1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
ME/CFS: A disease at war with itself
We can all agree that ME/CFS is a nasty disease, particularly in its severe form, but there are abundant nasty diseases in the world. What is unique and particularly confounding about our disease is that so much controversy surrounds it, and not only surrounds it, but invades it too.
Discuss the article on the Forums.

Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155

Discussion in 'Other Health News and Research' started by Waverunner, Jun 4, 2014.

  1. Waverunner

    Waverunner Senior Member

    Messages:
    999
    Likes:
    854
    This is a very interesting finding. Blocking mRNA-155 could offer a new way to treat BBB-leakiness. Does anyone know how to block mRNA-155? Do you inhibit the production of this molecule or do you try to inhibit its action?

    http://www.sciencedaily.com/releases/2014/06/140602104749.htm

    Until now, scientists have not known exactly how inflammation weakens the Blood-Brain Barrier, allowing toxins and other molecules access to the brain. A new research report appearing in the June 2014 issue ofThe FASEB Journal solves this mystery by showing that a molecule, called "microRNA-155," is responsible for cleaving epithelial cells to create microscopic gaps that let material through. Not only does this discovery help explain the molecular underpinnings of diseases like multiple sclerosis, but it also opens an entirely new avenue for developing therapies that can help penetrate the Blood-Brain Barrier to deliver lifesaving drugs.


    According to Ignacio A, Romero, Ph.D., "We are beginning to understand the mechanisms by which the barrier between the blood and the brain becomes leaky in inflammatory conditions. Based on these and other findings, drugs that reduce the leakiness of the barrier have the potential to improve symptoms in many neurological conditions." Romero is one of the researchers involved in the work from the Department of Life, Health and Chemical Sciences of the Biomedical Research Network at The Open University in the United Kingdom.

    To make this discovery, Romero and colleagues first measured microRNA-155 (miR-155) levels in cultured human cells and compared them to cells under inflammatory conditions. Researchers then measured levels in the blood vessels of inflamed brain areas of patients with multiple sclerosis (MS) and compared them to non-inflamed areas. In both cases, miR-155 was elevated in inflammation. Then, in mice, normal mice were compared with mice that were genetically altered to lose miR-155. When an inflammatory reaction was induced in these two groups of mice, the mice that could not express miR-155 had a much reduced increase in "leakiness" of the Blood-Brain Barrier than normal mice. Finally, scientists investigated in cultured human cells the mechanism by which miR-155 levels cause leakiness of the barrier and concluded that miR-155 affects the organization of the complex structures that form the tight connections between endothelial cells.

    "This study has the potential to be a game-changer in terms of how we treat neurological conditions and how we deliver drugs to the brain," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Since it was first discovered, the Blood-Brain Barrier has always been a touch elusive. Now, after careful analysis, we are learning exactly how our bodies keep our brains safe and that microRNA-155 is a key player."

    EDIT: Here we go. Seems someone has already been trying to block it and it seems to have nice potential:

    http://www.alzforum.org/news/conference-coverage/blocking-microrna-slows-motor-neuron-disease-mice
     
    Last edited: Jun 4, 2014
    cigana, merylg, Wayne and 5 others like this.
  2. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    I like the human stuff. The mouse stuff is pointless and irrelevant. We are not mice. There is on average an approx 50% chance that results from non-human studies will be similar to those in humans, and a 50% chance that they won't.

    I yearn for the day when scientists stop using animal 'models' and we can stop wasting time reading about such studies!

    No need to take my word for it:

    http://forums.phoenixrising.me/index.php?entries/the-flawed-paradigm-of-animal-models.1549/
     
    garcia and Waverunner like this.
  3. Waverunner

    Waverunner Senior Member

    Messages:
    999
    Likes:
    854
    Yes, I fully agree. Many parts of the scientific community have completely detached from the clinical practice. The scientists cure diabetes in mice and make all kinds of great breakthroughs but they always end their studies with the same wishful conclusion: "The finding...could/should...lead/lay ground to...new therapy/treatment."

    In the end, 99% of this is pure dreaming. The findings will never be put to practice because regulation is from the last millennium and is much too expensive. If patients have 2 months to live, they need experimental treatment now, not 15 years later. The only reason scientists do animals models is because they are free of regulation and can do whatever they want.
     
    MeSci and garcia like this.
  4. xchocoholic

    xchocoholic Senior Member

    Messages:
    2,940
    Likes:
    1,612
    Florida
    I only have 1 bottle left of my anti mRNA-155 serum that I'll sell to you for $10,000 (Make that $100,000 if you're rich). That's a bargain considering all the ingredients are from all natural sources and it's FDA approved. Disclaimer. Anti mRNA-155 might cause all your vital organs to shut down. Results may vary.

    Sorry. I couldn't resist.

    I clicked on this to see how this study was done. This may he a dumb question but why aren't they doing more studies directly on brains of live people ? They're gaining access via various medical procedures. Are they gathering biopsies during those ?

    Tx .. x
     
  5. Hip

    Hip Senior Member

    Messages:
    3,255
    Likes:
    3,141
    I'd like to see some published scientific papers that have come to that conclusion.
     
  6. Waverunner

    Waverunner Senior Member

    Messages:
    999
    Likes:
    854
    Well, animal models probably aren't useless but results sometimes/often cannot be transferred to humans. Why do we focus so much on mice and why can't we treat terminally ill patients? Why can't we let patients decide?

    Let us make the hypothetical case for mRNA-155. It worked in mice. Fine. Now if we were to try it in humans, we should try it in cell cultures first. If this turns out positive as well, why can't we use it for patients? The patient should sign a paper which says, that nobody can be sued in case of adverse events and possible risks include death or severe damage. Done.

    The easiest way now would be to use very, very small amounts of the drug and then slowly increase the doses. Even if a side effect occurred, it should be manageable then.We would have a thousand times more drugs at cheap prices within a few years. Add genomic medicine and we finally could deliver the right drug to the right patient.

    What is the presence? I read a paper about etrolizumab for IBD today. They said the drug was a great success. The results of a phase-2 trial were, that 20%(!) of patients treated with the optimal dose of the drug went into remission. Is this a bad joke? 20%? After 10 years of testing and hundreds of millions of dollars they come up with a drug that puts only 20% into remission and celebrate it as success?

    Clearly, something needs to change.
     
  7. Hip

    Hip Senior Member

    Messages:
    3,255
    Likes:
    3,141
    I would like to know just how many new drug compounds get rejected at an early stage in animal testing, due to severe or fatal side effects. In the drug discovery process, I would imagine that the use of animal testing weeds out a lot of dangerous compounds at early stages, and thus protects humans; but I have not seen any stats regarding this.
     
  8. Waverunner

    Waverunner Senior Member

    Messages:
    999
    Likes:
    854
    I can't give you the numbers but I guess you can weed out many compounds. The problem I have is, that even if the compound is safe in mice, 99% of them never reach the clinical practice because the approval process is innovation hostile and much too expensive. An easy example: If you don't choose cancer patients based on genomic tumor parameters, none of the targeted therapies would have been approved by now. If only 20% of patients have a HER2 positive tumor, only 20% will benefit from HER2 targeted therapy. If you compare this to chemotherapy, which works in much more patients because it is unspecific, has lots of side effects and doesn't help in certain cancers at all, a HER2 drug will never get approved because of cost-effectiveness issues. However, if you only take HER2 positive patients, you have a much higher response rate and the drug will likely be approved. If you look at all other diseases except cancer, however, patients never get stratified according to their genetic makeup. This means, that hundreds of drugs were never approved, despite the fact, that they work perfectly well for many patients. The only problem was, that we couldn't identify these patients with tests and had a completely heterogeneous patient population when conducting trials. A patient has to decide, if a drug works for him, not some one-size-fits-all trial.
     
    MeSci likes this.
  9. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    I have found many many such papers during my paid work on this topic. Here are two:

    http://drhadwentrust.org/downloads/publications/LangleyValidityofAnimalResearchEnglish09__2_.pdf

    http://altweb.jhsph.edu/wc6/paper125.pdf

    Here is another by authors who unfortunately still feel unable to abandon the irrational paradigm of animal models altogether, perhaps under pressure from publishers, but it has some good stats:

    http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245

    There are even fundamental and crucial differences in heart physiology between humans and dogs - a species commonly used in heart research:

    http://videolectures.net/eccs07_tusscher_vfh/

    There is a vast range of evidence against animal models, and I can't do justice to the subject in a forum post - one reason why I have started a PR blog on the subject. It is so important to any patient group, as there is so much propaganda based on animal models that gives people false hope.
     
  10. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    There is a long sequence of testing processes before human trials are reached. This includes, for example:

    1. Electronic screening of a large number of candidate compounds which have been identified as having promising chemical properties.
    2. Computer modelling (in silico 'testing') of those selected in the first process.
    3. In vitro testing using cells.
    4. In vitro testing using organs (human or otherwise) or simulated organ systems.
    5. Animal testing may be done at this point (small animals).
    6. Testing on larger animals is commonly done after the small animals.
    7. Becoming more common but still relatively rare is human microdosing (as suggested by @Waverunner )
    8. Clinical trials, perhaps preceded by normal dosing in healthy volunteers.

    An increasing number of scientists are proposing that we miss out the non-human-animal steps as they are so unreliable and cause unnecessary delays and false dawns.
     
  11. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    As well as low success rates and adverse effects, chemotherapy drugs sometimes turn out to kill as many people as they treat 'successfully' (which I think usually means survival for about 5 years, but many only increase lifespan by a few months and raise the risk of other serious illnesses, notably cardiovascular disease, in the longer term, which needs to be taken into account especially for younger patients).
     
    Waverunner likes this.
  12. adreno

    adreno 3% neanderthal

    Messages:
    2,604
    Likes:
    1,967
    Tundras of Europa
    In this case the findings from the mouse model correlates with findings in humans:

    Therefore I see the results from the mouse model as improving the credibility of the hypothesis.

    The problem with neuroscience is that you can't cut up peoples brains to see what is going on at the cell level, and scans do not provide this information.
     
  13. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    Here's another one:

    http://www.bmj.com/content/334/7586/197
     
  14. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,864
    Likes:
    4,625
    Cornwall, UK
    Imaging (scanning) techniques are improving rapidly, and some individual molecules can now be tracked.

    All animal models can do is to show you that the same thing happens in another species - or doesn't. Do we really need to know this?

    I spent years studying species differences and the failures of animal models to translate to human treatments.
     
  15. adreno

    adreno 3% neanderthal

    Messages:
    2,604
    Likes:
    1,967
    Tundras of Europa
    This is a huge subject, and I don't have time to study all the details. @MeSci, did you conduct an exhaustive research of all relevant data, and did you find no studies that support the use of animal models? It's hard to believe that animals models are so widely used in research, if all data proves it invalid. Perhaps there is conflicting data on the subject, or perhaps animal model work better for some subset of research or domains of physiology than others?

    This study is perhaps more nuanced, it concludes that the use of animals models has to be more rigorously evaluated:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC351856/
     
    Last edited: Jun 5, 2014
  16. Hip

    Hip Senior Member

    Messages:
    3,255
    Likes:
    3,141
    Note that creating animal models of human disease is only one of many different categories of animal testing. There is actually a list of all the various purposes for animal testing in this Wiki article.

    I know that knock-out gene testing is particularly invaluable to science. If you want to work out the function of a newly discovered cellular receptor, for example, you breed a mouse which has the genes for that receptor deleted, and this allows you to start to figure out the function of that receptor.

    And then there is toxicology testing, which allows you to work out which, out of the plethora of chemicals created, might cause cancer, might damage the skin or eyes, etc. These can be among the most cruel tests.

    I saw a TV program a few years ago about a company in the UK that had developed a way to grow actual human skin in a petri dish. The idea is that this can be used instead of animal toxicology tests.
     

See more popular forum discussions.

Share This Page