Neurology Center

So apparently: Left wing or right wing? It's written in the brain

A bombshell has just gone off in the continuing debate over XMRV, the virus that may or may not cause chronic fatigue syndrome. Actually, 4 bombshells.

A set of papers out today in Retrovirology (1,2,3,4) claim that many previous studies claiming to have found the virus haven't actually been detecting XMRV at all.

Here's the rub. XMRV is a retrovirus, a class of bugs that includes HIV. Retroviruses are composed of RNA, but they can insert themselves into the genetic material of host cells as DNA. This is how they reproduce: once their DNA is part of the host cell's chromosomes, that cell is ends up making more copies of the virus.

But there are lots of retroviruses out there, and there used to be yet others that are now extinct. So bits of retroviral DNA are scattered throughout the genome of animals. These are called endogenonous retro-viruses (ERVs).

XMRV is extremely similar to certain ERVs found in the DNA of mice. And mice are the most popular laboratory mammals in the world. So you can see the potential problem: laboratories all over the world are full of mice, but mouse DNA might show up as "XMRV" DNA on PCR tests.

Wary virologists take precautions against this by checking specifically for mouse DNA. But most mouse-contamination tests are targeted at mouse mitochondrial DNA (mtDNA). In theory, a test for mouse mtDNA is all you need, because mtDNA is found in all mouse cells. In theory.

Now the four papers (or are they the Four Horsemen?) argue, in a nutshell, that mouse DNA shows up as "XMRV" on most of the popular tests that have been used in the past, that mouse contamination is very common - even some of the test kits are affected! - and that tests for mouse mtDNA are not good enough to detect the problem.

• Hue et al say that "Taqman PCR primers previously described as XMRV-specific can amplify common murine ERV sequences from mouse suggesting that mouse DNA can contaminate patient samples and confound specific XMRV detection." They go on to show that some human samples previously reported as infected with XMRV, are actually infected with a hybrid of XMRV and a mouse ERV which we know can't infect humans.
• Sato et al report that PCR testing kits from Invitrogen, a leading biotech company, are contaminated with mouse genes including an ERV almost identical to XMRV, and that this shows up as a false positive using commonly used PCR primers "specific to XMRV".
• Oakes et al say that in 112 CFS patients and 36 healthy control, they detected "XMRV" in some samples but all of these samples were likely contaminated with mouse DNA because "all samples that tested positive for XMRV and/or MLV DNA were also positive for the highly abundant IAP long terminal repeat [found only in mice] and most were positive for murine mitochondrial cytochrome oxidase sequences [found only in mice]"
• Robinson et al agree with Oakes et al: they found "XMRV" in some human samples, in this case prostate cancer cells, but they then found that all of the "infected" samples were contaminated with mouse DNA. They recommend that in future, samples should be tested for mouse genes such as the IAP long terminal repeat or cytochrome oxidase, and that researchers should not rely on tests for mouse mtDNA.

"Wikileaks is great. It lets people leak stuff."

"Hang on, so you're saying that no-one could leak stuff before? They invented it?"

"Well, no, but they brought leaking to the masses. Sure, people could post documents to the press before, but now anyone in the world can access the leaks!"

"Great, but isn't that just the internet that did that? If it weren't for Wikileaks, people could just upload their leaks to a blog. Or email them to 50 newspapers. Or put them on the torrents. Or start their own site. If it's good, it would go viral, and be impossible to take down. Just like Wikileaks, with all their mirrors, except even more secure, because there'd be literally no-one to arrest or cut off funding to."

"OK, but Wikileaks is a brand. It's not about the technical stuff - it's the message. Like one of their wallpapers says, they're synonymous with free speech."

"So you think it's a good thing that one organization has become synonymous with the whole process of leaking? With the whole concept of openness? What will happen to the idea of free speech, then, if that brand image suddenly gets tarnished - like, say, if their founder and figurehead gets convicted of a serious crime, or..."

"He's innocent! Justice for Julian!"

"Quite possibly, but why do you care? Is he a personal friend?"

"It's an attack on free speech!"

"So you agree that one man has become synonymous with free speech? Doesn't that bother you?"

"Erm... well. Look, fundamentally, we need Wikileaks. Before, there was no centralized system for leaking. Anyone could do it. It was a mess! Wikileaks put everything in one place, and put a committee of experts in a position to decide what was worth leaking and what wasn't. It brought much-needed efficiency and respectability to the idea of leaking. Before Wikileaks, it was anarchy. They're like... the government."

"..."

Edit: See also The Last Psychiatrist's take.

Last week I was at a discussion about New Media, and someone mentioned that they'd been put off from writing content online because of a comment on one of their articles accusing them of being "stupid".

I found this surprising - not the comment, but that anyone would take it so personally. It's the internet. You will get called names. Everyone does. It doesn't mean there's anything wrong with you.

I suspect this is a generational issue. People who 'grew up online' know, as Penny Arcade explained, that

The sad fact is that there are millions of people whose idea of fun is to find people they disagree with, and mock them. And they're right, it can be fun - why else do you think people like Jon Stewart are so popular? - but that's all it is, entertainment. If you're on the receiving end, don't take it seriously.

If you write something online, and a lot of people read it, you will get slammed. Someone, somewhere, will disagree with you and they'll tell you so, in no uncertain terms. This is true whatever you write about, but some topics are like a big red rag to the herds of bulls out there.

Just to name a few, if you say anything vaguely related to climate change, religion, health, the economy, feminism or race, you might as well be holding a placard with a big arrow pointing down at you and "Sling Mud Here" on it.

The point is - it's them, not you. They are not interested in you, they don't know you, it's not you. True, they might tailor their insults a bit; if you're a young woman you might be, say, a "stupid girl" where a man would merely get called an "idiot". But this doesn't mean that the attacks are a reflection on you in any way. You just happen to be the one in the line of fire.

What do you do about this? Nothing.

Trying to enter into a serious debate is pointless. Insulting them back can be fun, just remember that if you find it fun, you've become one of them: "he who stares too long into the abyss...", etc. Complaining to the moderators might help, but unless the site has a rock solid zero-tolerance-for-fuckwads policy, probably not. Where the blight has taken root, like Comment is Free, I'd not waste your time complaining. Just ignore it and carry on.

The most important thing is not to take it personally. Do not get offended. Do not care. Because no-one else cares. Especially the people who wrote the comments. They presumably care about whatever "issue" prompted their attack, but they don't care about you. If anything, you should be pleased, because on the internet, the only stuff that doesn't attract stupid comments is the stuff that no-one reads.

I've heard these attacks referred to as "policing" existing hierarchies or "silencing" certain types of people. This seems to me to be granting them far more respect than they deserve. With the actual police, if you break the rules, they will physically arrest you. They have power. Internet trolls don't: if they succeed in policing or silencing anybody, it's because their targets let them boss them around. They're nobody; they're not your problem.

If you can't help being offended by such comments, don't read them, but ideally you shouldn't need to resort to that. For one thing, it means you miss the sensible comments (and there's always a few). But fundamentally, you shouldn't need to do this, because you really shouldn't care what some anonymous joker from the depths of the internet thinks about you.

How do you know whether a scientific idea is a good one or not?


The only sure way is to study it in detail and know all the technical ins and outs. But good ideas and bad ideas behave differently over time, and this can provide clues as to which ones are solid; useful if you're a non-expert trying to evaluate a field, or a junior researcher looking for a career.

Today's ideas are the basis for tomorrow's experiments. A good idea will lead to experiments which provide interesting results, generating new ideas, which will lead to more experiments, and so on.

Before long, it will be taken as granted that it's true, because so many successful studies assumed it was. The mark of a really good idea is not that it's always being tested and found to be true; it's that it's an unstated assumption of studies which could only work if it were true. Good ideas grow onwards and upwards, in an expanding tree, with each exciting new discovery becoming the boring background of the next generation.

Astronomers don't go around testing whether light travels at a finite speed as opposed to an infinite one; rather, if it were infinite, their whole set-up would fail.

Bad ideas generate experiments too, but they don't work out. The assumptions are wrong. You try to explain why something happens, and you find that it doesn't happen at all. Or you come up with an "explanation", but next time, someone comes along and finds evidence suggesting the "true" explanation is the exact opposite.

Unfortunately, some bad ideas stick around, for political or historical reasons or just because people are lazy. What tends to happen is that these ideas are, ironically, more "productive" than good ideas: they are always giving rise to new hypotheses. It's just that these lines of research peter out eventually, meaning that new ones have to take their place.

As an example of a bad idea, take the theory that "vaccines cause autism". This hypothesis is, in itself, impossible to test: it's too vague. Which vaccines? How do they cause autism? What kind of autism? In which people? How often?

The basic idea that some vaccines, somewhere, somehow, cause some autism, has been very productive. It's given rise to a great many, testable, ideas. But every one which has been tested has proven false.

First there was the idea that the MMR vaccine causes autism, linked to a "leaky gut" or "autistic enterocolitis". It doesn't, and it's not linked to that. Then along came the idea that actually it's mercury preservatives in vaccines that cause autism. It doesn't. No problem - maybe it's aluminium? Or maybe it's just the Hep B vaccine? And so on.

At every turn, it's back to square one after a few years, and a new idea is proposed. "We know this is true; now we just need to work out why and how...". Except that turns out to be tricky. Hmm. Maybe, if you keep ending up back at square one, you ought to find a new square to start from.

There are three basic schools of thought on the Israel / Palestine thing.

• Those evil Israelis are out to destroy Palestine, and the Palestinians are just fighting back.
• Those evil Palestinians are out to destroy Israel, and the Israelis are just fighting back.
• It's a cycle of violence, where both sides are fighting back against the other.
  

the number of Qassams fired increases by 6% on the first day after a single killing of a Palestinian by Israel; the probability of any Qassams being fired increases by 11%; and the probability of any Israelis being killed by Palestinians increases by 10%. Conversely, 1 day after the killing of a single Israeli by Palestinians, the number of Palestinians killed by Israel increases by 9%, and the probability of any Palestinians being killed increases by 20%

....retaliation accounts for a larger fraction of Palestinian compared with Israeli aggression: in the levels specification, 10% of all Qassam rockets can be attributed to prior Israeli attacks on Palestinians, but only 4% of killings of Palestinians by Israel can be attributed to prior Palestinian attacks on Israel.... 6% of all days on which Palestinians attack Israel with rockets, and 5% of all days on which they attack by killing Israelis, can be attributed to retaliation; in contrast, this is true for only 2% of all days on which Israel kills Palestinians.

Over one half of Israelis and three quarters of Palestinians think the other side seeks to take over their land. When accounting for their own acts of aggression, Israelis often claim to be merely responding to Palestinian violence, and Palestinians often see themselves as simply reacting to Israeli violence.

You've got an idea: a new way of doing things; a change; a paradigm shift. It might work, it might be no better than what we've got already, or it might end up being a disaster.

The honest way to present your proposal would be to admit its novelty, and hence the uncertainty: this is a new idea I had, I can't promise anything, but here are my reasons for thinking it's worth a try, here are the likely costs and benefits, here are the alternatives.

However, let's suppose you don't want to do that. That's hard work, and if your idea is crap, people could tell. How else could you convince them? By making it seem as though it's not a new idea at all.

You could dress your idea up as:

• the glorious past. Your idea is nothing more than how we did things back in the golden age, when everything was great. For some reason, people strayed from the true path, and things went bad. We should go back to the the good old days. It worked then, so it'll work now. You'll use words like: restoring, reviving, regaining, renewing... "re" is your friend.
• the next step. Your idea is just the logical progression of what we're already doing. Things used to be bad, and then they started to change, and get better. Let's make them even better, by doing more of the same. It's inevitable, anyway: you can't stop history. You'll use words like: progress, forward, advance, build, grow...
  
• catching up. You're just saying we should bring stuff into line with the way things are done elsewhere, which as we know, is working well. It's not even a matter of moving forward, so much as keeping up. It would be weird not to change. We don't want to be dinosaurs. You'll use words like: modernization, rationalization, reform...
  
• keeping things the same. Things are fine right now, and don't need improving. But in order for things to stay great, we must adapt to changing circumstances, so we'll have to make a few adjustments, but don't worry, fundamentally things are going to stay just as they are. You'll use words like: preserving, maintaining, protecting, upholding, strengthening...

According to the BBC:

Koran protests sweep Afghanistan... Thousands of protesters have taken to the streets across Afghanistan... Three people were shot when a protest near a Nato base in the north-east of the country turned violent.

The dust is starting to settle after the Hauser-gate scandal which rocked psychology a couple of weeks back.

Harvard Professor Marc Hauser has been investigated by a faculty committee and the verdict was released on the 20th August: Hauser was "found solely responsible... for eight instances of scientific misconduct." He's taking a year's "leave", his future uncertain.

Unfortunately, there has been no official news on what exactly the misconduct was, and how much of Hauser's work is suspect. According to Harvard, only three publications were affected: a 2002 paper in Cognition, which has been retracted; a 2007 paper which has been "corrected" (see below), and another 2007 Science paper, which is still under discussion.

But what happened? Cognition editor Gerry Altmann writes that he was given access to some of the Harvard internal investigation. He concludes that Hauser simply invented some of the crucial data in the retracted 2002 paper.

Essentially, some monkeys were supposed to have been tested on two conditions, X and Y, and their responses were videotaped. The difference in the monkey's behaviour between the two conditions was the scientifically interesting outcome.

In fact, the videos of the experiment showed them being tested only on condition X. There was no video evidence that condition Y was even tested. The "data" from condition Y, and by extension the differences, were, apparently, simply made up.

If this is true, it is, in Altmann's words, "the worst form of academic misconduct." As he says, it's not quite a smoking gun: maybe tapes of Y did exist, but they got lost somehow. However, this seems implausible. If so, Hauser would presumably have told Harvard so in his defence. Yet they found him guilty - and Hauser retracted the paper.

So it seems that either Hauser never tested the monkeys on condition B at all, and just made up the data, or he did test them, saw that they weren't behaving the "right" way, deleted the videos... and just made up the data. Either way it's fraud.

Was this a one-off? The Cognition paper is the only one that's been retracted. But another 2007 paper was "replicated", with Hauser & a colleague recently writing:

In the original [2007] study by Hauser et al., we reported videotaped experiments on action perception with free ranging rhesus macaques living on the island of Cayo Santiago, Puerto Rico. It has been discovered that the video records and field notes collected by the researcher who performed the experiments (D. Glynn) are incomplete for two of the conditions.

Glynn was not an author on the only paper which has actually been retracted [the Cognition 2002 paper that Altmann refers to]... according to his resume, he didn't arrive in Hauser's lab until 2005.

Update: Lots of stuff has happened since I wrote this post: see here for more.

A major scandal looks to be in progress involving Harvard Professor Marc Hauser, a psychologist and popular author whose research on the minds of chimpanzees and other primates is well-known and highly respected. The Boston Globe has the scoop and it's well worth a read (though you should avoid reading the comments if you react badly to stupid.)

Hauser's built his career on detailed studies of the cognitive abilities of non-human primates. He's generally argued that our closest relatives are smarter than people had previously believed, with major implications for evolutionary psychology. Now one of his papers has been retracted, another has been "corrected" and a third is under scrutiny. Hauser has also announced that he's taking a year off from his position at Harvard.

It's not clear what exactly is going on, but the problems seem to centre around videotapes of the monkeys that took part in Hauser's experiments. The story begins with a 2007 paper published in Proceedings of the Royal Society B. That paper has just been amended in a statement that appeared in the same journal last month:

In the original study by Hauser et al., we reported videotaped experiments on action perception with free ranging rhesus macaques living on the island of Cayo Santiago, Puerto Rico. It has been discovered that the video records and field notes collected by the researcher who performed the experiments (D. Glynn) are incomplete for two of the conditions.

Late last year, Science published a bombshell - Lombardi et al's Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. This paper reported the presence of a recently-discovered virus in 67% of the blood samples from 101 people with chronic fatigue syndrome (CFS).

The question of whether people with CFS are suffering from an organic illness, or whether their condition is partially or entirely psychological in nature, is the Israel vs. Palestine of modern medicine - as a brief look at the Wikipedia talk pages will show. So when Lombardi et al linked CFS to xenotropic murine leukaemia virus-related virus (XMRV), they were hailed as heroes by some, less so by others. For some balanced coverage of this paper, see virology blog. Everyone agreed though that Lombardi et al was, as the saying goes, "important if true"...

But it wasn't, at least not everywhere, according to a paper out today in PLoS ONE: Erlwein et al's Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome. The findings are all there in the title - unlike Lombardi et al, these researchers didn't find XMRV in the blood of any of their blood samples from 186 CFS patients.

Still, before people start proclaiming that the original finding has been "debunked", or decrying these results as flawed, some things to bear in mind...

This was a different country. Erlwein et al used patients attending the CFS clinic at King’s College Hospital, London, England. The patients in the original study were drawn from various parts of the USA. So the new results don't mean that the original findings were wrong, merely that they don't apply everywhere. Notably, XMRV has previously been detected in prostrate cancer cells from American patients, but not European ones, so geographic differences seem to be at work. So maybe XMRV does cause CFS, it's just that the virus doesn't exist in Europe, for whatever reason - but bear in mind that even the original study never showed causation, only a correlation. There are many viruses that infect people in certain parts of the world and don't cause illness.

On the other hand, it was a similar group of patients in terms of symptoms: Diagnosing CFS can be difficult, as there are no biological tests to confirm the condition, but Erlwein et al say that

Both studies use the widely accepted 1994 clinical case definition of CFS. Lombardi et al. reported that their cases ‘‘presented with severe disability’’ and we provide quantifiable evidence confirming high levels of disability in our subjects. Our subjects were also typical of those seen in secondary and tertiary care in other centres.

These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8.

For identification of gag, 419F and 1154R were used as forward and reverse primers.

The positive control was a dilution of a plasmid with a full-length XMRV (isolate VP62) insert, generously gifted by Dr R. Silverman.

"Statistically, airplane travel is safer than driving..." "Statistically, you're more likely to be struck by lightning than to..." "Statistically, the benefits outweigh the risks..."

What does statistically mean in sentences like this? Strictly speaking, nothing at all. If airplane travel is safer than driving, then that's just a fact. (It is true on an hour-by-hour basis). There's no statistically about it. A fact can't be somehow statistically true, but not really true. Indeed, if anything, it's the opposite: if there are statistics proving something, it's more likely to be true than if there aren't any.

But we often treat the word statistically as a qualifier, something than makes a statement less than really true. This is because psychologically, statistical truth is often different to, and less real than, other kinds of truth. As everyone knows, Joseph Stalin said that one death is a tragedy, but a million deaths is a statistic. Actually, Stalin didn't say that, but it's true. And if someone has a fear of flying, then all the statistics in the world probably won't change that. Emotions are innumerate.

Last week, I wrote about a paper finding that the mosquito repellent chemical, DEET, inhibits an important enzyme, cholinesterase. If DEET were toxic to humans, this finding might explain why.
But it isn't - tens of millions of people use DEET safely every year, and there's no reason to think that it is dangerous unless it's used completely inappropriately. That didn't stop this laboratory finding being widely reported as a cause for concern about the safety of DEET.

This is putting the cart before the horse. If you know that something happens, then it's appropriate to search for an explanation for it. If you have a phenemonon, then there must be a mechanism by which it occurs.

But this doesn't work in reverse: just because you have a plausible mechanism by which something could happen, doesn't mean that it does in fact happen. This is because there are always other mechanisms at work which you may not know about. And the effect of your mechanism may be trivial by comparison.

Caffeine can damage DNA under some conditions. Other things which damage DNA, like radiation, can cause cancer. But the clinical evidence is that, if anything, drinking coffee may protect against some kinds of cancer (previous post). There's a plausible mechanism by which coffee could cause cancer, but it doesn't.

Medicine has learned the hard way that while understanding mechanisms is important, it's no substitute for clinical trials. The whole philosophy of evidence-based medicine is that treatments should only be used when there is clinical evidence that they do in fact work.

Unfortunately, in other fields, the horse routinely finds itself behind the cart. An awful lot - perhaps most - of political debate consists of saying that if you do X, Y will happen, through some mechanism. If you legalize heroin, people will take more of it, because it'll be more available and cheaper. If you privatize public services, they'll improve, because competition will ensure that only the most efficient services survive. If you topple this dictator, the country will become a peaceful democracy, because people like peace and democracy. And so on.

These kinds of arguments sound good. And they invite opponents to respond in kind: actually, legalizing heroin is a good idea, because it will make taking it much safer by eliminating impurities and infections... And so the debate becomes a case of fantasizing about things that might happen, with the winner being the person whose fantasy sounds best.

If you want to know what will happen when you implement some policy, the only way of knowing is to look at other countries or other places which have already done it. If no-one else has ever done it, you are making a leap into the unknown. This is not necessarily a bad thing - there's a first time for everything. But it means that "We don't know" should be heard much more often in politics.

Over at Bad Science, Ben Goldacre decries an article about a spurious "study", lifted straight from a corporate press-release, in his own newspaper The Guardian:

On Monday we printed a news article about a “report” “published” by Nuffield Health, headlined “No sex please, we’re British and we’re lazier than ever”. “This is the damning conclusion of a major new report published today,” says the press release from Nuffield ... I asked Nuffield’s press office for a copy of the new report, but they refused, and explained that the material is all secret. The Guardian journalist can’t have read it either. I don’t really see how this “report” has been “published”, and in all honesty, I wonder whether it even exists, in any meaningful sense, outside of a press release.

Nuffield Health are the people who run private hospitals and clinics which you can’t afford....the Guardian gave free advertising to Nuffield, for their unpublished published “report”, which nobody even read, in exchange for 370 words of content. This is endemic, and it creeps me out.

Watch out! The BBC report that -

Deet bug repellent 'toxic worry'