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Male Scent May Compromise Biomedical Research (sciencemag.org)
193 points by WestCoastJustin 763 days ago | past | web | 59 comments



Richard Feynman spoke specifically to this point in his Cargo Cult Science piece:

http://neurotheory.columbia.edu/~ken/cargo_cult.html

"That is the experiment that makes rat-running experiments sensible, because it uncovers that clues that the rat is really using-- not what you think it's using. And that is the experiment that tells exactly what conditions you have to use in order to be careful and control everything in an experiment with rat-running."

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First, thank you. I have been looking for this for years! Now i have something to search for to find the paper.

I worked in a rat lab for a while that tried testing smells. It was impossible to get data, but sure enough, the professor insisted that stuff was there and published weak papers that were rejected thoroughly. We had about 15 rats and at least 50 major variables to test, if not more confounding variables.

I used to read PhD comics as a salve, and then realized that it was a shield. So many grad students feel so badly precisely because they know that the science is crap and no-one will read it anyway because we all know it is crap[0][1]. The rule is getting to be; If the P-value is at 0.05, flip a coin; heads I read it, tails I eat lunch.

This isn't just isolated to the ivory tower either. The public sees this and not just from friends and family. These back and forth studies screaming 'coffee is a super-food' and then 'coffee is poison' are an example. They give the public an impression that we scientists don't have a clue. And, true, we may not, but allowing the press to scream these things for funding and publicity's sake is a tragedy of the commons. Yes, I know, you can't expect everything to be perfect. But what we have is so very far from that (and yes, I know, China or India are waaay worse). Still, to see in the grad student's eyes that they know the last 6 years were total crap is tragic, especially when the professor insists it isn't to new students and older ones know they can do nothing to persuade the new ones differently.

[0]http://www.economist.com/news/briefing/21588057-scientists-t...

[1]https://en.m.wikipedia.org/wiki/John_P._A._Ioannidis

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> These back and forth studies screaming 'coffee is a super-food' and then 'coffee is poison' are an example. They give the public an impression that we scientists don't have a clue.

I think that is more the fault of the type of science journalism the public is exposed to. The paper says "compound extracted from coffee found to enhance cell uptake of flavonoids in mice" and the media screams "coffee: the new superfood?"

Weak science is one thing, but no matter how strong the science is you can count on the media to get it wrong.

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True, but then you have a responsibility (according to Dr. Feynman) to go back out there and state the limits and facts. Not to just sit by and throw up your hands and say 'oh, it's just clickbait, who cares, everyone knows it is BS'. That leads the public to think scientists don't care and it leads grads students to think it's ok that your research gets maligned and strewn as long at it's 'publicity.' Science is better than that, as least to Dr. Feynman. Personally, I agree with him.

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This kind of response by lab animals to stressors in their environment reminds me of the "Rat Park"[1] experiment, in which rats who were stressed out from being kept isolated in small cages (rats are social animals) had a tendency to become addicted to morphine, but those who lived in a pleasant environment did not.

[1] https://en.wikipedia.org/wiki/Rat_park

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BTW, Stuart McMillen made an excellent comic about Rat Park. I think it may have been linked on HN before, but just in case:

http://www.stuartmcmillen.com/comics_en/rat-park/

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this one, too, and this one is really confounding because the LAW requires animals to be handled at RT.

http://www.nature.com/news/chilly-lab-mice-skew-cancer-studi...

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There is a great video about these sorts of effects called Lullaby For A Mouse: http://vimeo.com/33803995

The basic gist is that most research done on mice (and other animals) is complete crap:

- Almost all laboratory mice are morbidly obese and get little to no exercise.

- They're all starved of social contact.

- The variations in the daily schedule of the researchers mess with their circadian systems.

- The results vary enormously based on how the researchers treat the animals. The title comes from the fact that one of the researchers started singing to his mice in order to get better results.

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I worked in a laboratory with mice for about two years after college.

* None of our mice were morbidly or even slightly obese (I know because I had to cut them open).

* The mice lived in groups of up to 6 in a cage, which I don't know how it compares to their normal situation, but it's not "starved of social contact."

* I don't remember how we dealt with the mice's circadian rhythms, but I think that we had the lights on timers for this.

* Research is inherently subject to variation. There might be compelling reasons why results would vary based on how researchers treat their animals, but I think it would depend a lot on what kind of experiments were being performed. Stating that in a blanket fashion, I think, is misleading. Biological science is just plain hard, and many experiments fail, often with no clear explanation why. That someone could get frustrated enough to start singing to their animals is not an indication that mouse research is inherently flawed.

At the end of the day, a vast quantity of scientific knowledge is owed to mouse research. Denouncing it as "[mostly] complete crap" is just plain false.

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It's good that the lab you worked in had good standards in place but can you be sure this is the case for most labs?

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The hypothesized mechanism is very interesting. Perhaps mice vary their behavioral response to pain depending on how safe it is to express distress from pain. VikingCoder has already given the definitive comment: further controlled experiments will tease out how important this effect is over what range of behaviors. There are many, many, many kinds of mouse experiments (I am currently doing reading on behavior genetics research on learning and intelligence and fear and aggression in mouse model organisms), and some will be more influenced by what the interesting preliminary report here suggests than others.

See the book How Genes Influence Behavior[1] for a fascinating description of how we can learn about human behavior by studying mouse behavior (and even by studying fruit fly behavior!).

[1] http://global.oup.com/academic/product/how-genes-influence-b...

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Why inflict pain instead of pleasure ?

From my experience experiments on animal subjects tend to focus on negative responses. Beside specifically testing negative agents, is there a logical reason for this approach ? Why not measure attraction instead of avoidance ? Do mice exhibit visible joyful facial expressions vs the grimacing this article describes ? It sounds silly, but couldn't we measure how much we delight the mice ?

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I think this serves as a good example of (one of) the issues with animal testing. The scientist in this article doesn't think that we need to "redo decades of animal research", but it certainly casts doubt on previous results.

In general, testing on animals isn't effective. Considering the amount of suffering it inflicts on animals, I'm not sure that it's morally defensible. The British Union for the Abolition of Vivisection has a [good resource][1] on the issues.

[1]: http://buav.org/humane-science/key-criticisms/

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It's clearly not just the male scent, because it gets cancelled out by the female scent. There's obviously more to this.

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Huh? How can scents be canceled out?

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In the original article, the effect that the male scent had on the mice was cancelled out by the female scent also being present - not sure of the actual mechanism, but it's not the actual 'scents cancelling out'

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Maybe researchers should then just always use suits, or at least put on a clean shirt each time before getting close to the rat cages and handling them.

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You are being down voted because people are amusingly misinterpreting the kind of "suit" you meant

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This could certainly be plausible. Fairly rigorous studies. Just needs to be repeated in other labs

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> “It’s a primordial response,” he says. “If you smell a solitary male nearby, chances are he’s hunting or defending his territory.” If you’re in pain, you’re showing weakness.

I don't know about those results, but this explanation sounds preposterous: it doesn't work if you're hunted down by a lioness (which does the hunting while the male lion sleeps); it also doesn't work if you're spotted from the air by an eagle (which is one the main hazards if you're a small rodent).

Why does every behavior has to be explained in terms of survival, we'll never know. Stephen Jay Gould was so good at debunking those easy explanations; how I miss him.

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Lions hunt alone. Lionesses usually hunt in packs.

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2 Theories:

1) It's the brain's way of telling the body: "Another male is nearby, do not show weakness or submission because that male may try to dominate you and you may end up getting into a fight or dying." I'd assume this evolutionary response would only work for same species scents. Apparently it works between species. Men have a tendency not to get into fights with confident men.

2) During a fight with another male, the mind needs to ignore pain in order to continue on and win the fight. In all species, males who didn't have this trait lost battles, died, and did not pass on their genes. Males who had this mutation didn't let the pain get to them, went on to win the fight, lived, reproduced, and passed on these characteristics.

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a theory I had :

perhaps due to past generations of male experimenters, mice have developed a central nervous system which deadens pain in the expectation of a painful experiment when exposed to male scents.

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What would be the selective advantage of pain resistance in the context of a lab environment? It seems to me like the rodent's chance of passing on it's genes would have no correlation with resistance to pain.

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That's a good question.

We know that pain stresses the nervous system, and that it also increases incidence of depression. Both pain and depression lower survival chances, as they both increase the chances for negative effects on the host such as sudden weight fluctuation, abnormal sleep cycles, and uncoordinated muscle control.

I have not worked in such a lab setting, so i'm unsure if any of the mice that survive experimentation are exterminated or repurposed.

If repurposed, one can imagine that a pain-reduction schema would be useful in such environments for the sake of species proliferation. Mice/rats better suited to the pain thresholds required of them would eat better, sleep better, and ultimately breed more.

Again, just an armchair theory and little more.

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On the technical literature, these are called "evolutionary Just-So stories" after Rudyard Kipling. One can.just as easily make up theories that go the other way.

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Their conclusion that "Male odors seemed to act like painkillers" seems like only one of several possible interpretations?

My first reaction was that the possible presence of other male mammals provided a selection bias for individuals who displayed less pain. Amongst individuals of the same species, showing pain would be a sign of weakness, obviously, but it might be a similar marker for possible predators. So perhaps all the animals are feeling the same discomfort, but those who sense other males are less willing to perform their discomfort behaviourally?

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The article addresses this:

> Further testing showed that the rodents exposed to male odors were actually feeling less pain, rather than simply hiding the pain they were in. The male aroma ramped up their stress levels, which deadened the hurt. “It’s really astounding that such a robust effect could have been missed for so many years,” Mogil says.

Though, to be fair, they don't go into detail about how exactly they determined that the rodent was "actually feeling less pain"...

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It's properly addressed in the actual paper [0]:

True SIA should be accompanied by decreased immediate-early gene expression in the pain-processing neurons of the spinal cord dorsal horn; we observed a dramatic (≥50%) decrease in Fos protein–positive neurons in mice injected with zymosan and exposed to male but not female experimenters or shirts (Kruskal-Wallis test statistic: 12.0, degrees of freedom = 4, P < 0.05; Fig. 2d). Much is known about the neurochemistry of SIA, which exists in opioid (naloxone-reversible9), non-opioid (cannabinoid-1 (CB1) receptor–mediated10) and mixed opioid/non-opioid11 forms. The male experimenter SIA seen here was found to be the latter, as it was blocked (observer × drug interaction: F3,56 = 2.8, P < 0.05) by the broad-spectrum opioid receptor antagonist naloxone (1 mg per kg body weight (mg/kg); P < 0.05), by the inverse CB1 receptor agonist AM-251 (10 mg/kg; P < 0.05) and by a combination of the two drugs (P < 0.01), at doses not affecting pain sensitivity per se (Fig. 2e).

In other words, pain in mice is associated with a particular protein binding neurons in a particular part of the brain. The researchers showed that in mice handled by men, the proportion of those neurons bound by the pain-associated protein was significantly decreased, supporting the hypothesis that male-handled mice are actually experiencing less pain.

http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth...

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If you think about it, feeling less actual pain is necessary.

For example, you are alone at your home and bump your little finger on a chair, it hurts like hell.

But in a warzone, or if you are fighting for you life with a a animal attacking you, or if you are fearful in a certain situation, you can get shot, stabbed, break bones, and still function much better (of course, to a point...) than when you hit your finger in a chair... Not because you are pretending to have less pain, but because if you feel pain now, you die (after you are "safe" you can feel your pain later...)

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The original title seems both linkbaity and misleading, so we changed it. If anyone can suggest a better title, please do.

Edit: Ok, since most people who commented don't agree that it was a bad title, we changed it back.

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Which? 'Male Scent May Compromise Biomedical Research' seems better than 'Experimenter gender is a confounding factor in lab animal research', but which was the original?

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Yeah, the 'male scent' (original) title is better. When I read 'Experimenter gender' I was expecting to read an article about some sort of gender-originated cognitive bias.

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actually should be "experimenter sex". Gender is a social term.

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The current changed title is overbroad, it's certainly not shown by this study that experimenter sex is an issue in all animal research. I would simply suggest the title of the paper itself: "Olfactory exposure to males, including men, causes stress and related analgesia in rodents". It's fairly straightforward, and not as jargon-filled as scientific titles go.

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A suggestion: When you make such changes please write in your comment what the old and new titles were.

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Well, right now, the title is wrong, because the female scent also affects the studies.

> Placing a woman’s T-shirt next to a man’s T-shirt negated the impact.

I think you should be more careful with titles such as this, especially with all the pro/anti-sexist shit going on currently.

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That's actually why I called the original title misleading, and the linkbait (Male Scent!) seemed obvious to me as well. However, this was clearly a case where it was impossible to please everyone, so we retreated to the original.

It's often a little tricky to come up with accurate, neutral titles. It would be good if people would suggest them.

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Maybe this affects only certain kinds of experiments. There is a reason why only male mice are used in experiments and why scents (peppermint) is usually used to denote context.

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To elaborate, male rodents are typically used because they do not go through estrus[0]

[0]https://en.wikipedia.org/wiki/Estrous_cycle

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It sounds like each test involved the same person both giving injections and sitting in the room. I wonder if they can somehow mechanically inject the irritant without human involvement. Then they could have male/female participants sit in the room without knowing if any animals are present. This would help distinguish whether the rodents were reacting to a general difference in scents, or males and females give off different signals when handling rodents.

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"Mogil’s group discovered that this gender distinction alone [...]"

It's sex, not gender distinction. Gender - what you identify as, sex - what you are. Males that identify as females would still throw their test off. Yah, nipicking. And call me paranoid, but this seems to have agenda....

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Wow. I didn't really know there was an 'animal grimace scale'.

I have to say, after googling that a minute ago, I have actually become an superfluous animal testing opponent, after having suspected animal testing was done excessively.

I dare you to google it.

These researchers... what assholes.

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This is like the "Heartbleed" backdoor of the medical industry .. how many previously-though-defensible studies are now trash because of this? Its mind-boggling, to be honest ..

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We can only account for variables we can imagine, this is why science is so often proving itself wrong.

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This metaphorically reeks of being the sort of result that in six months will be quietly retracted. But at least there's a mechanism proposed that isn't utterly ludicrous...

(See expansion below, which describes why this triggers my BS meter. YMMV, but it's not just "reflexive".)

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This is just reflexive HN negativity. As a pain researcher who's completely unaffiliated with the group that did this work, I find this to be an excellent paper - carefully done, with good controls, standard sample sizes for the field, and sensible assays.

People interested in more of the details can read the Nature Methods article here: http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth...

It also fits into a long history of work out of the Mogil lab about the limitations in our current assays for pain. It's worth noting that this is by no means an easy problem. Pain is inherently subjective, and measuring and quantifying it in humans is difficult, let alone in rodents. The only way forward is more work like this - that carefully quantifies the sources of potential bias and error in our assays, and proposes solutions for how to get around them.

Edited to add: Vox has a good interview with Mogil that goes more into this. You can read it here: http://www.vox.com/2014/4/28/5653444/mice-get-stressed-out-f...

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I'll take the liberty of rephrasing jerf's comment: this is the sort of paper I'll be more likely to believe after it's been reproduced by multiple labs. Until then, I'd just as soon not even be told about it.

It sounds too much like any number of "xxx affected by cell phone radiation!!1!!" results that historically have given rise to much panic, intense discussion, and clicking of links, but have never, ever, ever proven to be consistently replicable. At some point, skepticism and even a bit of "HN negativity," as you put it, becomes the most rational response to initial reports of such phenomena.

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My point is more that there are differing levels of the prior probability of a study being true. Yes, 'xxx affected by cell phones' stories are bunk, however, those stories tend not to be published in Nature Methods, tend not to come out of highly respected laboratories, and tend not to have voluminous documentation and results, with 9 Supplementary Figures.

I've been reading this paper closely over the past 30 minutes, it's important enough that I'm sure it'll be heavily discussed at conferences and meetings this year. I can't think of a single thing that these researchers could have done that they haven't done. They've approached the question carefully, looked into a ton of second-order explanations and effects, and provided a plausible discussion of how and why they see their effects.

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Please do expand on your thought there. What makes it likely this will be retracted?

The experimental set-up seems fairly sound. They controlled for the obvious factors that could influence the outcome. It is somewhat consistent with what we know in other areas - yes, pain is felt less under increased stress, and yes, the presence of other males is a stressor.

The interesting part is that it's an inter-species stressor. But then again, testosterone as a male hormone is shared across a lot of species - it's not entirely unreasonable to assume that scent markers might be similar too.

So, what makes your BS sensor go off? (I ask in all seriousness. I'm always interested in calibrating my sensor, and it didn't go off for this).

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Like I said, and I meant it seriously, it does at least propose a non-silly mechanism that makes sense. But it A: proposes a sweeping result which, if taken seriously, ought to invalidate a lot of other experiments and B: pushes a moderately political button with the gender issue.

Neither of those is a disqualifier, but A in particular at least somewhat gets into the realm of "an extraordinary claim that will require extraordinary confirmation".

The proposed mechanism would also seem to imply that female hunters don't exist. I would have preferred a proposal that you're inclined to hide your weaknesses around a male in general (lest he either take your woman or harass you in other ways), and the mechanism is likely keyed off of testosterone in general rather than mouse smells in particular, which seems reasonable.

My head isn't going to explode if this is established by further experiment. But it's suspicious to me.

To siyer's point, impeccably-done research can still come up with coincidental results, unfortunately.

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"and the mechanism is likely keyed off of testosterone in general rather than mouse smells in particular, which seems reasonable."

Yes, this is what Figure 1c and 1d of the paper demonstrate. (To be precise, not testosterone, but adrostenone, androstadienone, and 3M2H).

"My head isn't going to explode if this is established by further experiment. But it's suspicious to me."

Supplementary Fig. 1 and Supplementary Fig. 3 describe replications performed in two other laboratories, one at the University of Alabama, Birmingham, and the other at another laboratory at McGill.

Look, I'm all for scientific skepticism, and it's true that there's a lot of low-powered stuff out there. However, papers are best evaluated on what they actually say (which, incidentally, is why open-access/archiving is important), rather than on a filtered impression of what a press release says. If you'd like a copy of the paper, let me know, I'd be happy to send you a pdf.

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The sweeping button pushing is the headline, not the study. I'm ignoring headlines these days, since they're all written as click bait :(

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No, the mechanism is increased stress, and it has already been experimentally verified (although I'd like to see it repeated). Mogil has a guess about why that might happen, and it's called out as supposition, not an "extraordinary claim". Other potential explanations include a few male rat-farmers who were rough with the rats, which made the rats edgy around males later in life.

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No, the mechanism is increased stress, and it has already been experimentally verified (although I'd like to see it repeated)

Until it has been repeated, it has not been verified. That is how experimental science works.

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Science is repeatable, not repeated. It's not true that one experimental result is meaningless but two are gospel. The first has a probability of being a fluke, and the second reduces that probability, that's all.

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Indeed, this is true as well. Science isn't the right place to look for absolute certainty. But still, there are some obvious things you can do to increase confidence in a result, and one of those is to get other people to try to reproduce those results.

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This particular study seems fairly solid, but the linked one about a cardboard cutout appears contradictory. The comment about predators seems careless, in that light, but the person making the comment has clearly been theorizing about the effect for a while.

So I don't expect the study to be retracted, but I expect half a dozen more papers and then a theory that will be eventually debunked in favor of a more politically convenient one.

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This metaphorically reeks

I see what you did there.

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