Autism Science Foundation interview: Christie Buchovecky

18 Jun

Christie Buchovecky is a pre-doctoral research at Baylor College of Medicine. Her research project, Identifying Genetic Modifiers of Rett Syndrome in the Mouse, is supported by the Autism Science Foundation. Here is a video interview of Ms. Buchovecky from IMFAR 2011. It is very interesting to hear about Rett syndrome and the learning that has happened into the genetic link and the potential for treatment.

One thing I like about the ASF is their focus on funding new researchers, pre-doctoral and post-doctoral. It strikes me as highly important to pull new people into the field.

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42 Responses to “Autism Science Foundation interview: Christie Buchovecky”

  1. Christie Buchovecky June 18, 2011 at 03:20 #

    *hides* …I sounded so nervous….

    • Sullivan June 19, 2011 at 04:04 #

      Christie Buchovecky,

      I know what you feel. There’s an interview waiting to be uploaded of this big green hairy monster. I remember the whole time thinking, “wow, I hope I don’t look as nervous as I am”.

      That said, I think you did great. You showed knowledge and passion for your work.

  2. Harold L Doherty June 18, 2011 at 17:57 #

    Just out of curiosity how many $$$$, if any, does LBRB receive from the ASF, advertising revenue for Offit & Mnookin book ads and any pharmaceutical company sources?

    • Sullivan June 19, 2011 at 04:01 #

      Harold L Doherty

      on March 20th, you asked much the same question:

      Does lbrb receive ad revenue for the Mnookin & Offit books on the sidebar of this site?


      To which Kev replied

      Yes and No. Yes in the sense that we would if anyone bought them via a link in this page from Amazon.co.uk and no in the sense that nobody has yet.

      Can I ask, do you think there has been a change, or did you not read the answer then?

      From my perspective, I can answer simply: I have never been paid for anything at LBRB. I have contributed to the costs of running LBRB, making this a losing proposition for me financially. I don’t handle the books for this site, but I feel very confident saying that pharmaceutical companies have not contributed to this site.

      It is public information that I have been offered a travel grant by the ASF to attend IMFAR. That offsets actual travel costs (i.e. it is a reimbursement for actual expenses occurred, up to a set amount). If you do the math you will find that the amount does not cover the full costs of attending IMFAR.

      Can I ask why you pose the question now? Do you find it odd that I would post a video interview from ASF? I’ve done so before, even before the travel grant. Do you think I would need a financial incentive to post an interview with (a) a researcher working on Rett Syndrome (an ASD) and (b) a person who has commented in the past on Left Brain/Right Brain? For the record, ASF didn’t even inform me that the interview had been posted. I merely checked their YouTube site yesterday. On Monday, you will see here a video by Alex Plank on the IMFAR tech demo awards. He covered IMFAR for Autism Speaks. The video features Geraldine Dawson of Autism Speaks. I am not receiving anything from Mr. Plank, his website or Autism Speaks to post his videos. My guess is that frequent readers of this site will not be surprised that Autism Speaks has no ties to Left Brain/Right Brain.

      I have started writing for the ASF blog. I have offered to do this for free. However, I see nothing wrong if I should be paid for that effort. I would see nothing wrong with being paid for what I write here. But, as noted above, this is a blog not a business. There is nothing to pay me with.

      I’ve received a few free books. Some of them “free” only if I consider my time to have no value, as I’ve given feedback to the authors.

      I am aware of only one autism blog that makes a significant amount of revenue from advertisers and sponsors. I feel confident that none of those advertisers and sponsors have offered Kev a dime.

  3. Christie Buchovecky June 19, 2011 at 05:02 #

    Thanks Sullivan, and thanks for posting. I’m glad to start getting my work out there. Also, ASF didn’t inform ME that the interview was posted either… I’ll have to go check the others out.

  4. Harold L Doherty June 19, 2011 at 07:12 #

    “I have started writing for the ASF blog. I have offered to do this for free. However, I see nothing wrong if I should be paid for that effort. I would see nothing wrong with being paid for what I write here”

    I didn’t say there was anything wrong with receiving or soliciting funds from ASF but such ties should be disclosed.

    I am a “neutral” in the vaccine autism wars who believes, unlike the ASF and the interests which have financed its start up under controversial circumstances, that science is not “closed” on all possible vaccine neurological damage, including autism, issues. I think the campaign to stop discussion of vaccine autism issues, a campaign in which ASF, Offit and Mnookin all play significant parts, delays our understanding of the possible side effects of some vaccine ingredients in the development of some children. It is no surprise that LBRB is in the “science is closed on vaccine autism issues” camp but you should be more open about it, less defensive, and drop any pretense of objectivity.

    • Sullivan June 20, 2011 at 20:15 #

      Harold L Doherty

      the notion that you are “neutral” on the idea of vaccine causation is somewhat belied by statements you make like: “I think the campaign to stop discussion of vaccine autism issues, a campaign in which ASF, Offit and Mnookin all play significant parts”. Where do they try to stop the discussion? Having an opinion is a good thing. Voicing an opinion–especially an opinion based on facts–is a very good thing. This is especially true when the opinions voiced in support of vaccine causation are (a) based on very poor science and (b) damaging to public health and the the autism community.

      What you call “neutral” actually comes across as “indecisive”. There is a mountain of data available. There is by far enough data to make some very clear and simple statements. One can say that the rise in autism prevalence is not related to mercury in vaccines nor is it related to the MMR vaccine.

      What you call “neutral” actually comes across as “leaning towards vaccine causation”. Your critiques of people like Dr. Offit, Seth Mnookin, and ASF suggest this. Have you ever voiced an opinion of the ethical violations of people such as Andrew Wakefield or Mark Geier? Given that Andrew Wakefield has been found guilty, it would seem clear that one could voice indignation as to what he did. Remember, he wasn’t struck off the register for his views on vaccines, he was struck off for his ethical violations. Dr. Geier has had his license suspended. Again, not for his views on vaccines, but for ethical lapses in his practice.

      One can make a decision, based on the data available (especially when there is so much) and still remain open and objective to new information. That is what being “open minded” means. “Open minded” doesn’t mean, “I’m going to wait and not make any definitive statements until more data comes in”. That’s indecisive.

      At this juncture, being indecisive is actually harmful. No, I am not telling you to stop talking (as if I could), trying to “stop discussion”. Rather I am pointing out that people who want to ride to fence on this subject are fueling a debate which rightfully should be over. If anyone is causing the damage here, it isn’t people like Paul Offit, it is people promoting the vaccine-causation idea and, frankly, fence sitters such as yourself.

      You have the right to be indecisive. You have the right to be wrong. You have the right to voice your opinions, even though they cause harm in the community. I have the right, the responsibility even, to voice the conclusions which are supported by the science available.

      There will likely be more really bad science on vaccine causation (such as the recent paper by SafeMinds and the PACE/NYU study). There will likely be a few more studies using quality methods. I suspect a follow on study to the Price study on thimerosal is in the works (much as there was a follow on study to the Thomson study in 2007). There will likely be some study on mitocondrial dysfunction and vaccine-induced fevers. Sure, someone may come up with another mechanism where perhaps, in rare cases, vaccines cause autism. At which point we look at the data objectively. But, one can not objectively look at the data available and say there is any sense leaving the door open on the “mercury in vaccines caused an autism epidemic” or “Wakefield’s theory on MMR and autism has any validity”.

      Which is my way of pointing out: since you haven’t been able to make up your mind yet, you will likely be riding the fence on this forever.

  5. RAJ June 19, 2011 at 13:40 #

    The Baylor laboratory is not the only group engaged in ‘translational research’. Genetically engineered mouse models have been developed for a number of named genetic syndromes including the Rett Syndrome group at Baylor headed by Dr. Huda Zoghbi, the discoverer of the MECP2 gene that causes Rett Syndrome.

    Genetically engineered Mouse models for Rett Syndrome, Fragile X, Tuberous Sclerosis and Phalen McDermid Syndrome (SHANK3)have been created and all of these groups have a similar set of characteristics and exagerrated claims. They all have alliances with the pharmaceutical industry to develop novel pharmaceutical treatments that can treat or even cure Retts Syndrome, Fragile X, Tuberous Sclerosis and Phalen-McDermid Syndrome.

    They have all taken out patents for their discoveries, including Dr. Zoghbi:

    http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.htm&r=5&f=G&l=50&d=PTXT&S1=Zoghbi-Huda-Y$.INNM.&OS=IN/Zoghbi-Huda-Y$&RS=IN/Zoghbi-Huda-Y$

    I have no objection to researchers who take out patents for their discoveries but would only point out that Sullivan himself railed against Andrew Wakefield when it was discovered he had applied for a patent for a ‘safer’ vaccine accusing Wakefield of no having no interest in improving the lives of auitstic children and implying that he was a snake oil salesman only interested in lining his own pockets.

    All of the goups engaged in transational research make similar claims, if we can cure Retts Sydrome, Fragile X, Tuberous Sclerosis or Phelan-McDermid Syndrome these novel drug therapies might also be effective in treating even curing other forms of autism. Dr. Zoghbi had gone even further claiming these novel drug therapies might eventually become treatments or cures for schizophrenia, bi-polar disorder even Alzheimer’s.

    There are many, many pathways that can disrupt normal brain development, nueronal migration and the establishment of aberrant synaptic connections. They include not only congenital genetic syndromes but also environemtal congenital syndromes with a high autism risk including valproate acid syndrome, for which a mouse model has also been created, as well as congenital rubella, prenatal exposure to thalidomide, prematurity and low weight babies.

    What is the rational for applying the novel therapies in children who do not a MECP2 mutation and have normal MECP2 expression in the brain. Would not applying these therapies induce a disruption of normal MECP2 expression in the brain? I would certainly think that applying these novel therapies to ‘normal’ mice who do not have an MECP2 mutation might even disrupt normal MECP2 expression in the brain. Before experimenting on children who do not have an MECP2 mutation the consequences of disrupting normal MECP2 expression in the brain needs to addressed in mouse studies.

  6. observer June 19, 2011 at 15:38 #

    Sadly, the Wakefield case was entirely different. The case against him was not that he had taken out a patent, it was that he had commercial interests which only stood any chance of success if confidence in MMR was damaged. That was an undisclosed commercial conflict of interest, the GMC found, and he did not disclose it when calling for single vaccines at a time when he held a patent on a purported single vaccine.

    Discovering a cure for Rett’s disease would be a landmark accomplishment for a disorder that presently has no cure.

  7. Christie Buchovecky June 19, 2011 at 15:56 #

    RAJ wrote: “They all have alliances with the pharmaceutical industry to develop novel pharmaceutical treatments that can treat or even cure Retts Syndrome, Fragile X, Tuberous Sclerosis and Phalen-McDermid Syndrome.”

    Actually… No. Our lab has no ties to pharma as far as I know. The Rett research has been funded by non profit advocacy organizations (IRSF, RSRT, and ASF at various stages).

    I can’t speak for Huda, but I know Monica’s primary drive in all of this is to help the girls as quickly as possible. Therefore, we are doing things like my interview and presentations at science conferences, presenting unpublished research a bit earlier than she is comfortable with in order to get the science community thinking about Rett in a new way, because the cholesterol pathway involvement aspect that I talked about at the end of my interview hasn’t really been studied in this disorder before. That said, we also know this will be a high impact paper and don’t want to be scooped on it (science is competitive and you need good publications to get funding) so we have filed a disclosure. I don’t understand all of the legal side of things, but we will be filing specific patents as well. It’s more of an intellectual property thing than a make money thing, but one lab member also pointed out that, by us patenting, it prevents a big pharmaceutical company from doing so and charging exorbitant prices for treatment. Of course, if the rest of the rett community finds our research as exciting as we do, it will eventually be passed to a drug company, or at least another lab that is better equipped to perform drug trials. I have some ongoing pilot studies in mice, but it is literally just myself and Monica working on it, so it won’t go very far very fast.

  8. Christie Buchovecky June 19, 2011 at 16:27 #

    RAJ asked “What is the rational for applying the novel therapies in children who do not a MECP2 mutation and have normal MECP2 expression in the brain?”

    I see your point here. I am certainly not advocating the use of any proposed treatment that comes from my research in all of autism (or schizophrenia, Alzheimer’s, etc) without testing in animal models, or at least confirming that there is a problem in that pathway in a given patient. SLO is an example of a disorder of cholesterol biosynthesis on the autism spectrum. My point was that there may be others, as adding Rett to the list means we may be seeing a pattern of cholesterol dysfunction causing autistic symptoms and that that pathway should be further investigated in various syndromic autisms. Also, to Huda’s claim about other neurological disorders: it’s really not as crazy as you make it sound, it just depends on what treatment you are talking about; many of the same genes have been implicated in many different neurological disorders, it stands to reason that some of the same pathways are involved.

    He continued ” Would not applying these therapies induce a disruption of normal MECP2 expression in the brain? I would certainly think that applying these novel therapies to ‘normal’ mice who do not have an MECP2 mutation might even disrupt normal MECP2 expression in the brain.”

    Again, it depends on what treatment you’re talking about. Valproic acid? Probably, as it is an HDAC inhibitor, altering biology at the epigenetic level. The cholesterol biosynthesis pathway, however, is a downstream target of Mecp2. We don’t yet fully understand the regulation mechanism, but it is highly unlikely that there is a significant feedback loop by which altering cholesterol biosynthesis alters Mecp2 function (we already alter this pathway in humans and have seen no evidence of it).

    That said, this also means we are treating just a symptom, not the cause of Rett. This is not a cure, but it does improve lifespan and “quality of life” (at least, in the mice), which is a good start. Furthermore, because this is a newly implicated pathway, it is likely that it will have additive effects when combined with existing treatments.

  9. Dedj June 19, 2011 at 23:23 #

    “Just out of curiosity how many $$$$, if any, does LBRB receive from the ASF, advertising revenue for Offit & Mnookin book ads and any pharmaceutical company sources?”

    Just out of curiosity, what makes you think this is a relevant question?

  10. Sullivan June 20, 2011 at 20:35 #

    I have no objection to researchers who take out patents for their discoveries but would only point out that Sullivan himself railed against Andrew Wakefield when it was discovered he had applied for a patent for a ‘safer’ vaccine accusing Wakefield of no having no interest in improving the lives of auitstic children and implying that he was a snake oil salesman only interested in lining his own pockets.

    RAJ, you are mistaken in this statement. The problem with Mr. Wakefield’s patent (as already noted on another comment above) is not that he took out a patent. It is that (a) he hid the patent and (b) the patent presented a considerable conflict of interest for him.

    Frankly, patents are very useful. In general, the money for a clinical trial will not be available without a patent in place to insure that the company performing the trial will recoup the expense.

    Conflicts of interest are not an automatic “game over” in a discussion either. Undeclared conflicts of interest are a problem because they don’t allow the public to make an informed decision. Again, Mr. Wakefield had an undeclared conflict of interest.

    One addition point made by Mr. Wakefield’s patent is the fact that he denies to this day what is in plain English–an invention intended to create a vaccine (in the classic sense). This goes to Mr. Wakefield’s credibility.

  11. Sullivan June 20, 2011 at 20:49 #

    Christie Buchovecky,

    I don’t understand all of the legal side of things, but we will be filing specific patents as well. It’s more of an intellectual property thing than a make money thing, but one lab member also pointed out that, by us patenting, it prevents a big pharmaceutical company from doing so and charging exorbitant prices for treatment.

    I hope and expect your group to seek patent protection for any ideas you create. This will be incentive for a company to do the clinical trials necessary to test if these therapies are (a) effective and (b) safe.

  12. Harold L Doherty June 21, 2011 at 08:57 #

    Sullivan I actually found your last comment funny. I am sure you did a search on all my internet, blog, and twitter commentary is a vain search for a single time in which I have ever stated that vaccines cause autism. I have never taken that position. So you launched a tirade based on indecisiveness? Funny.

    My failure to adopt your closed minded approach is not “indecisive” in any way. I have decided that the evidence as it now stands does not convince me that vaccines cause autism disorders. I do not accept that further study is unwarranted.

    Maybe you can help me by providing links to all the studies which have demonstrated the effects on children of women who received various vaccines while pregnant. Dr. Bernadine Healy pointed out that some vaccines administered to pregnant women actually contain the mercury based thimerosal and that mercury crosses the placenta. That was a couple of years ago in the CBS interviews. I would appreciate it if you could provide a list of studies which have explored Dr Healy’s questions concerning autism among children of women who were vaccinated while pregnant.

    • Sullivan June 21, 2011 at 18:07 #

      Sullivan I actually found your last comment funny. I am sure you did a search on all my internet, blog, and twitter commentary is a vain search for a single time in which I have ever stated that vaccines cause autism. I have never taken that position. So you launched a tirade based on indecisiveness? Funny.

      It’s OK by me if you find humor in my statements. Just so long as you don’t use this as a way to wave away the comment and not give it the due consideration it deserves. I will point out that you are “sure” of something which didn’t happen. I based my statement on your previous writings and on your statement above where you claimed to be “neutral” in the autism-vaccine wars. Given your misconceptions, perhaps I could encourage you to look again at this discussion.

      I will point out at this juncture that your very language belies your position. You position yourself as ” a “neutral” in the vaccine autism wars”. Perhaps rather than paint this as a war, you could enter the reasoned discussion of the science and the effects the discussion has had on the autism communities and society as a whole? By framing this as a “war” and you as a “neutral”, you have painted the people involved incorrectly in a bad light. I, for one, am not involved in a “war”. I do have opinions and I have come to decisions. If you wish to take part in a “war” as a neutral or otherwise, you are welcome to continue the “war” on your own blog rather than here.

      My failure to adopt your closed minded approach is not “indecisive” in any way. I have decided that the evidence as it now stands does not convince me that vaccines cause autism disorders. I do not accept that further study is unwarranted.

      Once again, you are projecting “closed mindedness” on others. Once again, taking a stance is not “closed minded”. Coming to a conclusion based on the evidence, is not “closed minded”.

      I also see that you are framing the issue as a single question. This allows people to avoid the clearly answered questions. This is what I consider to be indecisive. There is no single question of whether vaccines cause autism. There are multiple questions. The primary questions have been clearly stated and have been addressed in multiple studies. Do you wish me to provide links to all these studies? I assume you are aware of them. The two principle questions were (a) did thimerosal cause an epidemic of autism (alternatively: does thimerosal increase the risk of autism) and (b) does MMR increase the risk of autism.

      Both of those questions have been studied and both clearly answered. Neither thimerosal nor the MMR increase the risk of autism.

      Since I haven’t scoured your writing as you thought, perhaps you could correct me if I am incorrect and that you have failed to take a stance on either of those issues? My understanding is that your arguments elsewhere are the same as here: you lump the autism/vaccine questions into one big ball and then claim that there isn’t enough data for you to decide yet on the whole. My guess is you are aware of the idea of taking problems apart into manageable steps. You could do that with the vaccine/autism questions. Apparently you don’t. And that is where I come to the conclusion that you are indecisive.

      Maybe you can help me by providing links to all the studies which have demonstrated the effects on children of women who received various vaccines while pregnant. Dr. Bernadine Healy pointed out that some vaccines administered to pregnant women actually contain the mercury based thimerosal and that mercury crosses the placenta. That was a couple of years ago in the CBS interviews. I would appreciate it if you could provide a list of studies which have explored Dr Healy’s questions concerning autism among children of women who were vaccinated while pregnant.

      You are aware, I suspect, of the paper by Price et al. that showed “In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs. ”

      My suspicion is that a follow-on study will be published looking at just the number of vaccines given, not the thimerosal content. This was done with the previous study on thimerosal and vaccines (Thompson 2007).

      When it comes to maternal exposure to thimerosal through immune globulin injections, that has also been explored. Here is an example. The abstract concludes, “These data support previous findings that prenatal exposure to thimerosal-containing anti-D immune globulins does not increase the risk of autism.” Yes, there are multiple studies.

      Are you willing to take prenatal exposure to thimerosal off the table, either through immune globulin injections or (as in Price et al.) vaccines? The studies are there. Or are you going to stay in an open minded/indecisive state?

      I see that you cite Bernadine Healy. I suspect you will not be surprised to have the irony of that choice pointed out. Earlier in this discussion you asked if this site gets revenue from outside sources such as pharmaceutical companies. Bernadine Healy, as I suspect you are aware, spent a number of years accepting funding from tobacco companies while working for The Advancement of Sound Science Coalition. TAASC, as they were known, worked against tobacco litigation, including working against the notion that second hand tobacco smoke is harmful.

      More to the point, take a close look at what Dr. Healy had to say, years back. She decidedly does not take on the idea that there was an “epidemic” of vaccine induced autism. She instead promoted the idea of small susceptibility groups. Further, she called for research into “the children who got sick” (or something to that effect). Such a study has been performed on the MMR vaccine, Hornig et al., which looked at autistic children who have regression and GI disease. That study was good enough that Rick Rollens, one of the most vocal proponents of the idea that MMR causes autism, stated in the press conference that MMR was off the table.

      I’ll leave it to you whether you wish to address the questions of MMR and thimerosal. You tend to avoid those specific questions from what I’ve seen. That’s indecisive.

  13. Tom June 21, 2011 at 19:08 #

    Harold is such a hater.

  14. RAJ June 22, 2011 at 19:04 #

    Christie;
    Let me say that you did a terrific job in presenting your case in your video. I do have several questions about the mouse studies and Dr. Zoghbie’s interviews. Correct me if I am wrong.

    As far as mouse studies are concerned, they have importance but their importance is limited in that in the mouse you can certainly observe physical symptoms and the brain structure of ‘autistic’ mice whether it is done through knocking out genes or exposing the pups pre or postnatally to environmental pathogens (Valproate acid, Borna virus).

    What mouse studies cannot distinguish for any therapeutic intervention is if it has any impact on cognitive abilty (Mental Retardation) as there is no instruments that can check off an Autism Spectrum Questionnaire or calculate an IQ score in a mouse.

    The reversing of some symptoms of Rett Syndrome through genetic engineering is a remarkable achievement in itself, but it can only observe repair of physical symptoms (wringing of hands, gait ataxia) etc. Classical Rett Syndrome include the devasting impact of profound mental retardation and absence of speech. It remains to seen in clinical trials in humans whether drug therapy can repair and reverse profound mental retardation in Rett Syndrome.

    From what I can understand from Dr. Zoghbi’s interviews is that she considers Rett Syndrome is caused by aberrant synaptic connections but that the brain in Retts Syndrome develops normally and that is miscommunication between healthy normal neurons that causes the aberrant synaptic connectivity.

    I can’t comment on the neuropatholgy of Retts Syndrome, but in the autistic brain aberrant synaptic conections almost certainly does exist but it is a small part of the overall pathology in the autistic brain. The autistic brain does not develop normally.

    Saskia et al published a comprehensive review on autopsy studies in autism:

    http://brain.oxfordjournals.org/content/127/12/2572.long

    Is Dr. Zoghbi claiming that autistic brains are fundamentally intact and develop normally and the only problem is aberrant synatpic connectivity between normal healthy neurons? If she is then she is simply wrong when it comes to pathology of the autitic brain.

  15. Christie Buchovecky June 23, 2011 at 19:16 #

    RAJ,

    Very insightful post. I agree with a lot of it, though I believe we do have some phenotypic outputs of autism and MR related brain function (see work by J Crawley and R Paylor). They’re far from perfect, but do provide some insights. What I’d argue though, at least in the case of Rett, is that MR is the least of their worries. If we can treat the epilepsy, loss of motor function, and cardiopulmonary issues, the quality of life for these girls and their families would improve greatly. Furthermore, since some of these symptoms ARE neuronal, there is the possibility that treating them will help treat the MR as well, and we do have the ability to go in and look at mouse brains to see if the neuronal anatomy is altered with treatment. Granted, this level of severity of physical symptoms is rare in the general autism world.

    As far as what Dr Zoghbi is claiming when it comes to autism, you’d have to ask her (though, she’s primarily a neuroscientist; I’m sure she’s familiar with the the autistic brain literature and aware that there is gross anatomical changes). The idea that “brains are fundamentally intact and the only problem is aberrant synaptic connectivity between normal, healthy neurons” is certainly viable in Rett (well, maybe not the ‘normal, healthy’ part by the time symptoms occurr, but certainly reparable), but is clearly not th case in all of autism. I would argue, however, that there may be other subsets of ASD cases for which this may be true and that the potential treatability of Rett means we should be actively looking for them.

  16. Sam Regenbogen June 23, 2011 at 23:38 #

    Mr. Doherty,

    Please kindly disclose any and all potentially relevant financial ties to this topic. I see that you have what appears to be a fairly active blog; do you receive any revenue based on page views or advertising on it? Do you ever promote or display advertisements for “alternative medicine” or, indeed, any type of medicine with a commercial interest in the field of autism? Have you ever received ANY type of compensation – whether monetary or otherwise – from any group/individual/business that is involvedin the war you mention? If so, please describe these in detail. If you do not, can we safely assume that you are a paid shill for BigNutra?

    Additionally, please provide citations for your previous publications relating to the fields of neurology, mammalian genetics, epidemiology, autism spectrum disorders, and/or Rett syndrome. A description of your credentials would be appreciated also (e.g., where did you get your PhD? In whose lab did you study? What was the topic of your thesis?) If these cannot be provided, please provide a brief summary of your personal research (including, ideally, an inclusive list of the literature you have read) that has contributed to your current level of expertise in the field. If you do not, can we safely assume that your façade of scientific credibility belies a firmly rooted preconception supported only by half-understood snippets of scientific studies and confirmation-biased rememberings of anecdotal evidence?

    tl;dr version: stop trolling

  17. PeripheralPerspective June 27, 2011 at 05:17 #

    Hi Christie,

    I have a question. Sorry if this is too over-simplified, I don’t use scientific jargin well, so please correct me if my logic is faulty here (besides it’s very late :)). But let’s say Rett is an extreme version of this dysfunction of cholesterol homeostasis, a sort of knock-out mouse. And some forms of Autism, impacted by the environment with a similar genetic suscpetibility, in my world I might venture a hypothesis that certain brains, like those that have denser white matter proliferation may have genes “tweeked” in favor of producing more or needing more or being more sensitive to cholesterol production for this white matter insulation. And let’s say we are exposed to things that disrupt this homeostasis of cholesterol balance and absorbtion (again in my world I look at things like microbiota, fat balances, onset of NAFLD etc.and then the impact stressors have on particular subsets of the population who are neurodiverse in that they inherently process information differently so therefore may require unique genetic programming for more resource intake and usage, like cholesterol for white matter). So if we think, or suggest that our current environmental factors/impacts alter the genes (you’ll have to tell me there), if the gene is altered, and we tweek it back on-line. While I might think that if someday we may be able to re-alter the gene in this manner, after it has been altered environmentally (in an attempt to adapt or in response to needs or damage), this may assist in rebalancing the system… and what I ponder sometimes is to what measures are we taking that it is the correct adaption to the world we are putting it back into? That’s a really complicated question, if it makes any sense, if we re-adapt something, are we sure we can adapt it correctly? Are we sure it didn’t adapt for a purpose? What stage are we setting? (Sort of like if we down-regulate a system to be less aware of danger… are we sure there isn’t danger they need to be aware of?) And second question, are there other measures say nutritionally or lifestyle that can assist in this type of genetic change-making or improving in concert the genetic change-making? I believe this MECP2 is also in close association with BDNF and Rett, as many disorders, complicated and interactive with Oxidative Stress (meaning some level of stress, like exercise, can be assistive, but too much or other stressors can also impact outcomes, manifestations and degradations).

    So… I’m trying to figure out my question here. :). And I think it is; While I think the genetics are great and quite telling of the situation (possibly here with cholesterol pathways), what are your thoughts on how we might someday combine these direct therapeutic measures (like genetic solutions) with other more indirect therapeutic measures (like stress/nutrition)? Do you see this as a future direction?

  18. stanley seigler June 27, 2011 at 18:27 #

    [Christie Buchovecky say] “hides …I sounded so nervous…”

    you did not…and regardless of what i said re funding research on other LBRB threads…believe your work is a plus…

    thanks for your interest in the quality of life for those on the spectrum.

    stanley seigler

  19. PeripheralPerspective June 30, 2011 at 15:34 #

    Further question. From what I’m reading of MeCP2, and this is I believe from Christie’s group at Baylor, Dr. Huda, is that there needs to be this balance, too much or too little activation in MeCP2 can create too much or too little cellular proliferation and neurogenesis. Big issues. But it’s not about something being simply “good or bad”, “too much or too little”, but about balance. And that something like Valproic acid, can both assist in the regulation OR potentially cause this disregulation, as I would believe oxidative stress also has this potential, upstream of HDAC. It can be both helpful or harmful if it throws the balance off through neuroadaptation. Stress can be a good and needed thing… but when is it to much and to whome would/could it be too much that it throws the system out of balance?

    And since I know this site is heavily involved in the vaccine argument and Sullivan mentioned Thompson and let’s scrutinize this under this same light. That it has the potential to throw off regulation for good or bad outcomes, if it becomes a stressor or can alter this ‘fine-tuning’. This is in relation to the Thimerosal studies. And what might be suggested by the evidence in TMR is that it can have both positive and negative impacts. (described in the concept of hormesis as well). That it has an impact and we won’t necessarily understand that impact until we look at the individual, look at the stress levels, and look to see if that adaptation, even if it “improved” cognition, if it disregulated the other factors of neurogenesis (like excessive HPA/amygdala activity). So if we look at the studies in that light, the evidence may tell a different story. (an interesting side note is the suggested possibility, novel use, of a specific vaccination to re-regulation BDNF and glutamate/GABA regulation in depression).

    So can we, should we, be looking at the TMR through a different lens of balancing and adaptation… rather than strictly damage (I also look at the more subtle, indirect impacts, of nutritional factors), to see if there may remain a question of their impact in ASD-dysfunctions of hyper-activity or hypo-activity?

    REFERENCES

    Fine Tuned synapse number critical to brain health
    http://www.bcm.edu/fromthelab/vol07/is2/0308-4.html
    common mutations in RETT alter brain size
    https://sfari.org/news/-/asset_publisher/6Tog/content/common-mutations-in-rett-gene-alter-brain-size?redirect=%2Fnews
    Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation
    http://www.cell.com/neuron/abstract/S0896-6273(06)00775-6
    Vaccination as a novel approach for treating depressive behavior.

    http://www.mendeley.com/research/vaccination-as-a-novel-approach-for-treating-depressive-behavior/
    Oxidative stress and macrophage function
    http://www.biochemsoctrans.org/bst/035/0284/0350284.pdf
    Tobacco use and response: Oxidative stress and Histone deacestylase
    erj.ersjournals.com/content/29/3/438.full
    epigentics and psychoneuroimmunology
    linkinghub.elsevier.com/retrieve/pii/S0889159110004587
    Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway
    http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2008.00403.x/full
    Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells.
    http://www.ncbi.nlm.nih.gov/pubmed/19584079
    Antioxidative role of selenium against the toxic effect of heavy metals
    http://www.ncbi.nlm.nih.gov/pubmed/18665459
    Dietary selenium affects host selenoproteome expression by influencing the gut microbiota.
    http://www.ncbi.nlm.nih.gov/pubmed/21493887
    Products of the colonic microbiota mediate the effects of diet on colon cancer risk.
    http://www.ncbi.nlm.nih.gov/pubmed/19741203
    In conclusion, the results support our hypothesis that the microbiota mediates the effect diet has on colon cancer risk by their generation of butyrate, folate, and biotin, molecules known to play a key role in the regulation of epithelial proliferation.
    Gut Type Can Explain Efficiency Of Uptake Of Nutrients And Medicines
    http://www.asbp.org/siterun_data/news/doc5252585351303397815.html
    Differences in vitamin production
    It is notable that the vitamin production between the different groups varies strongly. People that belong to the Bacteroides group have more gut bacteria that produce vitamins C, B2, B5 and H. The Prevotella group showed higher numbers of B1 and folic acid-producing flora.
    http://jama.ama-assn.org/content/305/21/2162.1.extract
    http://www.mdpi.com/2072-6643/3/1/118/pdf
    Folate status and the immune system.
    Dhur A, Galan P, Hercberg S.Prog Food Nutr Sci. 1991;15(1-2):43-60.
    http://www.ncbi.nlm.nih.gov/pubmed/1887065
    Alterations in immune system functions could lead to decreased resistance to infections, as commonly observed in folate-deficient humans and animals.

    Folate administration increases n-3 polyunsaturated fatty acids in rat plasma and tissue lipids.
    Pita ML, Delgado MJ.Thromb Haemost. 2000 Sep;84(3):420-3.
    http://www.ncbi.nlm.nih.gov/pubmed/11019965
    However, n-3 PUFA significantly increased in plasma lipid fractions and in platelet, erythrocyte and intestinal phospholipids. It is well known that n-3 PUFA show antithrombotic properties. Thus, the increase of n-3 PUFA observed after MTHF administration might contribute to the prevention of vascular disorders.
    Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix.
    http://www.ncbi.nlm.nih.gov/pubmed/17320366
    These findings suggest an alternative mechanism for how folate deficiency leads to changes in gene expression and altered cell function.
    —-
    Inhibitors of Histone Deacetylase and DNA Methyltransferase Synergistically Activate the Methylated Metallothionein I Promoter by Activating the Transcription Factor MTF-1 and Forming an Open Chromatin Structure
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134057/

    Mecury: Selenium interaction and health implications
    http://www.wfoa-tuna.org/Fralstonraymond.pdf

    THIMEROSAL

    THOMPSON 2004: “results were equally divided between positive and negative effects”

    HERON 2004: “Results of this study were contrary to expectation; it was common for the unadjusted results to suggest a beneficial effect of thimerosal exposure.”

    ANDREWS 2004. “Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association”… Except for Tics, larger doses of TMR had lesser impact.
    http://pediatrics.aappublications.org/cgi/content/full/114/3/584?maxtoshow&HITS=10&hits=10&RESULTFORMAT&fulltext=Thiomersal+cognitive&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

    http://het.sagepub.com/content/19/7/420.short
    Hormesis: A stress response in cells exposed to low levels of heavy metals. doi: 10.1191/096032700678816133
    Hum Exp Toxicol July 2000 vol. 19 no. 7 420-430
    These results suggest that hormetic activity is a specific cellular response, and most likely, a stress response to low but harmful levels of toxic agents and may therefore provide a rapid test for the presence of toxicants at concentrations associated with chronic toxicity.

  20. PeripheralPerspective July 1, 2011 at 14:14 #

    (Part 1 of 3)
    Further question. From what I’m reading of MeCP2, and this is I believe from Christie’s group at Baylor, Dr. Huda, is that there needs to be this balance, too much or too little activation in MeCP2 can create too much or too little cellular proliferation and neurogenesis. Either way can create issues. So to me it’s not just about something being simply “good or bad”, “too much or too little”, but about balance. Something “good” can also be “bad” depending on the circumstance and the system it’s put into. An example would be Valproic acid, it can both assist in the regulation OR potentially cause this disregulation, as I would believe oxidative stress also has this potential, upstream of HDAC, as HDAC/MeCP2, correct me if I’m wrong, but one of their primary concerns is to assess and adapt to cellular stress. So many things can be both helpful or they can be harmful if they throw off the balance through this neuroadaptation.

    Stressors can be good and needed things… but the question will be when is this too much and to whom and when might it be too much that it throws the system out of balance or into a constant balancing act?

    And since I know this site is heavily involved in the vaccine argument and Sullivan mentioned Thompson et al. 2004, I suggest an intellectual exercise scrutinizing the evidence under this same light: That it may have the potential to throw off regulation for good or bad outcomes, that it could potentially alter this ‘fine-tuning’.

    So what might be suggested by the evidence from the TMR studies is that it can have both positive and negative impacts. (This phenomenon is described in the concept of hormesis). That it has an impact is certain but that we won’t necessarily understand that impact until we look at the individual, look at the stress levels, and look to see if that adaptation, even if it “improved” cognition, if it disregulated the other factors of neurogenesis (like excessive HPA/amygdala activity), and this may happen under the pretense of many other regulatory factors or set-points being present for stress regulation… not just the stressor itself (like nutrition and genetic predisposition or state of the system). So if we look at the studies in that light, the evidence may tell a different story.

    (*An interesting side note is the suggested possibility, novel use, of a vaccination for BDNF and glutamate/GABA re-regulation in depression, basically a novel concept of re-stressing a system that may have been altered by stress, using stress to re-adapt or up-regulate from the other combination or suggesting that stresses may have downregulated the system… interesting concept, the same concept I believe about exercise creating a stress to help re-adapt the system through the BDNF channels as well).

    Could we look at the TMR through a different lens of balancing and adaptation? Rather than strictly through damage or that the epidemiological studies, that show positive results, instead of coming to the conclusion that they cause no problem, that instead, thinking this may show they have the potential of an adaptive impact. Not saying it had been causative or that it causes, but that when anything has the potential to alter this “fine-tuning” of brain balancing, it needs to be taking seriously and considered if full context. So to me their remains an unanswered question about their impact or possible role in ASD-dysfunctions because of their potential impact of cognitive function balancing that may lead to hyper-activity or hypo-activity. And there would remain many other combination of factors, but I think the research for finding a solution through the NADC-MeCP2-BDNF, may be very telling or give us hints to its cause, as one of the primary functions of this pathway is to ascertain and adapt to cellular stress (Christie correct me if I’m wrong there).

    What I look at are the more subtle, indirect impacts, of nutritional or other stress regulating factors, which genes/traits will also be a part of as I believe them to have neurobiological correlates creating unique set points to stress. See if feel we may need to continue with the possibility that TMR may have been able to have this impact, depending on the system, and wonder, Sullivan, if you may see this perspective that we should continue to evaluated the potential vaccines (if the rest of the environmental factors have lowered our stress resistance to what would have been a helpful stress) within the context of these complex systems?

  21. PeripheralPerspective July 1, 2011 at 14:15 #

    (Part 2 of 3)
    REFERENCES

    Fine Tuned synapse number critical to brain health
    http://www.bcm.edu/fromthelab/vol07/is2/0308-4.html
    Common mutations in RETT alter brain size
    https://sfari.org/news/-/asset_publisher/6Tog/content/common-mutations-in-rett-gene-alter-brain-size?redirect=%2Fnews
    Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation
    http://www.cell.com/neuron/abstract/S0896-6273(06)00775-6
    Vaccination as a novel approach for treating depressive behavior.

    http://www.mendeley.com/research/vaccination-as-a-novel-approach-for-treating-depressive-behavior/
    Oxidative stress and macrophage function
    http://www.biochemsoctrans.org/bst/035/0284/0350284.pdf
    Tobacco use and response: Oxidative stress and Histone deacestylase
    erj.ersjournals.com/content/29/3/438.full
    epigentics and psychoneuroimmunology
    linkinghub.elsevier.com/retrieve/pii/S0889159110004587
    Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway
    http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2008.00403.x/full
    Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells.
    http://www.ncbi.nlm.nih.gov/pubmed/19584079
    Antioxidative role of selenium against the toxic effect of heavy metals
    http://www.ncbi.nlm.nih.gov/pubmed/18665459
    Dietary selenium affects host selenoproteome expression by influencing the gut microbiota.
    http://www.ncbi.nlm.nih.gov/pubmed/21493887
    Products of the colonic microbiota mediate the effects of diet on colon cancer risk.
    http://www.ncbi.nlm.nih.gov/pubmed/19741203
    In conclusion, the results support our hypothesis that the microbiota mediates the effect diet has on colon cancer risk by their generation of butyrate, folate, and biotin, molecules known to play a key role in the regulation of epithelial proliferation.
    Gut Type Can Explain Efficiency Of Uptake Of Nutrients And Medicines
    http://www.asbp.org/siterun_data/news/doc5252585351303397815.html
    Differences in vitamin production
    It is notable that the vitamin production between the different groups varies strongly. People that belong to the Bacteroides group have more gut bacteria that produce vitamins C, B2, B5 and H. The Prevotella group showed higher numbers of B1 and folic acid-producing flora.
    http://jama.ama-assn.org/content/305/21/2162.1.extract
    http://www.mdpi.com/2072-6643/3/1/118/pdf
    Folate status and the immune system.
    Dhur A, Galan P, Hercberg S.Prog Food Nutr Sci. 1991;15(1-2):43-60.
    http://www.ncbi.nlm.nih.gov/pubmed/1887065
    Alterations in immune system functions could lead to decreased resistance to infections, as commonly observed in folate-deficient humans and animals.

    Folate administration increases n-3 polyunsaturated fatty acids in rat plasma and tissue lipids.
    Pita ML, Delgado MJ.Thromb Haemost. 2000 Sep;84(3):420-3.
    http://www.ncbi.nlm.nih.gov/pubmed/11019965
    However, n-3 PUFA significantly increased in plasma lipid fractions and in platelet, erythrocyte and intestinal phospholipids. It is well known that n-3 PUFA show antithrombotic properties. Thus, the increase of n-3 PUFA observed after MTHF administration might contribute to the prevention of vascular disorders.
    Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix.
    http://www.ncbi.nlm.nih.gov/pubmed/17320366
    These findings suggest an alternative mechanism for how folate deficiency leads to changes in gene expression and altered cell function.
    —-
    Inhibitors of Histone Deacetylase and DNA Methyltransferase Synergistically Activate the Methylated Metallothionein I Promoter by Activating the Transcription Factor MTF-1 and Forming an Open Chromatin Structure
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134057/

    Mecury: Selenium interaction and health implications
    http://www.wfoa-tuna.org/Fralstonraymond.pdf

  22. PeripheralPerspective July 1, 2011 at 23:08 #

    For some reason can’t get my references to post if someone can help me out?

    • Sullivan July 1, 2011 at 23:18 #

      “For some reason can’t get my references to post if someone can help me out?”

      Sure–tell me before I go look for them: do you actually discuss the papers you are linking to, or are they like your “part 3 of 3” comment? If you aren’t taking the time to discuss your own links, why do you expect anyone else to? And if there is no discussion, why should the comments be approved?

  23. PeripheralPerspective July 1, 2011 at 23:09 #

    (Part 3 of 3)

    THIMEROSAL
    Inhibitors of Histone Deacetylase and DNA Methyltransferase Synergistically Activate the Methylated Metallothionein I Promoter by Activating the Transcription Factor MTF-1 and Forming an Open Chromatin Structure
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134057/

    Mecury: Selenium interaction and health implications
    http://www.wfoa-tuna.org/Fralstonraymond.pdf

    THOMPSON 2004: “results were equally divided between positive and negative effects”

    HERON 2004: “Results of this study were contrary to expectation; it was common for the unadjusted results to suggest a beneficial effect of thimerosal exposure.”

    ANDREWS 2004. “Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association”… Except for Tics, larger doses of TMR had lesser impact.
    http://pediatrics.aappublications.org/cgi/content/full/114/3/584?maxtoshow&HITS=10&hits=10&RESULTFORMAT&fulltext=Thiomersal+cognitive&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

    http://het.sagepub.com/content/19/7/420.short
    Hormesis: A stress response in cells exposed to low levels of heavy metals. doi: 10.1191/096032700678816133
    Hum Exp Toxicol July 2000 vol. 19 no. 7 420-430
    These results suggest that hormetic activity is a specific cellular response, and most likely, a stress response to low but harmful levels of toxic agents and may therefore provide a rapid test for the presence of toxicants at concentrations associated with chronic toxicity.

  24. PeripheralPerspective July 2, 2011 at 00:45 #

    Hi Sullivan.

    Sorry, that was before I realized I needed to break it down further. My first post was what I thought was my discussion of the links, and then the links were to support my discussion.

    Whether you choose to approve them or not is entirely up to you. I don’t mean to create confusion, but I do like or try to back up my discussion. I can try to embed the links, if you think that would make it more user-friendly. Let me know what you think is best.

    Thanks.

  25. PeripheralPerspective July 2, 2011 at 01:32 #

    So to be clear, again, sorry if I’m not. The post was huge and needed to be broken up.

    Part 1 was my discussion. I discussed taking a slightly different perspective of a Stress-Model to the issue of MeCP1 regulation. Then I discussed factors that might impact upstream, like valproic, being similar to adaptation models of stress. I also mentioned nutrition, and then factors from the environment that may impact nutrition that then may further impact adaption of those channels. So like mercury impacting selenium which impact microbiota which impacts folate which impacts HDAC which impacts MeCP2 which impact BDNF. So stress excessivity or nutritional deprivation may impact genes and vice versa. through complex feedback and interactive networks. Because stress can also enhance function, such as Valproic, which can be good or bad depending. I took that quandery to wonder if when looking at the TMR studies and thinking that because they can create “better” outcomes, that if our assumption is that this means they’re good or that vaccines with TMR were harmless, if that might be a misconception? Because if the studies show an impact even an inverse relationship, that could concievably show that they are impacting adaption at that neurophysiological level. Do we need to consider that? And finally, because i don’t think that vaccines are the cause, but merely a small factor in a much larger picture of What brings out dysfunctional aspects of information processing and its’ impact on memory, learning and cognition, I feel it’s imperative to look at and exam things with all of these factors, genes, environment, nutrition and stressors involved. Genes to me especially as the may set the stage for this vulnerability to stressors… but that would take a monstrousity of links. But here in this context I thought the HDAC-MeCP2-BDNF was a nice example.

    Happy to discuss, or do my best to clarify further. Again sorry if I’m not being clear or too vague. Let me know.

  26. Christie Buchovecky July 2, 2011 at 04:21 #

    Peripheralperspective:
    Wow, that’s a lot to take in. A couple things: I don’t work for Huda, she just happens to be at the same institution, and, related to that, we don’t yet know how the cholesterol impact neurons, or if it does.

    You’re right that too much mecp2 causes a problem, not just too little, but we believe the cholesterol involvement is downstream of mecp2, creating some symptoms of rett, but not all of them. Humans have already altered their cholesterol biosynthesis pathway, both with drugs and diet in a response to heart disease and obesity, and this has not led to them developing rett symptoms.

    You talk about “tweaking” genes back to what they’re meant to be after alteration by the environment. The thing is, this happens all the time; gene expression is constantly being regulated by what is taking place in the cell. Are there some cases of more permanent imprinting? Yes, but they are relatively rare and we know little about how they work and even less about how to change them, particularly in an adult.

    To your comments about Valproic acid, there is some evidence that it helps in Rett, but potntially for reasons other than it’s HDAC activity. And, as far as I know, we understand even less about BDNF.

    Lastly, your comments about thimerosal: while I think you have a point about “environmental fine-tuning” of our genes, all of the evidence we have about using drugs that potentially create epigenetic modifications to help rett points towards need for chronic treatment. I see no reason to think that a few acute introductions of small amounts of thimerosal that MAY do something that MAY result in some epigenetic modification (test tube does not equal human body) would produce any lasting changes that affect development or brain function… Especially when we see no epidemiological evidence of it.

  27. RAJ July 2, 2011 at 15:05 #

    Hi Christie;
    I had thought that about every debate an argument over your work in Rhett Syndrome had been exhausted, but I’ll bring up another one.

    What causes Rhett Syndrome and is anyone at Baylor doing any research into the causes and possible preventions?

    A great deal of excitement has recently been generated by the discovery of small genetic ‘glitches’ and copy number variations and its association with autism risk in ideopathic autism. This new important research has come about by the rapid increase in technological advances in genome scanning and the rapidly lowering costs of these technological advances. Genetic scans are now routinely taken of parents (and siblings) in families where a child has been diagnosed with a genetic disorder.

    While all the excitement is of de novo mutations occuring in simplex families, even more interesting is the rapidly emerging understanding of the etiology of the single gene disorders with an identifiable genetic cause. In the last ten years what is known about the single gene disorders with an identified genetic cause is that in most of the single gene orders the mutations are not inherited at all but are the consequences of a germ line reproductive error (egg or sperm).

    Fragile X Syndrome appears to be an exception in that it appears to follow a pattern of Mendelian inheritance. Rhett Syndrome (MECP2) and Downs Syndrome (Trisomy 21) both have high rates of co-occuring autism but in both these genetic disorders 99% of cases the mutation is not inherited but are the consequence of a reproductive error (egg or sperm).

    Arthur Bedeau one of the leading researchers in the field of Angelmans syndrome and Prader-Willis Syndrome and also does his research at Baylor has stated:

    ‘In terms of potential lessons for other disorders, it should be noted that almost all of these genetic and epigenetic cases of PWS and AS are de novo as contrasted to being inherited events’

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427262/

    Other named single gene disorders where the majority of cases like Rhett Syndrome are caused by germ line de novo mutations and are not inherited include:
    Tuberous Sclerosis
    Duplication 15 Syndrome
    Klinefelter Syndrome
    Timothy Syndrome
    Turner Syndrome
    Williams Syndrome
    16P Syndrome
    22Q Syndrome
    CHARGE Syndrome

    Autism is a complex multifactorial disorder but is its now recognized that etiology of the single gene disorders also are complex and likely multifactorial that may involve biological (parental age) factors, genetic influences, epigenetic mechanisms and enviromental pathogens that lead to mutagenesis in the fetus.

    My question is: Is there any research projects at Baylor or in the Rhett Syndrome arena into identifying the mechanisms underlying these de novo mutations that eventually might possibly lead to prevention strategies.

    The NIH has created an easily accesible genetic reference data base that is continuosly updated by leading scientists in the particular genetic disorder.

    Here is the current knowledge of Downs Syndrome the most common sngle gene disorder with high rates of co-occuring autism:

    http://ghr.nlm.nih.gov/condition/down-syndrome

  28. Christie Buchovecky July 2, 2011 at 16:06 #

    RAJ,

    I assume by asking “what causes Rett Syndrome” and then going into explaining single gene disorders with de novo mutations, you mean what does the altered gene do in the body that leads to the syndrome. The answer is, we really don’t know. We know Mecp2 is involved with modulating epigenetic modifications across the rest of the genome and that this leads in some way to problems in the girls, but we can’t trace the genetic pathways by which everything goes wrong yet, though it is becoming more and more clear that there are many of them to trace. We know that the neurons in the brains of these girls do not make as many connections as in NT brains (typically described in the literature as decreased dendrite outgrowth), and some people (myself included) have interpreted this as a lack of neuronal maturation in certain brain regions (there’s various evidence for this, but I’d have to look up references, which is a pain to do on my iPAD. If you’re interested, let me know during the week while I’m sitting at my desk). Furthermore, our group has found this problem with cholesterol dysregulation in the mice, but have yet to tie it back satisfactorily to mecp2 regulation. We also know the girls have breathing problems, the evidence for the cause of which keeps coming back contradictory. There’s more, but you get the point.

    Also, you gave a great description of single gene disorders typically being caused by de novo mutations, but I think you may have underestimated how often they get passed on. Basically, the only reason they are always de novo is that the people who first get the mutation rarely go on to have kids. However, especially in Rett, where there is random x inactivation that can lead to mild symptoms, a mild mutation in mecp2 can be passed down. I’m not sure what the percentage is where this happens – certainly still rare, but more than 1%. we’re probably still underestimating the number of mild mutations that are out there, though we are detected some in the autism population with recent whole exome sequencing projects.

    Which brings me to your last question: there are certainly studies going on, at Baylor and elsewhere, to identify new de novo mutations that cause ASDs, as well as looking at treatment. But you were asking about underlying mechanism and prevention…. The thing is, we already understand why (and usually how) a lot of these mutations happen and I don’t think it’s anything we can prevent any time soon. (That said it’s an interesting, think outside the box question. You really had me considering it until I realized all that it would entail)

    There are 2 kinds of mutations we need to talk about: point mutations (single base pair changes) and CNVs (also transpositions, in which the dna is moved but not replicated, but the mechanisms are similar).

    It is inherent in our dna replication machinery that point mutations occasionally happen. This is a very rare occurrence in humans (and other mammals) compared to the rate at which it occurs in many single celled organisms. Evolutionarily speaking, this is considered a good thing, as it creates diversity and adaptability, but more practically, our replication machinery has hit upon the point where it is most efficient (fastest with fewest errors). In theory, we could design a more efficient set of proteins and constantly modulate their levels in cells of a developing embryo, but the technical (not to mention ethical) hurdles are probably insurmountable.

    CNVs are created in multiple ways: 1) a replication hiccough where a piece of DNA is copied multiple times in a row or slips through without replication (this is more common with triplet repeats, like in fragile x). 2) Misuse (arguably) of another set of cellular machinery used for crossing over between homologous chromosomes that crosses over at near-homologous sites on other chromosomes. 3) genomic dna being carried along for the ride by so called “jumping genes”, or ancient viral sequences that have become incorporated in the the human genome. Again, the technical hurdles to fix any one of these are huge. They would all have to be done in vitro, and if you’re going to go that route anyway, it’s a heck of a lot easier to let existing machinery do the work and just screen for a healthy embryo prior to implantation (We’re not entirely there yet either, but i believe that’s comming). Plus, I’m not competely convinced that IVF doesn’t come with its own set of issues related to improper imprinting (though a group at Harvard recently found no correlation between IVF and autism.)

    Ok, I feel like I just taught an undergraduate genetics lecture. Hopefully I’ve answered your question.

  29. PeripheralPerspective July 2, 2011 at 22:55 #

    Hi Christie.

    Before I post some monstrosity of information. I wanted to take a quick pulse check and ask you to do me a solid. You dropped the big “E” word. Epidemiology. Since you already feel like you’re back lecturing undergrad I’m going to take you back to first year. Do you remember the name of the school of thought and the postulates that epidemiological methods are based on? Koch’s Postulates right? And do you remember what assumptions are made and when Koch’s postulates would be apropro? For everything? Well, maybe not quite, koch’s postulates are used for diseases that come from single sources and have single outcomes. Like germs and genetic diseases. So is Autism a single source causation or outcome? Would koch’s postulate be relevant to that type of dynamic interactive and variable causes and outcomes?

    Think about that and let me know. Because studying Stress-models of medicine and can tell you point blank that the same thing can cause different outcomes and different things can cause the same outcome. So how relevant or appropriate is that framework and methods of scientific reasoning and methods to the situation at hand? Sort of like using a ruler when you need a compass?

  30. esattezza July 3, 2011 at 00:42 #

    Hi PeripheralPerspective,

    Actually, though I have met Koch’s postulates in passing, I didn’t remember them, so I had to look them up. It seems you did not remember them very well either. They were designed to deal specifically with microorganisms that cause disease and are as follows:

    1) The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
    2) The microorganism must be isolated from a diseased organism and grown in pure culture.
    3) The cultured microorganism should cause disease when introduced into a healthy organism.
    4) The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

    Not really what we’re talking about when it comes to autism and the role that thimerosal seems not to play in triggering it. While Koch’s postulates do not apply, they are not the only thing upon which epidemiology is based.

    I’d say trying to use Koch’s postulates for autism is less like trying to use a ruler when you need a compass and more like trying to use a microscope when you need population based data. Luckily, there are other branches of epidemiology that apply statistics to population based data and these have found no correlation between thimerosal exposure and autism. In fact, I had one statistician describe our level of certainty about this particular hypothesis as “if there were more than 5 kids per year that have had their autism triggered by thimerosal in vaccines, we would have caught it given the statistical measures and sample sizes we’ve looked at.” Now, I’m not a statistician, but that’s pretty impressive to me.

  31. RAJ July 3, 2011 at 04:33 #

    PeripheralPerspective wrote:

    ‘You dropped the big “E” word. Epidemiology’.

    Epidemiolgy in autism is only meaningful if you can define what autism is and what it is not. Autism epidemiology studies are currently based on DSM-IV-TR (2000) diagnostic criteria. Allen Francis was the chair of the entire task force that eventually led to the publication of DSM-IV in 1994. Here’s what he wrote about the consequences of the introduction of DSM-IV:

    ‘The DSM IV field trials were meticulously conducted, but completely failed to predict the later false epidemics in attention deficit, bipolar, and autistic disorder’.

    http://www.psychologytoday.com/blog/dsm5-in-distress/201011/the-dsm-5-field-trials-part-2-asking-the-wrong-question-will-lead-irrel

    Where is DSM-V headed. A number of studies have looked at the proposed criteria for what will be called Autism Spectrum Disorder (previously labelled Pervasive Developmental Disorder).

    Matilla et al found that proposed DSM-V criteria was less sensitive in identifying high functioning and Aperger individuals.

    Mandy et al found that the DSM-V draft criteria would exclude PDD/NOS from the autism spectrum disorder category and Happe reported that children diagnosed with PDD/NOS would likely be placed under a new DSM category Social/Communication disorder.

    Dyck et al looked at the validty of psychiatric diagonoses and found there were no definitive boundaries between disorders (autism, schizophrenia, ADHD, language disorders etc.) and no definitve boundaries between disorder and normality.

    Since this discussion started with Rett Syndrome, DSM-V appears to be headed towrds excluding Rhett Syndrome from the Autism Spectrum Disorders. It is likely that Rett Syndrome and other single gene disorders with a high rate of co-occuring autism might land in the newly revised Intellectual Disability category. Rett Syndrome was included in DSM-IV-tr only after a great deal of debate and argument.It was felt that while Rett Syndrome may share many superficial autism features with ‘ordinary’ autism it was a condition that was clearly distinct from what has been called’ordinary’ autism.

    Where is DSM-V headed? Its a big question but my view is that false autism epidemic caused by DMS-IV (1994) may be heading towards significant declines in autism prevelance rates. The danger is that many children who have been given a passport (autism) to special education and evidence based early intervention based on a diagnostic label will fall through the cracks.

    That’s why autism epidemiology studies may be interesting but completly uninformative perhaps even misleading.

    http://www.ncbi.nlm.nih.gov/pubmed/21705192

    http://www.ncbi.nlm.nih.gov/pubmed/21298812

    http://www.ncbi.nlm.nih.gov/pubmed/21621142

  32. PeripheralPerspective July 3, 2011 at 16:15 #

    Thanks for the input Raj. Yes, highly relevant this move from categorical to dimensional views of disorders. It is in stark contrast to our assumption that these are all separate outcomes. And it’s an important philosophical turning point of not seeing single outcomes as entirely separate, but rather “variations on the tune”.

    Christie, thanks for yours as well.

    And Christie, I see where you could confuse when I mentioned Koch’s Postulate you might assume that it refers to Micro-organisms. I should have been clearer as to what I meant so you would not have been so confused. I meant the philosophy behind it. But yes, Koch’s Postulates were born from the discovery of Pasteur’s germs and then The Germ Theory of disease became the dominant cornerstone of modern medicine. And you’re right Epidemiology is more than just that. And it is certainly much more than the confines that GTM influence of diseases coming from single sources, impacting the entire population they come in contact with and being present in everyone who has the disease. But that philosophy is a very powerful undercurrent to much of what people think of as science and ways in which to ‘disprove’ associations. Epidemiology and I think some would agree is only as good as the assumptions we start with and the knowledge we have of what we are looking for. I do think epidemiology is some of the coolest science we have out there; the mathematics is astoundingly beautiful… but fallible. Again depends on the inputs and assumptions. And if we over-simplify by thinking “one cause – one outcome” that can lead to trouble (“epidemiologists Rothman and Greenland emphasize that the “one cause – one effect” understanding is a simplistic mis-belief.”)

    So we always need to take caution that people aren’t assuming that if autism existed before “x” then “x” doesn’t cause it, or if “x” isn’t found in a system that has Autism then “x” didn’t cause it. Or if “x” supposedly causes Autism and a person wasn’t exposed to “x” then it doesn’t cause it. Because those would be fallacies of logic, b/c they are based on the assumption of “one cause-one effect”. And this one cause-one effect is the cornerstone of germ theory, so many virologists may be holding quite stringently to this type of logic when they present their arguments. At least that is what I have observed (happy to reference and go into detail).

    Can epidemiology properly ascertain and delineate this dynamic? I think absolutely some day if they get to know the variables they are controlling for… and the diversity of separate but intimately connected outcomes, which takes a major change in the assumptions we make. Epidemiology is a science that will ALWAYS continue to evolve and grow, and be immensely useful. But the question is: Are we there right now? And I don’t think so. But I bet they’re getting closer every day, IF/when they move away or properly apply the assumption of “single cause – single effect”. I will always believe that science will prevail.

    I had to really cut down this post to get it to fit, but I hope it touches on my point.

    Happy 4th!! Hope you have a great holiday weekend!

  33. PeripheralPerspective July 3, 2011 at 16:39 #

    well, maybe it’s the holiday, but I can’t seem to get my posts to post, so I’ll try a super quick one (I sometimes save/edit in word and then past the post, is that a problem? Is length a problem? I’m I a problem :)?).

    Christie sorry for the confusion. You are correct that epidemiology is much more than that. It is. But it is also highly influenced by the cornerstone of our medical science which is the Germ Theory Model of medicine. Koch’s postulates which states that 1) diseases come from single sources 2) impact the entire population they come into contact with and 3) are present in everyone that has the disease…this is a very strong under-current as to how we do medical science. And epidemiology, some would agree is only as good as the assumptions and inputs we use to come to those conclusions. And yes, the GTM, has a great influence on this as you can imagine, but it is not the whole of epidemiology. Epidemiology is constantly evolving and discovering new ways to measure this intensely complex dynamic.

    As “epidemiologists Rothman and Greenland emphasize that the “one cause – one effect” understanding is a simplistic mis-belief.”

    So how often in Autism connections are people making those type of assumptions to dismiss the causes of autism? How often are those assumptions being used as definitive proof in their minds?

    And yes the GTM is not epidemiology, but how often do professionals and experts within that framework make conclusive statements using those methods and assumptions about what causes or doesn’t cause Autism? I beleive there is a very famous expert virologist using them to discredit this association and every reference I see using single-cause/single-outcome logic. Probably because he’s an expert in that logic, which is a great logic for single source disease, but like you said, obviously not for Autism.

  34. PeripheralPerspective July 4, 2011 at 13:03 #

    Christie: “We don’t yet know how the cholesterol impact neurons, or if it does.”

    I agree it may be insufficient for us to completely understand all of the hows and interactions, but I’m a little surprised to see you question whether it does or not? I thought there was sufficient information to support that it is important for development and may interact with neurons and neuronal development.I find it particularly interesting the interaction suggested with dopamine:

    Effects of cholesterol levels on the excitability of rat hippocampal neurons.
    http://www.ncbi.nlm.nih.gov/pubmed/18428037

    Oxysterols as markers of neurological disease–a review.
    http://www.ncbi.nlm.nih.gov/pubmed/19199127

    Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells
    http://www.cell.com/cell-stem-cell/retrieve/pii/S1934590909004032
    The study demonstrates that the formation of dopamine-producing neurons during brain development in mice is dependent on the activation of a specific receptor in the brain by an oxidised form of cholesterol called oxysterol. Dopamine-producing nerve cells play an important part in many brain functions and processes, from motor skills to reward systems and dependency. They are also the type of cell that dies in Parkinson’s disease.

    “Oxysterol contributes to a safer and better cultivation of dopamine-producing cells, which is a great advancement since it increases the possibility of developing new treatments for Parkinson’s disease,” says Professor Arenas.

    Christie: “Humans have already altered their cholesterol biosynthesis pathway, both with drugs and diet in a response to heart disease and obesity, and this has not led to them developing Rett symptoms.”

    I think this may be that fallacy of logic will be discussing about “single cause-single outcome”. But I feel that timing and the system it’s put into and other factors will impact, I believe, the manifested outcomes. Which is why I believe there is now discussion about MeCP2 “spectrum disorders”?

    The Power of a Single Gene: MECP2 Spectrum Disorders
    http://www.rsrt.org/MECP2-related-disorders

    So we wouldn’t just look at how those cholesterol pathways would create Rett, but rather the “Rett spectrum” or other outcomes… again depending on the system, timing and condition of the system it’s put into.

    Cholesterol and personality traits

    http://researchnews.osu.edu/archive/choles.htm

    Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation
    http://www.ncbi.nlm.nih.gov/pubmed/8790411

    Oxysterols, cholesterol homeostasis, and Alzheimer disease.
    http://www.ncbi.nlm.nih.gov/pubmed/17573819

    And thanks for the clarification that you do not work with or for Dr. Huda, but rather you both just happen to be at the same institution. But congratulations to Dr. Huda Zoghbi for Receiving a $500,000 Gruber Neuroscience Prize for Pioneering Work in Revealing the Genetic and Molecular Underpinnings of Neurological Disorders!! That’s exciting!
    http://www.gruberprizes.org/GruberPrizes/Neuroscience_PressRelease.php?awardid=61

    Stated within the content:
    Scientists have subsequently found that something similar occurs in other brain disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases

  35. Christie Buchovecky February 12, 2012 at 19:49 #

    Sulli,

    I know this thread has been dead for a while, but do you think you could clean up comments this post a bit? I had a parent contact me after reading here recently and I noticed that PP’s most recent comments are posted in quardruplicate or something like it.

    Also, I don’t want to get pulled back into a long-winded conversation on a dead thread, but I do want to clarify that when I said “We don’t yet know how the cholesterol impact neurons, or if it does.”, I meant specifically in our mouse model of Rett (ie, if we can alter cholesterol homeostasis in these mice, will it make their brains look more like neurotypical brains?). Clearly, as PeripheralPerspective linked to many interesting papers on the topic, cholesterol is involved in brain development and functioning more broadly.

  36. PeripheralPerspective February 12, 2012 at 21:14 #

    Thanks Christie, I had PMed Sullivan at that time for clarification on the posting procedures, and that there would be multiple repeated posts if they were in his holding and to please be aware, but they were all posted, and as you say i too thought it made a dead conversation that I thought was interesting (although I agree I can be quite long-winded on such an important topic worthy of deep consideration). I hope he can make the time to clean it up as well. And thank you, that comment you made did stayed in my mind about the cholesterol not impacting neurons, so your specificity does clarify that. kindest regards. PP

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