Reversal of Rett Symptoms

9 Feb

Reversal of Neurological Defects in a Mouse Model of Rett Syndrome.

Rett Syndrome is an ASD. My friend Kassiane has Rett Syndrome. I would bookmark her blog as I’m sure she will want to talk about this.

Yesterday, the news was published that claimed that symptoms of Rett Syndrome had been reversed in a mouse model of Rett. It seems like decent enough science and yet all the news reports I’ve seen are encouraging very worrying responses in some people.

First, lets go through the science at a level people like me can understand it.

Rett is ’caused’ due to mutations in the MECP2 gene. In simple terms what this paper described was the science team attempting to emulate Rett in mice and then turn on the MECP2 gene to see what happened. One of the things that happened was that in roughly half of the mice they did indeed reverse the symptoms of Rett.

This paper has made it into the Schafer Autism Report already. It is also being discussed on the Autism Yahoo Groups with a view to possibly extending these findings:

Is any one going to contact them in regard to our children’s symptoms?

Posted yesterday to the Autism-Mercury group.

What is worrying to me is two things. First is the applicability of this work to humans. One of my science guys whom I rely on to translate this kind of stuff said:

Simply put, this paper is good work, but it’s a headline job because it has no applicability to humans; this paper simply validated Zoghbi’s work.

That’s worrying enough but in a world inhabited by the likes of Rashid Buttar, the Geier’s and various others who leap from madness to madness in their frightening treatment regimes is the second and much more truly scary aspect of this paper that no one seems to be discussing.

I said above that in half of the mice Rett symptoms were indeed reversed. What about the other half?

….prior to symptom onset, revealed toxicity associated with abrupt Mecp2 reactivation as 9 out of 17 mice developed neurological symptoms and died….The data indicate that sudden widespread activation of the Mecp2 gene leads to either rapid death or complete phenotypic rescue.

This is quite literally, kill or cure.

I have a really horrible feeling that certain ‘doctors’ are going to be chasing this like a dog with a bone – already the Yahoo Groups are asking for details. No one is discussing this ‘detail’. A little bit of restraint is very much what’s required here.

UPDATE

Its begun already. Sallie Bernard posted a comment from Richard Deth on the Autism-Mercury group:

The just-published study shows “Rett syndrome” can be reversed in mice, lacking MeCP2, which binds to methylated DNA. Reversal was accomplished by turning on MeCP2 after symptoms (neurological and obesity) were fully developed. The important point is that an abnormal pattern of gene expression, due to interuption of the methylation-dependent epigenetic mechanism, can be reversed if the methylation-dependent epigenetic mechanism is brought back to normal.

The parallels for autism are clear. If impairments of methylation-dependent epigenetic regulation, caused by oxidative stress
rather than MECP2 deletion, can be reversed, then recovery can occur.

No mention of the rather important details that the reversal killed half the mice, instead just a comparison of this decent science with his own brand of poor science in order to lend it weight and credibility it doesn’t have,

30 Responses to “Reversal of Rett Symptoms”

  1. Catherina February 9, 2007 at 11:25 #

    Thank you for posting the paper, I was going to chase it up after I heard the news this morning on BBC (interestingly, they mentioned Edinburgh, but not the names of the researchers). In any case, the main point is (taken from the discussion):

    The experiments do not suggest an immediate therapeutic approach to RTT

    I am sure that sentence will be widely ignored.

    Catherina

  2. kristina February 9, 2007 at 13:51 #

    My first thought was “WWKS” (what will Kassiane say) and then, but this is about mice……..

  3. Joseph February 9, 2007 at 14:38 #

    I’m no expert in genetics, but the way they activated and deactivated the MECP2 gene in mice didn’t sound like something that could be easily applicable to natural mutations. Anyone know if that would be doable?

  4. Club 166 February 9, 2007 at 14:40 #

    I couldn’t imagine any IRB (Institutional Review Board) approving a human study when the animal study showed a 50% mortality rate.

    But then I’ve overestimated people before.

  5. anonimouse February 9, 2007 at 14:41 #

    Unfortunately, I think some people will say that they’d rather see their kid completely cured and if the treatment can kill them, then…

  6. anonimouse February 9, 2007 at 14:43 #

    Club 166 – the Geiers give Lupron to kids who don’t have precocious puberty and shouldn’t be taking it. They have a sham IRB “overseeing” their work. Wouldn’t be hard to another sham IRB to “oversee” this one either…

  7. Joel Smith February 9, 2007 at 14:44 #

    Right now, chelation is happening with no scientific evidence for its effectiveness and witha poo-pooing of any potential risks.

    I don’t see why injecting kids with various genes wouldn’t happen down the road. Cure or death is the motto of some of these people.

  8. Catherina February 9, 2007 at 15:49 #

    I don’t see why injecting kids with various genes wouldn’t happen down the road.

    Well, there is the problem precisely: the mice were engineered to have an inducible MECP2 gene. No human has that, it is inconcievable (to my mind) how you could get the gene into all brain cells of a 2 year old. On top of that, previous gene therapy for cystic fibrosis has had fatalities, so the chance for success without intolerable risk of side effects/death is really low.

  9. mcewen February 9, 2007 at 16:27 #

    Clearly we need to interview the mice and check how their quality of life has improved following their cure – those that survived that is.
    Cheers

  10. Brian Deer February 9, 2007 at 16:35 #

    Whaddya mean Club 166? Can’t get human research through an IRB?

    Hell, start your own. Mark Geier can tell you how!

  11. Catherina February 9, 2007 at 16:54 #

    I am somewhat surprised that the mice in this study clasp their hindlegs. I recently saw a presentation of mutant mice that were wringing their front paws.

  12. notmercury February 9, 2007 at 16:59 #

    “This is quite literally, kill or cure.

    If I read this correctly, what they are saying is that a sudden switching on of MECP2 was toxic so they opted for a more gradual increase of the gene product by slowly increasing the tamoxifen.

    Since the human Rett gene hasn’t been engineered in such a way that estrogen analogs can flip the switch, this isn’t about to work in humans with Rett Syndrome. Not to say that this isn’t fascinating work but it isn’t immediately applicable to humans.

    I am very intrigued by what this says about brain plasticity, at least in mice.

  13. Kev February 9, 2007 at 17:12 #

    _”If I read this correctly, what they are saying is that a sudden switching on of MECP2 was toxic so they opted for a more gradual increase of the gene product by slowly increasing the tamoxifen.”_

    Absolutely, but is that how a certain group of people are going to see this? I doubt it.

  14. laurentius-rex February 9, 2007 at 18:21 #

    Mice and Humans, not comparable

    I am reminded of the drug which was tested on primates an mice OK but had a devastating effect in the first human trials.

    http://www.newscientist.com/article/dn10747-horror-clinical-trial-in-test-tube-recreation-.html

  15. Kassiane February 9, 2007 at 19:38 #

    What Kassiane will say is the mice were genetically engineered so that they had the ‘healthy’ MECP2 gene there to turn on.

    So it’s sort of not quite like X inactivation in girls with Rett but not really, because switching the X in a human is a lot different from genetically controlling on single gene in a mouse.

    And of course, while it makes big headlines to say that the scientists cured a form of autism, no one at the Rett Syndrome Research Foundation is saying they did any such thing. They’re saying they demonstrated that even full on Rett Syndrome isn’t a “point of no return” degenerative or progressive thing, and that recovery of skills is possible, which was the aim of their study.

    I’ll be blogging this later in more detail. I just wonder, is no hormone sacred to the chelation folk?

  16. Kev February 9, 2007 at 20:02 #

    _”I’m no expert in genetics, but the way they activated and deactivated the MECP2 gene in mice didn’t sound like something that could be easily applicable to natural mutations. Anyone know if that would be doable?”_

    Certainly doesn’t sound like it but lets face it – the woo industry is centred around the fear-marketing of useless applications. How long before someone comes out with a homeopathic tamoxifen ‘guaranteed’ to reverse autism with no adverse effects?

  17. Ms. Clark February 9, 2007 at 20:14 #

    Thanks, Kev. I have visions of the DAN! dox cranking out the Tamoxifen prescriptions because “everyone knows that it’s the new hot cure for autism,” and the straight MD’s are working with Big Pharma to suppress any new cures for autism… except… Tamoxifen and Lupron are both big pharma drugs… never mind… If they are discussing it on autism-mercury you know they’ll find a mercury angle, like Tamoxifen breaks up mercury/testosterone lattices… and the mice in this experiment must have been given thimerosal containing vaccines…which flipped their MeCP2 genes… of course. :-/

  18. David N. Andrews M. Ed. (Distinction) February 10, 2007 at 16:19 #

    MsC: “Tamoxifen and Lupron are both big pharma drugs… never mind… ”

    They are, indeed.

    Funny how selective the mercury militia’s attention to this sort of detail is….

  19. RettMom February 10, 2007 at 23:56 #

    Nowhere in this study did I see anything proposing that this would be transferred into an easy cure for humans. I think the thing to do here is back up a bit and see it for what it was meant to do. The study was to see if the neurons in the brain could function appropriately if the right conditions were present even after supposed “damage” had been present for quite some time. This research is only a springboard for discovering a way to get the same positive results (hopefully safely and without death) for girls with Rett, and I don’t think the researchers or RSRF or anyother organization is promoting it any other way.

  20. Prometheus February 11, 2007 at 00:43 #

    I wanted to re-emphasize the fact that the tamoxifen used in this study WOULD NOT have the same effect in girls with Rett syndrome. The mice studied had a tamoxifen-sensitive regulatory element inserted to make their MECP2 genes controllable by tamoxifen. In girls with Rett syndrome, the MECP2 genes are inactivated by a mutation.

    Clearly, the researchers are not claiming that their results can be easily transferred to humans. Just as clearly, however, many “autism-therapy” practitioners have taken research out of context in the past.

    My fear is that some practitioner will read the study, not understand it, and will start giving tamoxifen to autistic girls (or even autistic boys – stranger things have been advocated). I hope that I’m wrong, but I fear that I am right.

    After all, if someone could read a paper about making crystals of testoserone and mercury by dissolving the two components in a minimal amount of hot (50 degrees C) benzene and think that somehow applied to autistic boys, anything is possible.

    Prometheus

  21. Kev February 11, 2007 at 00:54 #

    Hi RettMom,

    You’re absolutely right. However, as Prometheus comments (and as he and I know) there are a lot of very unscrupulous quacks who have ingratiated themselves with parents who have kids on the spectrum and who have prescribed things that have caused everything from minor illness to hospitalisation and even death to autistic kids.

    I’m not suggesting that this research is non-scientific or even bad but it is not being reported accurately or fully and I am very worried it will be picked up on by these quacks. These are people who have very little scruples.

  22. mike stanton February 11, 2007 at 19:37 #

    I just read your update on Deth. You only have to compare his methods with the real research work described by Bird. It is seventeen years since Bird discovered the MECP2 gene. Zoghbi spent 15 years looking for a genetic cause for Rett before she discovered the link to a mutation on MECP2 in 1999. Bird says that he expected a null result. At best they were hoping to halt further deterioration. Reversal was the least likely outcome but they deserve it after all those years of lab work. Then Deth comes along, sees the word ‘methylation’ and dashes off a solution in minutes. Bah! Humbug!

  23. Joseph February 11, 2007 at 23:05 #

    I think the key of this research is that it shows that Rett syndrome is not brain damage. It’s likely autism is not brain damage most of the time either. Those who claim autism is a metabolic disorder might take this as an indication that they are right.

    However, I would point out that a typical characteristic of Rett’s, microcephaly, is not likely reversible.

  24. notmercury February 12, 2007 at 00:01 #

    Dick left out a few ‘ifs’

    If [someday we discover and demonstrate] impairments of methylation-dependent epigenetic regulation [are in some way related to autism and IF they are shown to be] caused by oxidative stress [we will be one step closer to understanding autism and one potential cause and only then can we think about pathways that] can be [theoretically] reversed, then [theoretical] recovery can [theoretically] occur.

  25. Ms. Clark February 12, 2007 at 08:30 #

    They demonstrated some kind of reversibility in a sort of Rett MOUSE model! That’s supposed to bode something for humans that don’t even have Rett or a problem with MeCP2?

    So did anyone figure out what “oxidative stress” has to do with autism?

    What next b12 injections for schizophrenics with MeCP2 problems?
    http://www.webmd.com/content/article/131/118170

  26. anonimouse February 12, 2007 at 15:01 #

    Yeah, Ms. Clark brings up a good point.

    Is there such a thing as a mouse model for Rett? I always thought autism was unique to humans. Mady Horning might beg to differ, but seeing as she likes to torture animals with a genetic defect I’m not sure her opinion is relevant.

  27. Prometheus February 13, 2007 at 17:07 #

    Dr. Horning’s mouse model was one of autoimmunity – a phenomenon long associated with mercury – not autism. Although she says nothing about it in her paper, I have seen her claim (on video) that these mice “groomed” fellow mice to death, which she implies (and may have stated outright) is a behavior comparable to autism in some way.

    Two points:

    The first, amply made by Autism Diva and others, is that the particular strain of mice she exposed to thimerosal are known to “assault” other mice and need to be kept separate (except, one assumes, to breed).

    Secondly, grooming in rodents is a manifestation of social behavior – it is their primary social interaction.

    If these mice were truly “hyper-grooming” other mice (as opposed to simply trying to kill them), then their social interaction was increased over the normal level.

    Autism, so I’ve been told, is marked by decreased social interaction.

    So, apart from the “eeew!” factor, how does Dr. Horning rationalize the comparison between “hyper-grooming” and autism?

    It escapes me.

    It also escapes every animal behaviorist I’ve spoken to.

    Prometheus

  28. David N. Andrews M. Ed. (Distinction) February 13, 2007 at 18:55 #

    Prometheus: “Secondly, grooming in rodents is a manifestation of social behavior – it is their primary social interaction. If these mice were truly “hyper-grooming” other mice (as opposed to simply trying to kill them), then their social interaction was increased over the normal level. Autism, so I’ve been told, is marked by decreased social interaction. So, apart from the “eeew!” factor, how does Dr. Horning rationalize the comparison between “hyper-grooming” and autism?”

    So do we deduce here that Horning hasn’t the first bleeding clue what she is talking about?

    Because I bloody do!

    (yep… fucking angry at lazy and stupid researchers who cannot get their sodding act together and do something fucking useful for a bleeding change!)

  29. Ms. Clark February 13, 2007 at 20:41 #

    Male SJL-J mice that Hornig was experimenting on with thimerosal are dangerous to each other if the males are left with males past 8 weeks (I think that’s the age). Female “breeders” are known to chew on their own wounds. I don’t know if “breeders” means female mice of breeding age or ones that have been bred.

    Mady referred to one mouse that was attacking (hyper grooming?) as “he” and his cage mate as “his partner” which made me think that the cage mate was a male since she didn’t say, “mate.”

    I don’t know if the Columbia U IACUC would share Hornig’s animal protocol to see what she had been permission to do in that experiment. They are still investigating the mouse abuse on video, apparently. It’s been a few months now that they’ve been investigating this… probably hoping that it will all blow over and people will stop asking questions about what she did.

    Columbia got caught in a big stink over abuse of orangutans or baboons or some larger ape like that. PETA came in and sued them, I think. It wasn’t that long ago, Hornig didn’t think it was a big deal, apparently, and went ahead and set up her mice to attack each other and video taped it. That’s how it looks to me, anyway.

  30. notmercury February 13, 2007 at 21:23 #

    I don’t think there are many ideal or perfect animal models for any human disorder/condition but the mouse model for Rett is decent as mouse models go. It certainly helps to know the human and mouse gene(s) involved which is most certainly not the case for the majority of ASD.

    IIRC, the defective gene in SJL/J mice has more to do with muscular dystrophy or something. Mady infected the same strain with Borna Virus and declared them to be autistic too but she is only offering the thimerosal exposed SJL/J mice as a mouse model for autism.

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