Amy Bishop, Neuroscientist Turned Killer

Across at Wired, Amy Wallace has a long but riveting article about Amy Bishop, the neuroscience professor who shot her colleagues at the University of Alabama last year, killing three.

It's a fascinating article because of the picture it paints of a killer and it's well worth the time to read. Yet it doesn't really answer the question posed in the title: "What Made This University Scientist Snap?"

Wallace notes the theory that Bishop snapped because she was denied tenure at the University, a serious blow to anyone's career and especially to someone who, apparantly, believed she was destined for great things. However, she points out that the timing doesn't fit: Bishop was denied tenure several months before the shooting. And she shot at some of the faculty who voted in her favor, ruling out a simple "revenge" motive.

But even if Bishop had snapped the day after she found out about the tenure decision, what would that explain? Thousands of people are denied tenure every year. This has been going on for decades. No-one except Bishop has ever decided to pick up a gun in response.

Bishop had always displayed a streak of senseless violence; in 1986, she killed her 18 year old brother with a shotgun in her own kitchen. She was 21. The death was ruled an accident, but probably wasn't. It's not clear what it was, though: Bishop had no clear motive.

Amy had said something that upset her father. That morning they’d squabbled, and at about 11:30 am, Sam, a film professor at Northeastern University, left the family’s Victorian home to go shopping... Amy, 21, was in her bedroom upstairs. She was worried about “robbers,” she would later tell the police. So she loaded her father’s 12-gauge pump-action shotgun and accidentally discharged a round in her room. The blast struck a lamp and a mirror and blew a hole in the wall...

The gun, a Mossberg model 500A, holds multiple rounds and must be pumped after each discharge to chamber another shell. Bishop had loaded the gun with number-four lead shot. After firing the round into the wall, she could have put the weapon aside. Instead, she took it downstairs and walked into the kitchen. At some point, she pumped the gun, chambering another round.

...[her mother] told police she was at the sink and Seth was by the stove when Amy appeared. “I have a shell in the gun, and I don’t know how to unload it,” Judy told police her daughter said. Judy continued, “I told Amy not to point the gun at anybody. Amy turned toward her brother and the gun fired, hitting him.”

Years later Bishop, possibly with the help of her husband, sent a letter-bomb to a researcher who'd sacked her, Paul Rosenberg. Rosenberg avoided setting off the suspicious package and police disarmed it; Bishop was questioned, but never charged.

Wallace argues that Bishop's "eccentricity", or instability, was fairly evident to those who knew her but that in the environment of science, it went unquestioned because science is full of eccentrics.

I'm not sure this holds up. It's certainly true that science has more than its fair share of oddballs. The "mad scientist" trope is a stereotype but it has its basis in fact and it has done at least since Newton; many say that you can't be a great scientist and be entirely 'normal'.

But the problem with this, as a theory for why Bishop wasn't spotted sooner, is that she was spotted sooner, as unhinged, albeit not as a potential killer,by a number of people. Rosenberg sacked her, in 1993, on the grounds that her work was inadaquate and said that "Bishop just didn’t seem stable". And in 2009, the reason Bishop was denied tenure in Alabama was partially that one of her assessors referred to her as "crazy", more than once; she filed a complaint on that basis.

Bishop also published a bizarre paper in 2009 written by herself, her husband, and her three children, of "Cherokee Lab Systems", a company which was apparantly nothing more than a fancy name for their house. There may be a lot of eccentrics in science, but that's really weird.

So I think that all of these attempts at an explanation fall short. Amy Bishop is a black swan; she is the first American professor to do what she did. Hundreds of thousands of scientists have been through the same academic system and only one ended up shooting their colleagues. If there is an explanation, it lies within Bishop herself.

Whether she was suffering from a diagnosable mental illness is unclear. Her lawyer has said so, but he would; it's her only defence. Maybe we'll learn more at the trial.#

H/T: David Dobbs for linking to this.

The Mystery of "Whoonga"

According to a disturbing BBC news story, South African drug addicts are stealing medication from HIV+ people and using it to get high:

'Whoonga' threat to South African HIV patients

"Whoonga" is, allegedly, the street name for efavirenz (aka Stocrin), one of the most popular antiretroviral drugs. The pills are apparantly crushed, mixed with marijuana, and smoked for its hallucinogenic effects.

This is not, in fact, a new story; Scientific American covered it 18 months ago and the BBC themselves did in 2008 (although they didn't name efavirenz.)

Edit 16.00 pm: In fact the picture is even messier than I first thought. Some sources, e.g. Wikipedia and the articles it links to, mostly from South Africa, suggest that "whoonga" is actually a 'brand' of heroin and that the antiretrovirals may not be the main ingredient, if they're an ingredient at all. If this is true, then the BBC article is misleading. Edit and see the Comments for more on this...

Why would an antiviral drug get you high? This is where things get rather mysterious. Efavirenz is known to enter the brain, unlike most other HIV drugs, and psychiatric side-effects including anxiety, depression, altered dreams, and even hallucinations are common in efavirenz use, especially with high doses (1,2,3), but they're usually mild and temporary. But what's the mechanism?

No-one knows, basically. Blank et al found that efavirenz causes a positive result on urine screening for benzodiazepines (like Valium). This makes sense given the chemical structure:
Efavirenz is not a benzodiazepine, because it doesn't have the defining diazepine ring (the one with two Ns). However, as you can see, it has a lot in common with certain benzos such as oxazepam and lorazepam.

However, while this might well explain why it confuses urine tests, it doesn't by itself go far to explaining the reported psychoactive effects. Oxazepam and lorazepam don't cause hallucinations or psychosis, and they reduce anxiety, rather than causing it.

They also found that efavirenz caused a false positive for THC, the active ingredient in marijuana; this was probably caused by the gluconuride metabolite. Could this metabolite have marijuana-like effects? No-one knows at present.

Beyond that there's been little research on the effects of efavirenz in the brain. This 2010 paper reviewed the literature and found almost nothing. There were some suggestions that it might affect inflammatory cytokines or creatine kinase, but these are not obvious candidates for the reported effects.

Could the liver be responsible, rather than the brain? Interestingly, the 2010 paper says that efavirenz inhibits three liver enzymes: CYPs 2C9, 2C19, and 3A4. All three are involved in the breakdown of THC, so, in theory, efavirenz might boost the effects of marijauna by this mechanism - but that wouldn't explain the psychiatric side effects seen in people who are taking the drug for HIV and don't smoke weed.

Drugs that cause hallucinations generally either agonize 5HT2A receptors or block NMDA receptors. Off the top of my head, I can't see any similarities between efavirenz and drugs that target those systems like LCD (5HT2A) or ketamine or PCP (NMDA), but I'm no chemist and anyway, structural similarity is not always a good guide to what drugs do.

If I were interested in working out what's going on with efavirenz, I'd start by looking at GABA, the neurotransmitter that's the target of benzos. Maybe the almost-a-benzodiazepine-but-not-quite structure means that it causes some unusual effects on GABA receptors? No-one knows at present. Then I'd move on to 5HT2A and NMDA receptors.

Finally, it's always possible that the users are just getting stoned on cannabis and mistakenly thinking that the efavirenz is making it better through the placebo effect. Stranger things have happened. If so, it would make the whole situation even more tragic than it already is.

Cavalcante GI, Capistrano VL, Cavalcante FS, Vasconcelos SM, Macêdo DS, Sousa FC, Woods DJ, & Fonteles MM (2010). Implications of efavirenz for neuropsychiatry: a review. The International journal of neuroscience, 120 (12), 739-45 PMID: 20964556

The Other Brain

An interesting new book from R. Douglas Fields: The Other Brain.

"Glia" is a catch-all term for every cell in the nervous system that's not a neuron. We have lots and lots of them: on some estimates, 85% of the cells in the brain are glia. But to most neuroscientists at the moment, they're about as interesting as dirt is to archaeologists. They're the boring stuff that gets in the way. The name is Greek for "glue", which says a lot.

It's telling that most neuroscientists (myself included I confess) use the term "brain cells" to mean neurons, even though they're a minority. Hence the book's title: Douglas Fields argues that glia constitute a whole world, another brain - although of course, it's not seperate from the neuronal brain, and neuron-glia interactions are the really interesting thing and the central theme of the book.

Glia have historically been regarded as mere "housekeepers", keeping the brain neat and tidy by cleaning up the byproducts of neural activity. Douglas Fields explains that there's actually a lot more to glia than that, but that even if they were just housekeepers, the housekeeping they do is extremely important.

Astrocytes, one kind of glial cell, are key to the regulation of glutamate levels in the brain. Glutamate is by far the most common neurotransmitter yet it's also the most dangerous: glutamate can kill neurons if they receive too much of it (excitotoxicity). I previously wrote about some bad clams which can cause permanent brain damage if who eat them; the toxin responsible mimics the action of glutamate.

By quickly clearing up glutamate as it's released from neurons, astrocytes perform a vital function which saves the brain from self-destruction. Yet recent evidence has shown that they don't just mop up neurotransmitters, they also respond to them, and even release them. People are nowadays talking about the "tripartite synapse" - presynaptic neuron, postsynaptic neuron, and glia.


Glia even have their own communication network quite seperate from the neuronal one. Whereas neurons use electrical currents to convey signals, and chemicals to talk to other cells, astrocytes are interconnected via direct gap-junctions - literally, little holes bridging the membranes between neighbors.

Waves of calcium can travel through these junctions across long distances. The function of this glial network is almost entirely mysterious at present, but it's surely important, or it wouldn't have evolved. (A few types of human neurons do the same thing; in some animals it's more common.)

The subtitle is overblown, as subtitles often are ("From Dementia to Schizophrenia, How New Discoveries About the Brain are Revolutionizing Medicine and Science"); the book also repeats itself in a number of places, especially when it's castigating neuroscientists for overlooking glia for so long (a fair point, but it gets old.) Overall though it's very readable and it's got some nice anecdotes as well as the science.

The Other Brain makes an excellent case that neuroscience can't remain neuron-science if it hopes to answer the big questions. It's certainly opened my eyes to the importance of glia and given me ideas for my own research. As such it's one of those rare popular science books that will prove interesting to professionals and others too.

Link: Also reviewed here.
Disclaimer: I got a free review copy.

An Astonishingly Brilliant Epic Tour-De-Force

So I was browsing my local bookshop yesterday.

But what to buy? The back covers are not very helpful. Apparently, every novel published nowadays is, at the worse, a breathtaking masterpiece. Most are epoch-making, life-changing works of godlike genius.

OK, but which ones are actually good?

Why is this? Part of it, surely, is that literature is an incestuous world where the same authors who write the books are the first port of call when publishers want blurbs for everyone else's. Clearly you don't want to say anything bad about your peers lest you stop getting invites to dinner parties. Unless you're embroiled in a "bitter literary feud", but no-one has the energy to do that on a regular basis.

Because everyone is constantly complimenting each other in this way, praise inflation sets in and we soon reach the point where "This is a very good book" would be a serious insult.

There's also a theory, which has been around for a good few hundred years and maybe forever, that creative types are a breed apart from everyone else, possessed of divine powers and insight. Not just the really great artists, but any artist as a profession.

When Nietzsche wrote a book comparing himself favourably to Jesus, with chapters called "Why I Am So Clever" and "Why I Am A Destiny", people thought that was a bit much. (It didn't help that he went completely insane the next year.) You can't go on record and say that about yourself, but say it about your friends and get them to say it about you, and it seems to work quite nicely.

The Decline And Fall of Effects In Science

Nature has a piece called Unpublished results hide the decline effect.
This refers to the fact that many scientific findings which seem to indicate something big is happening, end up getting smaller and smaller as more people try to replicate them until they, eventually, may vanish entirely.

The Last Psychiatrist's take is that "The Decline Effect" just represents sloppy thinking, treating different things as if they were all instances of The One True Phenomenon. Someone does a study about something and finds an effect. Then someone else comes along and does a new study, of a related but different topic, and finds a different result. Both are right: there's a difference. Only if you, sloppily, decide that both studies were measuring the same thing does the "Decline Effect" appear.

This is perfectly true and I've touched on it before, but I think it's a bit optimistic. It assumes that the first study was true. Sometimes they are. But because of the way science is published at the moment, a lot of results that get published are flukes. Some even say that the majority are.

The problem is that there are so many ways to statistically analyze any given body of data that it's easy to test and retest it until you find a "positive result" - and then publish that, without saying (or only saying in the small print) that your original tests all came out negative. Combine this with selective publication of only the best data, and other scientific sins, and you can pull positive results out the hat of mere random noise.

In the Nature article, Jonathan Schooler discusses this and suggests that an open-access repository of findings (meaning raw data rather than the end product of analyses) would be A Good Thing. I agree. However, he seems to think that if we did this, we might still observe the "Decline Effect", and would be able to find out more about it. He even seems to suggest that some kind of weird quantum effect might mean that scientists are actually changing the laws of reality by observing them

Perhaps, just as the act of observation has been suggested to affect quantum measurements, scientific observation could subtly change some scientific effects. Although the laws of reality are usually understood to be immutable, some physicists, including Paul Davies, director of the BEYOND: Center for Fundamental Concepts in Science at Arizona State University in Tempe, have observed that this should be considered an assumption, not a foregone conclusion.

Hmm. Maybe. But there is really no need to posit such magical mysteries when plain old statistical conjuring tricks seem like a perfectly good explanation. On my view a raw result repository would not explain the decline effect, but just make it disappear.

Schooler doesn't go into detail as to how this repository would be set up, but he does cite the fact that we already have a pretty good one for clinical trials of medicines conducted in the USA. Anyone running a clinical trial is required to register it in advance, saying what they're planning to do and crucially, to spell out which statistics they are going to run on the data when it arrives.

What's really silly is that most scientists already do this when applying for funding: most grant applications include detailed statistical protocols. The problem is that these are not made public so people can ignore them when it comes to publication. Back in 2008 I suggested that scientific journals should require all studies, not just clinical trials, to be publicly pre-registered if they're to be considered for publication. This would be eminently do-able if there was a will to make it happen.

Schooler, J. (2011). Unpublished results hide the decline effect Nature, 470 (7335), 437-437 DOI: 10.1038/470437a