
Male Scent May Compromise Biomedical Research - WestCoastJustin
http://news.sciencemag.org/brain-behavior/2014/04/male-scent-may-compromise-biomedical-research
======
VikingCoder
Richard Feynman spoke specifically to this point in his Cargo Cult Science
piece:

[http://neurotheory.columbia.edu/~ken/cargo_cult.html](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."

~~~
Balgair
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...](http://www.economist.com/news/briefing/21588057-scientists-
think-science-self-correcting-alarming-degree-it-not-trouble)

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

~~~
kennywinker
> 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.

~~~
Balgair
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.

------
greenyoda
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](https://en.wikipedia.org/wiki/Rat_park)

~~~
vanderZwan
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/](http://www.stuartmcmillen.com/comics_en/rat-park/)

------
Alex3917
There is a great video about these sorts of effects called Lullaby For A
Mouse: [http://vimeo.com/33803995](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.

~~~
thinkpad20
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.

~~~
hoggle
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?

------
tokenadult
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...](http://global.oup.com/academic/product/how-genes-influence-
behavior-9780199559909;jsessionid=D71B0EC416B75938EC3C4BB81BDB7183?cc=us&lang=en&)

------
singlsrv0x99fa
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 ?

------
brortao
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/](http://buav.org/humane-
science/key-criticisms/)

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

~~~
Balgair
Huh? How can scents be canceled out?

~~~
cevn
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'

------
anon4
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.

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

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

------
bambax
> _“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.

~~~
fit2rule
Lions hunt alone. Lionesses usually hunt in packs.

------
ChrisNorstrom
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.

~~~
serf
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.

~~~
vectorpush
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.

~~~
serf
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.

------
cmyr
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?

~~~
Jemaclus
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"...

~~~
Blahah
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...](http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.2935.html)

------
dang
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.

~~~
TazeTSchnitzel
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?

~~~
anigbrowl
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.

------
return0
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.

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

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

------
neurobro
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.

------
MyGod
"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....

------
joeevans1000
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.

------
fit2rule
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 ..

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

------
jerf
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".)

~~~
siyer
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...](http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.2935.html)

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...](http://www.vox.com/2014/4/28/5653444/mice-get-stressed-out-from-
men#interview)

~~~
CamperBob2
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.

~~~
siyer
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.

