You might find this hard to believe, but sometimes I find the antivaccine crank blog Age of Autism to be useful. Obviously, I don’t find it useful in the same way that its editors think it is useful. Those paragons of the arrogance of ignorance and fetishism of hatred of science-based medicine don’t actually teach me anything about vaccines and autism. The torrents of pseudoscience, quackery, conspiracy mongering, and hostility do, however, serve their purpose. They keep my finger on the pulse of the “autism biomed” movement and what the latest “autism biomed” quackery du jour is. It looks like I just found out too, and I’m amazed. I thought that I had heard of every organization promoting autism quackery. The vast majority, but not all, of them are also rabidly antivaccine, but it’s not just antivaccinationism. Basically, if AoA likes something, the odds of its being based on good science are about as high as the odds of a single molecule of starting remedy being left in a 30C homeopathic solution. AoA is just that reliable when it comes to science.
This time around, AoA introduced me to something called AutismFreeBrain, whose tagline is “breakthrough science for a cure.” Now, whenever I see a phrase like “breakthrough science for a cure” applied to autism, it sets the skeptical antennae a’twitchin’ fast and furious, and there’s a lot on this site to set the frequency of this twitching to “vibrational frequencies” that would make a woo-meister envious. I guess I might as well start right at the beginning. See if you can see what I see in the way of red flags. It begins right on the main page:
Putting an End to Autism by Fighting Brain Immunity Storms™
AutismFreeBrain, Inc. was created to fund innovative research to develop a cure for Autism Spectrum Disorders (ASD). Our studies have identified inflammatory processes in the brain, we called Brain Immunity Storms, that are much like an allergic reaction, releasing surges of molecules that disrupt areas of the brain responsible for emotion and language.
First of all, whenever you see a website like this asserting that neuroinflammation is, in essence, the be-all and end-all of the pathogenesis of autism, you know that there’s likely to be some mighty fine woo there. There’s no doubt that there have been studies suggesting an association of markers of inflammation with autism, but the significance of these observations have not been worked out. Not that any of this deters antivaccinationists. As many of you quite correctly pointed out yesterday, the term “inflammation” is a term much beloved and abused by quacks of all stripes, and autism biomeddlers are no exception. This tendency to view autism as an inflammatory condition probably has a lot to do with the general antivaccine leanings of most such practitioners. Basically, inflammation is a convenient means for them to link their two greatest hatreds: vaccines and autism.
Once the “problem” (inflammation) has been identified, then the cure is obvious. Well, actually, no it isn’t, but that doesn’t stop autism biomed advocates from subjecting their children to all sorts of interventions that are claimed to be able to combat the inflammation that is supposedly at the heart of autism. They also make up terms that aren’t used in medicine, such as “brain immunity storm.” In fact, if you search for that term, bracketed in quotation marks to make sure that Google searches for only the exact term, the only hits you will get come from AutismFreeBrain and related sites. Amusingly (to me at least), an old Google site comes up as well. It isn’t nearly as slick as the current site, but it is, if you will excuse the wretched word choice, a damned sight more revealing, because the new website appears to have consciously toned down the antivaccine angle. On the new website, I couldn’t find a reference to vaccines anywhere.
On the old website, I find standard antivaccine talking points like this:
Brain immunity storms are an auto-immune chain reaction that leads to a storm of inflammatory and neurotoxic molecules in the brain and can lead to autism.
These storms may be started in many ways that are similar to those reported by parents and in studies including; heavy metals, chemicals, oxidative stress, fertilizers/pesticides, extreme prenatal stress, etc. Once started the immune system releases molecules that cause inflammation, disrupt intestinal function, cause allergies, and breakdown blood barriers, in other words the long list of medical conditions that is autism.
Do you think that AutismFreeBrain suddenly changed its mind about vaccines and “toxins” as a cause for these “brain immunity storms? Me, neither. However, the new website is really slick compared to the old one, and on it AFB claims to have had multiple scientific breakthroughs, and label these their “top five findings”:
- Brain Immunity Storms damage behavior and language brain regions affected in ASD
- A novel molecule, found to cause inflammation, will be targeted to inhibit Brain Immunity Storms
- Two blood biomarkers can be used for early and objective ASD diagnosis
- Laboratory experiments showed that Brain Immunity Storms can be prevented and reversed
- Clinical trials show that a unique natural formulation benefits 75% of children with ASD
These would all be impressive research accomplishments, were they true. Are they? I have no idea. The articles included as part of AFB’s research library don’t seem to directly support the claims being made in the website. A suspiciously large number of them are published in a single journal, one I’ve heard of before and one I’ve been suspicious of before as well, the Journal of Neuroinflammation. A lot of the appear to be basic science studies being extrapolated to make clinical claims, and a lot of them on first glance don’t look to impressive. Perhaps if I’m feeling energetic (and particularly self-destructive) one night, maybe I’ll do some in-dept reading and deconstruction of a couple of these papers.
But who’s behind AFB? It appears to be primarily the work of Theoharis Theoharides, MS, PhD, MD. His profile on the AFB website sure sounds impressive:
Theoharis C. Theoharides, M.S., Ph.D., M.D., F.A.A.A.A.I. is the Director of the Molecular Immunopharmacology and Drug Discovery Laboratory, as well as a Professor of Pharmacology, Biochemistry and Internal Medicine and Associate Professor of Psychiatry at Tufts University School of Medicine, Boston, MA, USA. He has published over 350 research papers and 3 textbooks. He has been placed in the top 5% of authors most quoted in pharmacological and immunological journals.
And so he is. If you peruse Theoharides’s publications on PubMed, one thing you’ll notice is that the non-autism papers seem pretty reasonable. However, 18 of his papers mention autism, and they all see to promote the hypothesis that autism is due to neuroinflammation. More specifically, Theoharides links autism to the release of cytokines from mast cells. Now that in and of itself isn’t what makes me wonder about him. What makes me wonder about him is his involvement with a company called Algonot and the sale of a supplement solution called NeuroProtek®, complete with a quack Miranda warning. (“THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FDA. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.”) Here’s what the Algonot website says about it:
NeuroProtek® is a unique all natural oral dietary supplement in a soft gel capsule. NeuroProtek® uses an exclusive combination of flavonoids, based on the scientific research of Dr. Theoharides M.D., PhD,. NeuroProtek® is formulated to maximize affects of flavonoids while also overcoming any absorption obstacles. NeuroProtek® contains the flavonoids: Luteolin, Quercetin, and Rutin. Unique to Algonot’s formulations is olive kernel oil, a powerful anti-oxidant that is instrumental in helping the body absorb and delivery the dry flavonoids found in each soft gel capsule.
Interestingly, there is no mention anywhere in the Algonot website of exactly what it is that Neuroprotek is supposed to treat or protect against, although Theoharides is not nearly as shy elsewhere, as you will see. Note that Luteolin is the compound listed on the AFB website as the treatment for autism that supposedly reverses it by reversing “brain immunity storms.” But based on what clinical evidence are these claims made? To find out, I decided to go to PubMed again. All I could find was a single case series by Theoharides. Is it a randomized, double-blind, placebo-controlled study? Silly boy! Of course not! It’s an open label, single-arm case series in 37 children with autism spectrum disorder. In other words, it’s damned near completely useless for determining whether Neuroprotek does anything whatsoever for children with ASDs. Big surprise, it found that eye contact and attention improved in 50%, social interaction improved in 25%, and speech improved in 10%. There was one other study out of Greece I could find for a formulation of luteolin and quercetin that sounds very similar to Neuroprotek. Guess what? It was an open label, single arm trial for 26 weeks. Not surprisingly, this trial showed benefit as well, this time in adaptive functioning as measured by using the VABS age-equivalent scores), as well as in overall behavior as indicated by the reduction in Aberrant Behavior Checklist subscale scores.
Then there is this video:
Yes, it’s an interview in which Theoharides is hawking a supplement. He uses all the buzzwords that the “autism biomed” movement likes, including “oxidative stress,” “autoimmunity,” food intolerances, and the like. It’s basically one big commercial for Neuroprotek. I will give Theo credit, though. The interviewer asks him if Neuroprotek is FDA approved, and he uses the same argument that supplement hawkers of all types use, namely that the ingredients don’t need FDA approval. I do, however, think that Theoharides is flirting with the very borders of the quack Miranda warning in that he does arguably appear to be making a claim to be able to treat a specific condition (autism). He also touts his preliminary clinical trial, while admitting that he hasn’t done a randomized clinical trial yet and is trying to get funding to support doing such a trial. In fact, I noticed on the AFB website that not only is Theoharides trying to get grant funding for his clinical trial, but he’s also hitting up the antivaccine faithful. Indeed, he’s trying to raise $1 million
Of course, my answer to such a defense of selling supplements is invariably this: You shouldn’t be selling this stuff if you don’t have solid clinical trial evidence that it does what you claim it does. Theoharides does not have the evidence, plain and simple, but he’s still selling the supplement. In fact, in light of these observations, it’s rather amusing to see Theoharides unable to answer most of the questions of the interviewer, such as, “What’s the dose?” or “When can one expect to see results?”
Oh, and it turns out that Neuroprotek isn’t Theoharides’ only foray into supplement sales. He also promotes a supplement known as Cystoprotek:
CystoProtek® is an all natural oral dietary supplement in a soft gel capsule. CystoProtek® uses an exclusive combination of the purist ingredients of flavonoids along with sodium hyaluronate. CystoProtek® contains glucosamine, quercetin and rutin as well as chondroitin sulfate and sodium hyaluronate. Unique to Algonot’s formulations is olive kernel oil, which is instrumental in helping the body absorb and delivery the dry ingredients found in each soft gel capsule. CystoProtek® is free from artificial colors or flavors, corn, milk products, preservatives, salt, starch, sugar, wheat or yeast. Our ingredients are not obtained from beef or beef by-products.
As is the case for Neuroprotek, there is no mention of what CystoProtek is actually supposed to treat (the quack Miranda warning, of course). However, Theoharides is much less shy in this video, as he is much less shy in the video above:
Oh, and if you don’t have interstitial cystitis, maybe you’re a middle-aged dude like me who’s entering the age range where benign prostatic hypertrophy becomes an issue. If so, then Algonot’s got you covered with Prostaprotek!
Of course, I now know why Algonot doesn’t say what its products are supposedly good for on its website and why the quack Miranda warning figures so prominently. There’s a little trick I’ve learned whenever I blog about something, and that’s to search the FDA website for it. Guess what I found here? Yes, indeed. It would appear that in 2011, Algonet got a major slapdown from the FDA in the form of one of those warning letters we all now know and love. The letter applied to pretty much all of Algonot’s products, including ProstaProtek, CystoProtek, and NeuroProtek. No wonder there’s no mention on the Algonot website of just what it is that each of these products is supposed to do, while, for NeuroProtek, at least, the promotion happens on the AFB website, in videos like the one above, and, of course, at autism biomed quackfests like Autism One.
Why am I not surprised? After all, AoA only promotes the finest woo. What’s sad about this one is to see the fall of a scientist who by all appearances started out not just respectable but prominent and well-published into selling supplements designed to treat not just autism but other conditions without any compelling clinical evidence in the form of randomized trials that it does what he claims it does.
ADDENDUM: Ack! How did I miss this? It’s been pointed out below that Dr. Theoharides gave a presentation this year at everybody’s favorite autism biomed quackfest, Autism One, just this May. This brings up what should be another blogging rule for me, just like the one that tells me to search the FDA website whenever I blog about a supplement. The rule? Whenever I come across “autism biomed” claims with which I’m not familiar or a new autism biomeddler whom I’ve never heard of, go to the Autism One quackfest website and search it to see if that person has ever presented at Autism One. Learn it, do it, love it, I will.
44 replies on “"AutismFreeBrain"? Selling supplements to cure autism”
Robert Scott Bell, broadcasting live from the Quackfest interviewed Dr Theo, who did a presentation in Chicago. Theo’s handout is a gem:
More useless products to make parents feel like they are Doing Something when all they are doing is wasting their time and money.
How can you be a 501(c)3 and hawk your wares like that–since Algonot is almost certainly not a non-profit?
The Algonot web site is incredibly vague about this “NeuroProtek” snake oil, but of course, you get sucked in from the AFB web site by all their beautiful claims and goals and cutesy icons, and before you know it, if you’re the parent of an autistic child, you’re probably thinking that $39.00 (minimum) a month for this isn’t so bad a deal.
I despise doctors who sell out for the sleazy side of non-SBM medicine. I do wonder if Tufts University has any ties/links/claims to any profit Dr. TTmakes from Algonot. If they did, exposing the link might be a black eye for Tufts, but then again, if there’s any CAM faculty members, they’ll stick up for this rubbish in a heartbeat.
Thanks for the heads up on this newer web site, Orac. I’m sure I’ll have a parent of an autistic child doing the “consult your physician” thing about AFB.
Flashback to 1990, the movie “Joe Versus the Volcano”, and Joe is told he has a “brain cloud”. Guess Joe was lucky he didn’t have a “brain immunity storm”.
I see the phrase “brain immunity storm” and find myself thinking that a storm of immunity to brains could certainly explain a certain amount of woo…
Did they seriously trademark “Brain Immunity Storm”? I mean, really? “Let’s make up a science-y sounding term to suck people in, but we need to put “TM” on it to deter others from using it.”
A quick search for the phrase at the Trademark Office’s website reveals that it has not been registered. In short, they just really, really like the term.
@Todd – sounds like a Cyberpunk reference to me…..
A defensive piece of software used by a Shadowrun decker, perhaps?
“They keep my finger on the pulse of the ‘autism biomed’ movement'”
I’m sure he diligently washes his hands carefully afterwards…
NeuroProtek? CysoProtek? A name like that reminds me of Cuforhedak, a spirited attempt to bypass early medical regulation in the US. Cuforhedak attempted to bypass the prohibition on false claims by not making any claims at all — they just had a name that, when when said out loud, basically *was* the medical claim, and pretended ignorance when told people were taking it as a cure for headaches. They were eventually put out of business in one of the first major FDA actions. Interestingly, their basic strategy is effective nowadays, since the FDA has had its teeth pulled by DSHEA, and now it’s legal to have highly suggestive product names in the absence of real safety/efficacy data.
Unfortunately the small, “curebie” segment of the autism community has created a void that is happily filled by charlatans such as Theoharides (and really, Dr. and PhD, MS, MD; how pretentious is that?). The biopeddlers have created a cottage industry for the biomeddlers and no one gives a rat’s arse that special needs children are dehumanised and experimented on. Shame on the AAP, AMA and FDA (more specifically the congress critters who neutered the latter) for allowing this rubbish to continue unabated.
Aren’t there any number of molecules known to inhibit mTOR and/or mast cell activation? Seems like it would be pretty straightforward to set up a trial demonstrating proof-of-principle–if, that is, mTor activity/mast cell activation has anything to do with autism.
Here are my notes on Theoharides from July 2011. I tossed a lot, but I believe he was in the first issue of Polly Tommey’s glossy rag, “Autism Science”, which I believe has suspended publication.
T.C. Theoharides, MD, Ph.D. developed the formulas for all of Algonot’s family of nutraceuticals.
The Scientific Advisory Board that guides Algonot’s family of nutraceuticals includes internationally acclaimed physicians and scientists. They have published extensively on inflammatory diseases. Abstracts and references to their research are available in the Research Portion of this CD-ROM.
The Scientific Advisory Board
All of Algonot’s Nutraceuticals are developed by T.C. Theoharides, Ph.D., M.D. The Scientific Advisory Board that supports Algonot LLC includes internationally recognized physicians and scientists who have published extensively on inflammatory diseases.
Philip W Askenase, M.D.
Professor and Chief
Section of Allergy and Clinical Immunology
Yale University School of Medicine
New Haven, CT
Jeffrey A. Gelfand, M.D.
Partners Health Care System
Center for Integration of Medicine and
Innovative Technology (CIMIT) (MIT/Harvard/MGH)
Professor of Medicine
Harvard Medical School
Grannum R. Sant, M.D.
Professor and Chairman
Department of Urology
Tufts University School of medicine
New England Medical Center
Egilius L.H. Spierings, M.D., Ph.D.
Associate Clinical Professor of Neurology
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA 02115
T.C. Theoharides, M.D., Ph.D.
Professor of Pharmacology and Medicine
Tufts University School of Medicine
New England Medical Center
Massachusetts Drug Formulary Commission (1986-2002)
From their facebook page, they have a Q&A
“Is it completely far fetched to say my 16 yr old severely autistic nonverbal son will one day speak more than just random words like he does now?”
“Hi my son talks about fires and he is observed what can I do to tell him it’s not good to set fires x”
“My ASD son is 6 years old and he has started to hit and kick. Generally it is because he does not want to do something. How do I help him to stop hitting and going into a meltdown?”
The answer, from AutismFreeBrain?
“Great questions! Keep them coming and please share with your friends. ”
Very sad. It would be more sad if they tried to answer these questions.
Goodness. Seems like their answers are about as meaningful as posts by spambots. They fail the Turing test, so I’m sure they don’t have an actual human reading the questions.
With all this talk of mast cells, I’m surprised they haven’t started recommending Benadryl, and then taking credit for the child being calmer as a result (unless the kid has the paradoxical reaction, of course).
Well, according to Theoharides, who *does* know quite a bit about mast cells, children with mastocytosis have autism at a rate of 1/10; i.e., PMID: 20074449. I think (?) this might have been what got him started on thinking about autism.
For all of the problems with him hawking supplements which may or may not affect the neuroimmune environment, I will say that his thoughts regarding extracellular mitochondrial components acting as danger signals are very similar to the insanely impressive study by Naviaux that came out a few months ago, Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model (PLOS / free full).
There are plenty of articles in pubmed speculating on mTor signalling in autism, and also conditions with high comorbidity; it looks like trials in TSC are ongoing.
according to Theoharides, who *does* know quite a bit about mast cells
A carpenter may know a lot about hammers but that does not mean that everything is a nail.
insanely impressive study by Naviaux that came out a few months ago
Some people read it and found it not so much “insanely impressive”, as a risible attempt at spinning one’s research to match the source of funding.
@herr doktor bimler –
Yes, it is so unusual to utilize poly:ic in utero challenge; nobody is doing that as a model for autism or other neurodevelopmental disorders. Oh wait, people are doing that all the time. They must all be ‘spinning’ their research. Good to know.
Oh yeah, plenty of studies are showing a reduction in Purkinje cell counts in the treatment group. Oh wait, nobody has done that.
Yeah, lots of groups have shown increases in IgG in the treatment group. Oh wait, nobody has done that.
Plenty of groups have shown normalized mitochondrial function in the treatment groups. Oh wait.
Yes, it is difficult to appropriately gauge mouse behaviors as they relate to autism. That being said, in utero immune stimulation as a modifier of neurodevelopment is here to stay, and children with autism have low IgG, decreased purkinje cell numbers, and reduced mitochondrial chain function in numbers far greater than their undiagnosed peers. Of course, you’d actually have to read the paper, and know something about autism research to understand that, otherwise, you might think that lego tests were the only thing in the study.
His first autism paper was “Novel therapeutic targets for autism.” which predates his mast cell prevalence paper.
In his “novel therapeutics” paper he goes into his theory of mast cells and autism. He does discuss his survey results.
They must all be ‘spinning’ their research. Good to know.
You do not help your case by reacting to criticism of one paper’s relevance with a hyperbolic strawman response.
Of course, you’d actually have to read the paper, and know something about autism research to understand that
At least one person (i.e. me) has actually read the paper, and knows something about autism research, and found it interesting but not relevant to autism… because (a) the only reason to describe “clumsiness from nerve damage” as “autism” is to placate the autism foundation providing the funding, and (b) “mouse models of autism” are unmitigated bollocks.
What I like is that all Algonot’s products appear to be more-or-less the same: quercetin (from the rare saphora – but hey, what’s a spelling error here and there), rutin (ditto), maybe something else – luteolin, maybe, and the magic olive oil kernel oil from Crete. I’m surprised they don’t cure headaches, bad breath, and whatever else ails you.
@ Derek: I’m still dealing with an AoA crank on other science blogs, who still believes “peanut oil” is a vaccine ingredient…and is the cause of peanut allergies. Then too, she’s still yammering about her child’s encephalopathy, (only diagnosed by her), caused by a hepatitis B vaccine, which caused her child’s ASD diagnosis…and the Td booster she received at age 21 for her own diagnosis of multiple sclerosis
Surprise, surprise, Parker has just informed her cronies at AoA, that she has been diagnosed with Asperger Syndrome.
Surprise, surprise, Parker has just informed her cronies at AoA, that she has been diagnosed with Asperger Syndrome.
oh well, that makes another one autistic who will be campaigning that vaccine cause autism.
How is ‘olive kernel oil’ any different from plain old olive oil?
Sounds like it would make a delicious salad dressing.
With Jake Crosby gone, AoA is going to have to find a replacement token autistic SOMEHOW.
(Pardon me if any of this was mentioned on another thread.)
Speaking of Crosby: Orac, you may be interested in Dan Olmsted’s weekly rant on there, in which he defends himself against Crosby and Bolen (without naming them) in his usual petulant way.
Crosby’s latest article on “Autism Investigated” spends a good amount of time challenging Seth Mnookin’s account of the time they shook hands.
“NeuroProtek? CysoProtek? A name like that reminds me of Cuforhedak, a spirited attempt to bypass early medical regulation in the US.”
However, its spinoff product, Jusfordeheckofit, made millions.
Its called glutathione to help protect and heal damaged neurons from all the vaccine induced infections added to the prion synergy of spirochetal disease we already have.
We show that prion infection of cells is extremely rapid occurring within 1 min of prion exposure, and we demonstrate that
the plasma membrane
is the primary site of prion conversion.
BBA70 of Borrelia burgdorferi is a novel plasminogen-binding protein.
In vitro, these latently infected B cells express only 10
of the approximately 80 genes
encoded by the virus
So you see they knew in 1956 when they infected us all with Henrietta’s Lacks Syphilis infected “Immortal” cells what caused Our Age of Syndromes. Now global research is finding IT in ALL Syndromes, psych, and cancers. ITs over.
Oh, great it is Silvermaven. Who is only slightly more entertaining than Thingy.
I think Prion Synergy would be a great name for a rock band.
Is there a point to your abstract-riddled word salad Silvermaven? All I see is another demonstration of your profound ignorance of human biology and immunology.
This is divine conspiracy theory. Care to elaborate oh ignorant one?
Please don’t maker her elaborate. It will just bring more insanity. Especially since syphilis is bacteria.
Brain Immunity Storms? Could this finally be the explanation for the Critical Thinking Immunity Storms at AoA?
@ Mephistopheles O’Brien:
I like ‘Our Age of Syndromes’ myself.
Maybe they could perform together:
Our Age of Syndromes would open for Prion Synergy.
*Someone* (Silvermaven), needs to take some basic science courses to be able to differentiate between a prion, a virus and a bacterium:
@ Sebastian Jackson:
“Crosby’s latest article on “Autism Investigated” spends a good amount of time challenging Seth Mnookin’s account of the time they shook hands.”
I don’t know if Orac, has commented on Jake’s encounters with Seth Mnookin, but Orac’s “friend” and others have commented:
I haven’t heard of this organization. Based on what I’ve read and looking over the website they want to fund research. Whatever the flaws are with this organization, it sounds more promising than autism speaks current research/grants. I’m a doctor as well as a mother of a moderate/severe child with autism. I’d much prefer the Ivy League doctors affiliated with Autism Brain than Autism Speaks.
And, of course, the all-natural anti-impotence supplement, mycoxifloppin.
“Brain immunity storm.” It sounds like someone heard of a cytokine storm and thought it sounded nifty, and decided to make up something that sounds equally nifty if you’re not too up on biology.
(Not so) O/T, The bot and Dr. Jay Gordon are on the move again, commenting on Dr. Sanjay Gupta’s CNN blog….
@Denice Walter – I’m presuming they’d both be progressive metal bands, or possibly goth. I’d buy tickets to that show.
Looking at the ingredients of these products, I’d say they’d be much more effective when applied to the skin. Maybe they’d help “cure” Skin Immunity Storms, whatever those might be. DJ Mycoxafloppin vs the Brain Immunity Storms sounds like a killer mix you’d find on You Tube.
M’OB: They’d do well in my corner of the world. We have a band that comes through sometimes called the Elusive Parallelograms. And I’m sure I saw a blurb for ‘Tragic Geometry’ in one of the club ads. So, yeah, I’d buy tix for DJ Mycoxafloppin or Age of Syndromes or Prion synergy.
This seems to be part of a trend in hope-based medicine. Blame everything on mast cells and/or methylation problems.