women.

A nice illustration of the problem:

reddit

Prediction: Some of you will read this and grab a roll of tape

“Ratters”. Ick.

These are pathetic people who use a canned remote administration tool (RAT) to seize control of other people’s computers…especially to activate their laptop cameras so they can spy on them (which is why I predict some of you will want to tape over your camera). Ars Technica has a whole article on these deeply creepy human beings.

Not all human beings, obviously. Unfortunately, most of them seem to be feeble little child-men.

By finding their way to forums filled with other ratters, these men—and they appear to be almost exclusively men—gain community validation for their actions. “lol I have some good news for u guys we will all die sometime, really glad to know that there are other people like me who do this shit,” one poster wrote. “Always thought it was some kind of wierd sick fetish because i enjoy messing with my girl slaves.”

Please, guys, could you stop making me ashamed of my sex? What the fuck is the matter with you?

What I taught today: farewell to flies (for a while)

A good portion of what I’ve been teaching so far uses Drosophila as a model system — it’s the baseline for modern molecular genetics. Unfortunately, it’s also a really weird animal: highly derived, specialized for rapid, robust development, and as we’ve learned more about it, it seems it has been layering on more and more levels of control of patterning. The ancestral system of establishing the body plan was far simpler, and evolution has worked in its clumsy, chance-driven way to pile up and repurpose molecular patterning mechanisms to reinforce the reliability of development. So I promised the students that this would be the last day I talk about insects for a while…we’ll switch to vertebrates so they can get a better picture of a simpler, primitive system. What we’ll see is many familiar genes from flies, used in some different (but related!) ways in vertebrates.

But today I continued the theme of epistatic interactions from last week. Previously, we’d talked about gap genes — genes that were expressed in a handful of broad stripes in the early embryo, and which were regulated in part by the even broader gradient of bicoid expression. The next level of the hierarchy are the pair rule genes, which are expressed in alternating stripes — 7 pairs of stripes for 14 segments.

First point: notice that we are seeing a hierarchy, a descending pattern of regulatory control, and that the outcome of the hierarchy is increasing complexity. One gene, bicoid sets up a gradient that allows cells to sense position by reading the concentration of the gene; the next step leverages that gradient to create multiple broad domains; and the pair rule genes read concentrations of gap genes and uses the boundaries between them to set up even more, smaller and more precise domains of stripes that establish the animal’s segments.

This is epigenesis made obvious. The 14 stripes of the pair rule genes are not present in the oocyte; they emerge via patterns of interactions between cells and genes. The information present in the embryo, as measured by the precise and reproducible arrays of cells expressing specific genes, increases over time.

So part of the story is hierarchy, where a complex pattern at one stage is dependent on its antecedents. But another part of the story is peer interaction. Cells are inheriting potentials that are established by a cascading sequence of regulatory events, but in addition, genes at the same approximate level of the hierarchy are repressing and activating each other. We can tease those interactions apart by fairly straightforward experiments in which we knock out individual pair rule genes and ask what the effect of the loss has on other pair rule genes. I led the students through a series of epistatic experiments which started out fairly easy. Knock out a pair rule gene that is expressed in odd numbered parasegments, for instance, and it’s complement, the pair rule gene expressed in even parasegments, expands its expression pattern to fill all segments. Sometimes.

Some of the experiments reveal simple relationships: hairy suppresses runt, and runt suppresses hairy. That makes sense. They have mutually exclusive domains, so it’s no surprise that they exclude each other. But then we looked at other pair rule genes which are expressed in patterns slightly out of phase from the hairy/runt pair, and there the relationships start getting complex. Genes like fushi tarazu are downstream from all the others, and their effects are straightforward (their loss doesn’t disrupt the other pair rule genes), but genes like even-skipped have much messier relationships, and the class was stumped to explain the results we get with that deletion.

So I asked them to come up with other experiments to tease apart these interactions. I was somewhat amused: when I think along those lines, I come up with more genetic crosses and analyses of expression patterns — I think about regulatory logic and inferring rules from modifications of the pattern. Students nowadays…they’re so much more direct. They want to go straight to the molecular biology, taking apart the genes, identifying control elements, building reporter constructs to see gene-by-gene effects. I felt so old-fashioned. But we also had to talk about the difficulty of those kinds of experiments, and that often the genetic approach is better for building a general hypothesis that can be fruitfully tested with the molecular approach.

Then we stopped — we’ll come back to flies later, and start looking at some specific subsets of developmental programs. Next, though, we’re going to take a big step backward and look at early events in vertebrates and progress through that phylum until we see how they build segments. I’m hoping the students will see the similarities and differences.

Slides for this talk (pdf)