The Mouse Trap: The dangers of using one lab animal to study every disease | Hacker News Reader

The Mouse Trap: The dangers of using one lab animal to study every disease

slate.com

56 pointsJacobAldridge20 comments

This problem is only a small subset of the problems inherent with essentialism, which in turn is only a small subset of the problems inherent in allopathy. There are dozens of epistemological and practical problems with modern medicine that run all the way up and down the abstraction layers. There is a good book called The Cult Of Pharmacology that discusses some of these:

http://www.erowid.org/library/review/review.php?p=269

edit: This article completely misses out on some of the most interesting problems inherent in the mouse model. For example, the efficacy of drugs is very closely tied to cultural context, so you have all sorts of researchers trying to create cultural experiences for their mice in order to get better results. And because of course their papers won't get published if they include this information even though it's essential that they do these things, it means that none of these experiments are reproducible, i.e. they are no longer within the realm of science. Nor does the author really explain how the market-driven model for drug research is responsible for these distortions, nor does he fully discuss the fact that there are an enormous number of drugs that have been washed out that may actually be effective in humans, etc. I just saw a really good talk on this a few weeks ago, I'll submit it in a couple months when it's posted online.

> so you have all sorts of researchers trying to create cultural experiences for their mice in order to get better results.

Can you give an example please?

A good example is that the background noise can apparently have an effect on the mice, including things that people might not even notice like a computer fan running in the corner of the room or whatever. Another example is timing, apparently you can get bad results if you're not running the experiments at the same time each day. A third example is the way the mice are selected for the experiment, apparently you can get better results if you practice picking up the mice and injecting them with saline each day for a week before you start injecting them with the actual drug. Apparently there are even people who will sing to their mice because they think it makes a difference. Not to mention things like whether your mice are waking up to natural light or an artificial light being turned on, how much ability they have to exercise, whether you are petting them each day, how much you're feeding them and how nutritious the food you're giving them is, etc.

Cultural experiences was probably the wrong term, but basically what's happening is that large portions of the protocol, which are apparently essential to obtaining the results, can't actually be written about in the paper, meaning the results can't actually be reproduced. (Although if you actually look at the Rat Park experiments and think of each environmental factor in terms of the larger whole, perhaps culture is the best metaphor after all.)

And even if you completely standardized the handling of the mice, there are all sorts of reasons why they mice model is still dubious beyond the many reasons discussed by the article. For example, some researchers have reported a 'tall left-handed blonde effect', where the results can only be duplicated by tall left-handed blondes. I think this is why historically such a large percentage of our medicine is derived from plants originally used by shamans or that otherwise had a historical ethnobotanical use, and why even today so many of the most promising compounds are also things that come to the attention of scientists based on anecdotal evidence. (E.g. MDMA for PTSD, LSD for cluster headaches, cannabinoids for treating cancer, etc.)

Very interesting, thanks.

My problem with this article and sentiment is that there is no good alternative suggested. I don't know enough about mouse research standards, but I would think that all these details should be targets of further research to understand the system better and make better protocols to control it, instead of the marathon of hand-wringing that I see in this article - most of it irrelevant to the model itself. Out of all the things discussed in the article, I literally cannot identify any actionable items. It's just a big discussion of various aspects of modern biology, framed in a contrarian manner.

I don't think this is like work where you should always go to the boss with a solution to the problem you're presenting to him.

Science is half about finding the problems in the present model and then everyone runs around and tries to find a solution to save it. They may even end up throwing the idea out and adopting a new one.

I felt otherwise. I believe the author not only pointed out other alternatives but talked with those people trying to do things differently. Namely the course of action is simply to try different and more varied things.

The whole problem that is being decried is that of following a rigid, fixed formula that tries to generalize for all cases. That of using the mouse model for everything, even those things for which it is not the best fit.

In software terms this is akin to Netflix's implementation of Chaos Monkey. Mainly that one shouldn't only check for certain failure conditions that have been previously specified, but to also create a framework where you try to look for faults in areas that are outside of the expected.

There are some major inaccuracies in the way biomedical research is presented in this article. For one, in nearly every mouse study, confirmatory studies are also carried out in human tissue cultures (Hela cells are a famous example), which are completely absent from their pie chart.

Secondly, the article completely ignores sequencing efforts - an astonishing oversight in my opinion. Obviously, we can't do genetic studies on humans, but inexpensive exome sequencing is rapidly allowing us to do observational studies in humans.

Think of it like this: maybe 10 years ago you thought "hey, why are we writing software for Windows when we could be writing it for Mac / Linux where it's so much nicer and easier?" And then you remember that most everyone else uses Windows and you know that if you want to make an impact, you have to use those platforms, until the balance slowly shifts.

The same goes for medical research: if you want others to be able to use and build on your result, it needs to be comparable and reproducible. That is, others have to be able to run your methods (read: software) on their animal models (read: OS).

So when he says:

Perhaps the researchers have come to resemble their favored species: So complacent and sedentary in their methods, so well-fed on government grants, that any flaws in the model have gone unnoticed, sliding by like wonky widgets on a conveyor belt.

It's kind of grating. It's not just "easier" and "cheaper" -- it's fundamentally more useful to other scientists and that's worth acknowledging.

"it's fundamentally more useful to other scientists and that's worth acknowledging."

But at the end of the day the goal isn't just to produce results that are logically consistent with the results of other scientists, it's also to discover drugs that can be used to cure real human diseases. Using a mice monoculture model is really bad for this, because there are lots of drugs that would work great in humans but that never get tested because they don't work in mice, and similarly there are tons of drugs that we waste millions of dollars testing solely because they were effective in mice. When looking at the results of mice studies is less predictive of what will work in humans than just looking at anecdotal reports from people, then it means that the scientific model of drug development has basically become less effective than 'alternative medicine' as a source for new ideas, which is problematic for obvious reasons. I have no idea what percentage of drugs with a history of enthnobotanical usage end up being able to demonstrate real efficacy, but I can guarantee it's a hell of a lot better than the 10,000 to 1 figure cited by this article as the rate of drugs that successfully go from petri dish to mice to humans.

So then I think we have to ask ourselves, why are we spending our money on mice when actually going out into the rainforest and talking with indigenous people could be literally two orders of magnitude more cost effective. And, much more importantly, why are we genociding indigenous cultures in favor of 'scientific progress', when empirically preserving traditional knowledge is so much more conducive to real progress and understanding. Hundreds of thousands of people throughout history have been willing to die in order to at least try to figure out which drugs work and which don't with the very limited tools they had, so ignoring what they have to teach us is a tragic waste, especially since we probably aren't going to go back to sacrificing millions of people in the name of scientific research any time soon.

In the past many discovery's where made by finding better animal models. For example, Guinea Pigs get scurvy mice don't and once we had a model it was possible to isolate vitamin C. But, today we can probably create mice that could get scurvy... Which suggest for many things tinkering with a mouse DNA may bet the best option because there is no good animal models for things like genetic diseases.

On what basis can you possibly conclude that we have exhausted our options in terms of discovering novel animal models? The article itself states that "[i]n 2009, a Japanese team created a transgenic line of marmosets—the first time that had ever been accomplished in a primate species."

My wife does stroke research with mice, but she also has described the importance of using multiple models as a way to expose new facets of the same issue. Animal research is learning by approximation, so it's critical to find new ways to examine similar problems.

transgenic line of marmosets

I first read that as transparent, and I though of the transparent line of zebrafish, and I imagined transparent marmosets and was about to google them when I realized it's transgenic.

And then I was kind of let down, and then I was embarrassed about being underwhelmed by transgenic primates!

for many things there is simply no good animal model so you are going to need to alter somethings DNA to get a good approximation of what's going on. Sure you can also alter the DNA of a primate but the downsides are A) we know less about primate systems than mice and B) they cost a lot more.

This is not to say a primate or even a zebra finches may not be a better animal model for many diseases, just that we share a lot of DNA with mice so there is a lot of relevant information we can gain from continuing to study them. Which when combined with their low cost means it's reasonable to spend more time and money looking at mice than our closer relatives.

PS: There is a vary vary large but finite set of useful drugs we can discover. As a first pass approximation being able to consider 30x the candidates at the cost of doubling our false positive and false negative rates is probably worth it (for now). Eventually, I suspect we will be able to accurately simulate many diseases in software based on human DNA or even an individuals DNA at which point we may be able to revisit a lot of these false negatives for lower cost. Between now and then we will probably start looking at a larger array of animal models based on our understanding of an ever more detailed understanding of DNA. But, until we can actually debug diseases the old shotgun approach has a lot of merit.

One of the things that interested me the most about this article was the unintended consequences of various measures used to gauge progress.

For example, researchers seem to be evaluated by the number of papers written, number of publications and peer acknowledgement. These metrics favor the mouse model heavily, with its cheap and fast methodology. It also seems to promote behaviors that seem at odds with what should arguably be the end goal of the work: creating working drugs.

It paints a rather bleak picture of the establishment with that goal in mind, despite the best intentions.

One more study to back up Taubes book about calories.

No, I didn't RTFA, but I'm going to blow off some steam anyway... experimenting on mice for human-related studies (behavioral, physical etc) is not only lazy, but fraudulent. It's a waste of tax payer money, and its overly cruel on en entire species of animal.

And we constantly reference these studies with lab mice again and again for answers to human problems. It's a fraud.

Ironic then, that this kind of testing is mandated by the government.

It's only ironic if you believe everything the government tells you.

Before a drug can be put on the market it has to be tested for it's efficiency and safety. It starts by giving the drug to volunteers to assess its safety. Would you rather we do not study the effects of the drug on animals before experimenting on humans?

Yes.

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