Friday, 18 August 2017

The mechanism is more important than the ethics. EAE experiments

Arima Y, Ohki T, Nishikawa N, Higuchi K, Ota M, Tanaka Y, Nio-Kobayashi J, Elfeky M, Sakai R, Mori Y, Kawamoto T, Stofkova A, Sakashita Y, Morimoto Y, Kuwatani M, Iwanaga T, Yoshioka Y, Sakamoto N, Yoshimura A, Takiguchi M, Sakoda S, Prinz M, Kamimura D, Murakami M.Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit.Elife. 2017 Aug 15;6. pii: e25517. doi: 10.7554/eLife.25517

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.



This is the type of post ,where I get called arrogant because I dare to say something not good about science.

However I have to say "not in my name" in public.

As part of public engagement in science, we need to talk about animal experiments. 


I have signed up to this and the UK Government want scientists to be more open about animal studies. 

We can be fluffy and say every thing is amazing but in reality some of it isn't. You know this.

Yes animal experiments are unpleasant, but they can lead to new understanding. 

However, the question at what cost to the animals?

These days virtually all animal experiments have to go through ethical review panels, but sometimes what they support horrifies me. Maybe in the UK, we care too much about our furry friends or maybe people elsewhere don't care enough!

This is a good example. I comment on it so when people click on the altmetrics to this paper, you will come to this blog post. 

This research is being done for people with MS. 
However, do you feel it is relevant to your disease? 

The opening statement says "To examine the impact of stress conditions in a transfer EAE model, we first employed a sleep disorder model, in which continuous stress is imposed on mice on a free rotation wheel for 2 days by the perpetual avoidance of water". They do this by filling the cage with water and make they run on a wheel.

Surely this is torture. Which ethical review panel would think this is OK. What is worse, is when when they transfer cells into the animals it causes death. 

Is it OK to kill animals, when there can be endpoints before this. 

I would have to say no, this does not have 3Rs merit.

The animals were dying and they had bloody stools which surely could have been used as an endpoint at the very least.

The authors say that changes in the circulation in the brain affect intestinal activity and further say vagal nerve activation is involved in the development of the severe gastrointestinal failure triggered by brain micro-inflammation.

However, there is no mention that vagal nerve stimulation in humans has been reported to inhibit autoimmunity so in complete contrast to the human potential reality 

The ARRIVE guidelines by the NC3Rs  asks for the translational value of the study. 

Is there any?

First thing. In the study they applied parametric statistics to non-parametric data and so the explanation of the data in the experiment maybe fatally flawed. It is underpowered as there are not enough animals in a group (such as n = 3) to give any real statistical meaning, using the proper statistrics. 

No wonder the three referees remained anonymous.

4 comments:

  1. That is truly horrible. What is the point of checks and safeguards if the people carrying them out are insufficiently knowledgeable to discriminate? A tick-box mentality, presumably. We - and the animals - deserve better.

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    Replies
    1. You have to read the paper for yourself to determine whether is is wonderful sexy science. The journal must think so..but if MS is not a CD4, Th17 problem the value disintegrates before it is even started.

      Next you ask what is the value of experimental design. Does a flooded cage and a wheel represent any useful human concept. This comes from a group that hangs a mouse by its tail for a month to argue that gravity makes a gate of cell entry in the lumbar spinal cord, when the data in so many other papers argues against the whole concept...eg. Look at studies where they make the spinal cord transparent and you can see that there is not a predilection of cell entry at L5.

      Delete
  2. We mice deserve better! Refuse to click on link do not wish to contribute to altmetric kudos

    ReplyDelete
  3. you should write to Elife. Rather than just post your opinion here.

    ReplyDelete

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