NYT OpEd on Immune disorder causes of autism: extremely suspect

The NYT has published an opinion piece by Moises Velasquez-Manoff claiming that at least 1/3 of autism is fundamentally an intrauterine inflammatory disorder associated with a widespread increase in immune disorders arising from our parasite-deficient modern lifestyle.

The extended essay includes this key phrase: "Generally, the scientists working on autism and inflammation aren’t aware of this — or if they are, they don’t let on."

That's a telling phrase. What we have here is an expansive theory outside the established research community claiming a dramatic breakthrough.

Well, those things do happen - particularly in medicine. I remember prion disorders and helicobactor pylori discoveries; two Nobel prize winning discoveries that were initially radical.

Except this appears to be Manoff's theory, and he's not a scientist. He has a BA in Literature and an MA in science writing. The number of breakthrough insights into long researched disorders delivered by non-scientist non-researchers is essentially zero.

Maybe our lack of a parasites is a problem; I well remember early studies on treating ulcerative colitis with iatrogenic parasite infection. Maybe there are immune abnormalities that correlate with some causes of autism. Maybe intrauterine inflammation, of microbial or other etiology, play some role in brain injury. 

But putting them all together into one package claiming a major breakthrough by a non-researcher? That's multiplying improbabilites. 

The New York Times should never have put this on the OpEd page. 

Ignore it.

Nature November 2011: Special issue on Autism, Mottron's view of the employed autistic and Calgary's Ability Hub

The Nov 2011 issue of Nature (v479, n7371, pp5-144) focuses on "The Autism Engima". It includes 3 reviews/news articles and 1 research article:

• Special issue on neuroscience: The autism enigma - introductory editorial
• The prevalence puzzle: Autism counts - a thorough 'news' review of the prevalence of autism. I came away with the impression that novel environmental changes might account for 0-20% of the increased diagnostic prevalence of autism, but that most of it is better diagnosis and reclassification. Studies of adults suggest that autism was far more common than most imagined -- these children were invisible.
• Scientists and autism: When geeks meet - autistic traits may be advantageous in some careers, but the hypothesis that assortative mating accounts for autism clusters doesn't sound too solid.
• Changing perceptions: The power of autism - this one is a research article, and is behind a closed-science paywall. Science Daily has a summary: Autistic people superior in multiple areas: Scientists must stop emphasizing autistics' shortcomings, expert urges.

I followed up on the Mottron article and came across an excellent National Post article ...

Autism’s advantages: Researcher says autistics need opportunities more than treatment | News | National Post

Because autism — characterized by repetitive behaviours, restricted interests and preoccupations and difficulties in basic social and communicative behaviours such as eye contact, intonation and facial expressions — is a lifelong disorder, parents can be caregivers for life. But as the population ages and parents get sick and die, there’s an even greater need to integrate people with autism into society by giving them the skills they need to become independent adults, experts say. Children tend to be the focus, autism organizations admit. Adults are overlooked.

“After 18 years of age they’re not kids anymore and they’re forgotten,” Dr. Mottron said over the phone this week from Lyon, France. “People have a cliché, that if he’s autistic you can do nothing with him. That’s not true. The fact that you have some terrible autistic life is not representative of autism in general.”

In his commentary, Dr. Mottron cites recent data, including an epidemiological study from Korea published this June that found the disorder is three and a half times more prevalent than common statistics suggest. “Among these 3.5%, about two-thirds have no adaptive problem at all,” he said, meaning they function relatively normally in society and should be able to take on a job.

... Ms. Dawson said it’s unfair to categorize someone as low functioning or high functioning. She and Dr. Mottron believe many tests that are used to determine level of functionality are inappropriate. Less commonly used tests such as Raven’s Matrices, which doesn’t require verbal instruction to complete, can actually reveal very high intelligence levels.

“To estimate the true rate, scientists should use only those tests that require no verbal explanation,” Dr. Mottron wrote in his paper. “If we were to measure the intelligence of a person with a hearing impairment, we wouldn’t hesitate to eliminate the components of the test that can’t be explained using sign language; why shouldn’t we do the same for autistics?”

Ms. Dawson said an entire session at this year’s International Meeting for Autism Research in San Diego focused entirely on finding out how to measure the intelligence of non-speaking autistics, who might be considered low-functioning....

... The founder of Specialisterne, a Danish company that has helped more than 170 autistics find work since 2004, said it’s OK to start such a movement with people who would be considered higher functioning.

“If we will be able to run a business on the skills of medium- or low-functioning, I’m not sure,” Thorkil Sonne said from Copenhagen. “But everyone deserves a chance to feel that they can produce something that others appreciate.”

... the Sinneave Family Foundation’s Ability Hub, a 17,000 square foot centre on the University of Calgary campus dedicated to helping people with autism gain life skills and work training...

... The Ability Hub opened in October and is just one of a few new centres devoted to getting autistic adults ready for the real world, said its executive director, Dr. Margaret Clarke, who has spent a career working with people who have autism — the Ability Centre is under construction in Whitby, Ont., and the Pacific Family Autism Centre to be built in Vancouver.

“Around the world we know that average lifetime cost to society to an individual with autism … is $3.4-million per individual. Three-quarters of those costs are incurred in adulthood largely around services to enable and facilitate individual vocations,” Dr. Clarke said, adding that some data suggests every dollar you invest in pre-vocational programming for people gives you a $7 return. “I actually think that number is going to be even better in the area of autism because individuals with autism have a great capability to learn, they’re just often held back by specific skill deficits or not given a chance.”

Intrauterine contributors to autism

A recent twin study (NYT.com) claims that only 40% of what the researchers considered "autism" was clearly genetic. Previous studies estimated a 90% rate. The greater causes was something occurring prior to birth.The researchers further claimed that most (about 58%) of the environmental causes were shared.

These are remarkable claims, and they will require remarkable evidence. I am very skeptical.

If there is a common intrauterine cause of brain injury, however,  we do need to look again at obstetric ultrasound.

See also:

• Be the Best You can Be: Ultrasound, neuronal migration, and autism (8/2006)
• Gordon's Notes: General weirdness on the net: ultrasound, autism and satire (An essay was published in 2006 on ultrasound, school violence, and autism. It was a satire.)
• Gordon's Notes: Ultrasound and the developing brain – lessons from manipulation of mouse neuron (1/2009)

Schizoprhenia and a suspicious retrovirus

Researchers have long looked for an infectious cause of schizophrenia, especially because of a relationship between a child's birth month and the later development of schizophrenia. The focus though has been on a maternal infection.

Now there is interest in an endogenous retrovirus as a contributing factor in the development of schizophrenia. This virus is present in the DNA of most of us, though there might be secondary infections triggers that would activate a quiescent retrovirus. It's quite speculative, but noteworthy.

Naturally everyone who wasn't already looking for an endogenous retrovirus in autism will redouble their efforts.

As always, there's a large caveat about this type of research. Autism and schizophrenia are labels we place on a variety of cognitive disorders that likely have diverse causes, courses, and therapies. Even if this early work bears fruit, not all of what we currently label "schizophrenia" will be related to a retroviral infection.

The sad story of the autism vaccination scam

Rahul Parikh, on the occasion of Lancet withdrawing the fraudulent Wakefield Autism/immunization paper, reflects on its legacy.

It's a sad story. Wakefield, who ought to be in prison, prospers. Parents agonize over immunization. Misguided publicity hounds perpetuate fraud. Children suffer from preventable illnesses. Credulous advocacy groups waste time and money chasing a lie.

There's no justice. It will take another decade to get this fraud behind us.

The end of autism

No, the problems of suboptimal neurodevelopment are not going away. The concept of "autism" has lasted longer than I'd expected, but the assault continues ...

Syndromic autism: causes and pathogenetic pathways. [World J Pediatr. 2009] - PubMed result

... Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems...

Of course even if we abandon use of the term "autism" in quality clinical care and research it will remain tightly bound to service delivery. It will take decades to remove the concept from legal, reimbursement, educational and policy frameworks - and the slow, ponderous, archaic evolution of the DSM "classification" will keep it in psychiatry texts.

Autism will be preceded, I hope, with the end of "Asperger's" - at least in scientific writing. "Asperger's" will join "the planet Pluto" in the netherworld of meaningless terms. Within 10 years "autism" should also be replaced with a classification of neurodevelopmental disorders (the neuroconnectopathies?)

It's not mere pedantics. Names are powerful. Names determine how we interpret research results, how we predict outcomes, and, above all, how we decide which therapies to try first, and how we assign services and support. More precise names for the the complex mix of neurologic injury and repair we currently call "autism" will mean less time wasted on ineffective treatments, quicker use of what works, better targeted research, and more creative thinking.

See also:

• Be the Best You can Be: diagnostic definition
• Be the Best You can Be: Controlling nerve cell connectivity - more developments
• Autism turns into Asperger's - how did that happen?
• Be the Best You can Be: Autism: the label given to a wide and diverse variety of neurodevelopmental disorders (May 2007)
• Be the Best You can Be: Autism no more -- the end of a diagnosis (Dec 2006)
• Be the Best You can Be: Psychiatric diagnoses: 200 years behind
• Be the Best You can Be: Very annoying: the diagnostic criteria for Asperger's are not all that useful (2005)
• Be the Best You can Be: A breakthrough in understanding the genetics of schizophrenia -- and perhaps of autism too

Federal court vaccine ruling was very science based

These Wall Street Journal health blog excerpts make it clear that the decision Federal vaccine court special masters was very clear cut. This was not a hard call, the scientific evidence is overwhelmingly against the vaccine-autism beliefs (emphases mine):

WSJ Health Blog : What the Court Said In the Autism Vaccine Cases

One ruling:

After careful consideration of all of the evidence, it was abundantly clear that petitioners’ theories of causation were speculative and unpersuasive. Respondent’s experts were far more qualified, better supported by the weight of scientific research and authority, and simply more persuasive on nearly every point in contention.

A second:

I concluded that the evidence was overwhelmingly contrary to the petitioners’ contentions. … The numerous medical studies concerning these issues, performed by medical scientists worldwide, have come down strongly against the petitioners’ contentions.

A third:

[P]etitioners’ experts tended to assign greater weight to speculative conclusions offered by the investigators involved in the studies than did the investigators themselves. Petitioners’ experts also urged reliance on a few carefully selected sentences from particular articles which, when considered in the proper context of the referenced articles, did not support the propositions advanced by the witnesses. Moreover, because petitioners’ experts relied on a number of scientifically flawed or unreliable articles for several important aspects of their causation theory, their testimony on those aspects of their offered theory could not be credited as sound or reliable. Finally, petitioners’ experts made several key acknowledgments during testimony that rendered their proposed theory of vaccine causation much less than likely.

The third opinion emphasizes that the petitioner's own experts, under examination, contradicted the belief that autism arises from immunization.

This won't be the end of the autism-vaccine meme of course. It long ago became a matter of quasi-religious belief rather than something amenable to data or reason. It will, however, make it very hard to press these arguments in the court system. It's not the judgments alone, it's the ferocity and clarity of the opinions that will make a difference going forward.

Update 9/20/09: Good f/u article on the decision. My favorite line:

... Among those expressing shock and disappointment was Rebecca Estepp, the mother of an autistic child, who is one of the claimants and the national manager of the advocacy group Talk About Curing Autism. "It's tough when you're taking parent support calls and you hear the same story day after day," she told the Wall Street Journal. "When does anecdotal evidence become enough?"

Her question isn't a new one, especially in a society where belief, emotion and science so often conflict. For scientists, the answer to Estepp's question is never.

Thousands of years of anecdotal stories about witches causing disease didn't make it true.

Vaccines and autism - a fraud from day one?

My distress at the Autism Society of America's vaccine obsession doesn't mean that it was necessarily always a bad idea to look for a link between immunization and autism. A legitimate study showing a correlation would deserve investigation, and when the correlation was disproved it would then be appropriate to move on (years ago, in this case).

Happens all the time. That's science.

But what if there never was a correlation to begin with? That would be one of the most harmful cases of scientific fraud in the past fifty years (emphases mine) ...

Aetiology: Vaccines and autism--can we stick a fork in it now, please?

Last fall, I wrote about a new research paper which tried to replicate some of Andrew Wakefield's original results, which not only claimed a correlation between MMR vaccination and autism, but also the presence of measles virus in intestinal tissue. Wakefield had suggested that an inappropriate response to the presence of measles virus in this tissue may trigger conditions such as bowel disease and autism. The more recent study was unable to replicate any of Wakefield's findings--not surprising, since so many papers in the last decade have found no connection between vaccination and autism.

There are plenty of reasons why the study may not have been replicated. The design of the new study was a bit different from Wakefield's (case-control versus a case series); it had larger numbers; investigators were blinded to the status of the patients and so less likely to bring in bias. However, a recent investigation by the Sunday Times (London) has another reason why the results of the two papers differ: Wakefield made up his data. More after the jump...

From the Times Online:

Confidential medical documents and interviews with witnesses have established that Andrew Wakefield manipulated patients' data, which triggered fears that the MMR triple vaccine to protect against measles, mumps and rubella was linked to the condition.

The research was published in February 1998 in an article in The Lancet medical journal. It claimed that the families of eight out of 12 children attending a routine clinic at the hospital had blamed MMR for their autism, and said that problems came on within days of the jab. The team also claimed to have discovered a new inflammatory bowel disease underlying the children's conditions.

However, our investigation, confirmed by evidence presented to the General Medical Council (GMC), reveals that: In most of the 12 cases, the children's ailments as described in The Lancet were different from their hospital and GP records. Although the research paper claimed that problems came on within days of the jab, in only one case did medical records suggest this was true, and in many of the cases medical concerns had been raised before the children were vaccinated. Hospital pathologists, looking for inflammatory bowel disease, reported in the majority of cases that the gut was normal. This was then reviewed and the Lancet paper showed them as abnormal.

This is truly incredible. Even being familiar with Wakefield's statements over the past decade about his research, and his complete denial about studies that have contradicted his own findings, it's still pretty shocking that he completely made up data, and then pushed it for ten years as children around the world became ill and even died in light of his research. It's even more disgusting in light of the fact that I doubt this new information will change many minds when it comes to vaccination--the meme has already spread too far to let a little thing like atrocious scientific misconduct rein it in now.

Wakefield's original Lancet coauthors retracted their interpretation of the data in 2004. The wikipedia article on Wakefield (reads like it's in an edit war) says his research misconduct trial was to commence a year ago, but it seems like this Feb release from the Times of London is the most definitive response thus far.

If the charges are corect, then was Wakefield delusional himself, or is he a sociopath? I'm hoping the former, it's not all that rare in science, but given his subsequent career I fear the latter.

Update 2/9/09: Excellent summary of reactions to the Times article. I scanned some of the skeptics responses, and this is also a list of interesting blogs to consider reading.

Autism Society of America has lost our donations – anti-Vaccine madness

The ASA has turned from the best available science. There are no roads on the trackless wasteland they’re traveling now (emphases mine) …

Autism Society of America: research_envirohealth_vaccines

Individuals living with autism need help today. There is a clear and present need for the government, scientific, medical and autism communities to probe further into all possible environmental causes of autism spectrum disorders (ASD) in a fair, unbiased and thorough way, particularly because findings may help us approach treatment and prevention more effectively. Research needs include, but are not limited to, research into the causal or contributory relationship to autism that may be attributed to thimerosal containing vaccines (TCV’s), the measles-mumps-rubella (MMR) inoculation and/or a combination of the two. The interaction of these vaccines with other potentially contributory environmental factors and vulnerabilities also needs serious investigation.

ASA strongly believes that:

1. Vaccines administered to children, teens and adults must be safe;
2. More unbiased and credible research needs to be done to:
   1. ensure and optimize safety,
   2. identify those who are at higher risk of injury and develop and implement appropriate accommodations for them,
   3. avoid injury altogether, and
   4. prevent unnecessary overexposure;
3. All those who are vaccine injured need to be justly compensated;
4. Development and availability of treatment for injuries from environmental factors, including but not limited to vaccines, needs to be prioritized.

Madness.

This is worse than a distraction from understanding the causes, prevention, treatment and management of the range of cognitive disorders we currently label as “autism”, it is going to cause harm to children and families by reducing immunization levels.

Science is never perfect, but it has a vastly better track record than the alternative. It’s an imperfect guide, but it’s the best guide we have. The science is as clear as it gets on thimerosal and MMR vaccination – they don’t make significant contributions to autism. We need to look elsewhere to understand the genetic and environmental interactions that alter brain development.

The ASA has done good things, but we can’t send them financial donations knowing that they going to use our contributions to, unwittingly, cause great harm.

This is a shame.

Update: The Executive Director of Autism Speaks has resigned over their anti-vaccination obsession.

Update 10/16/09: See also Jim Carrey - enemy of the enlightenment

Fragile X and memory

Pretty far from human application, but noteworthy ...

Fruit Flies, Fragile X and Foolery: Scientific American Podcast:

University of Alberta researcher Francois Bolduc keeps 300,000 fruit flies in a basement laboratory. He discovered that disrupting one gene known as FMR1 in the flies’ brains can wipe out their long-term memory. What’s interesting for us is that damage to that gene in people is associated with learning and memory problems, epilepsy and autism. That constellation of traits is known as fragile X syndrome. Bolduc then worked on curing his forgetful flies—he found a class of drugs that reduces the activity of the FMR1 gene. And the insects were able to regain their memory...

Working memory and COMT inhibitors - the nicotine example

Obviously, I'm not considering smoking as an aide to my son's limited short term memory. It is interesting, however, to note how substances associated with smoking act on the brain ...

FuturePundit: Gene Variant Makes Nicotine Withdrawal Harder

....

Spurred by their previous findings that carriers of the catechol-O-methyltransferase (COMT) val gene variant are more susceptible to smoking relapse, the Penn researchers set out to learn if smokers with this genetic background would be more likely to exhibit altered brain function and cognitive deficits during periods of abstinence from smoking.

...Results showed that smokers with the COMT val/val genotype suffered greater deficits in working memory and brain function when they had refrained from smoking for 14 or more hours, compared to their performance on this task when they had been smoking as usual....

... Inhibitors of this COMT enzyme might work to ease withdrawal from nicotine. Inhibitors of COMT already are known to increase working memory...

One method may be to offer carriers of this gene targeted therapies with drugs like COMT inhibitors, some of which have been shown to increase working memory in healthy volunteers.

The researchers were trying to understand why some people have a much harder time stopping smoking that others. It seems at least some of these persistent smokers experience brain dysfunction when they stop. The article does not tell us whether these people are experiencing a return to baseline cognition or whether they're experiencing a transient impairment. I assume the latter.

Even as smoking has become mercifully unusual in wealthier parts of North America, there's been more interest in the pharmacologic action of chemicals produced by the nicotine plant.

This related ticle on COMT inhibitors and executive function is interesting. Tolcapone is used to treat Parkinson's Disease (emphases mine):

Tolcapone improves cognition and cortical information processing in normal human subjects....

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction.

To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood.

Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI).

We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

Please note that some people got worse on Tolcapone. I think we're a long way (20 years) from a safe medicine that can improve working memory, but this will be an interesting thread to follow.

Controlling nerve cell connectivity - more developments

A day or two ago my post on Fragile X and autism research included a discussion of a general theme in current autism research ...

... Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.

The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect....

The idea is that neuronal connectivity is a delicate, dynamic, balance. Too much connectivity, or too little, can both prevent cognition from working correctly.

So now there's research on modulating neuronal interconnectivity. If they worked safely these drugs would inevitably be used on "normal" brains, probably illegally, but they could be of enormous benefit to persons with impaired cognition.

Note in this review the implication that autism and schizophrenia may be, in a simplistic sense, two sides of one coin.

A Switch to Turn Off Autism?: Scientific American

Scientists say they have pinpointed a gene in the brain that can calm nerve cells that become too jumpy, potentially paving the way for new therapies to treat autism and other neurological disorders...

... The brain is continually trying to strike a balance between too much and too little nerve cell activity. Neurologists believe that when the balance tips, disorders such as autism and schizophrenia may occur. They are not sure why neurons (nerve cells) go berserk. But Greenberg says he and his colleagues located a gene in mice and rats that helps keep neural activity in check—and may one day be manipulated to prevent or reverse neurological problems.

Researchers report in Nature that they discovered a gene called Npas4 churns out a protein that keeps neurons from becoming overexcited when they fire (communicate with one another through connections known as synapses). When scientists blocked the protein, the nerve cells fired or sent out more signals than normal; when they beefed up production, the neurons quieted down...

As scientists learn more about how brain cells stay balanced, Greenberg says they will be able to identify people who are genetically at risk for neurological disorders and develop new drugs to prevent and treat them. He notes that some of the other genes that Npas4 affects also have been linked to autism...

Drugs to treat these disorders are years away from common use -- if ever. In the near term understanding the protein products of these genes may help us better classify and organize brain disorders, though we can also expect that prenatal testing will lead to more abortions.

These developments may also increase the value of doing genetic testing on persons with cognitive disorders, so that if appropriate trials are available one might, very carefully, consider enrolling.

The rise and fall of autism vaccine theories

Salon features a book review by a physician journalist that traces the rise and fall of theories relating autism to vaccines. These theories are as dead as phlogiston, but strong supporters persist. Some of those supporters have financial motivations, but for others the belief has come to resemble religious devotion.

Most of the story was familiar to me, though I recall far more early skepticism than Dr. Parikh mentions. I think there was more early support among UK scientists, but US physicians were more suspicious. Those suspicions were justified, Lancet retracted the original article and the primary author is now suspected of fraud (emphases mine):

Salon.com Books | Inside the vaccine-and-autism scare

By Rahul Parikh

Sep. 22, 2008 | ... Dr. Paul A. Offit's new book, "Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure,

... Offit begins by tracing the history of the anti-vaccine movement to its roots in England in 1998: That's where a young, charismatic and ambitious researcher named Andrew Wakefield held a news conference to reveal he had discovered that the measles-mumps-rubella (MMR) vaccine causes autism. The prestigious medical journal Lancet subsequently published his paper. Soon, headlines warning parents about "child jabs" appeared on the front page of newspapers all over the U.K., and droves of parents began refusing the MMR vaccine. Despite the resurgence of measles in the U.K. as a result, Wakefield was hailed as a muckraker. The BBC even made a biopic about his fight against the establishment.

... Among the resulting press were Robert F. Kennedy Jr.'s "Deadly Immunity," published simultaneously in Rolling Stone and Salon, and David Kirby's blockbuster book, "Evidence of Harm," a damning account of the link between autism and vaccines and of our government's efforts to cover up a link between the two...

... it wasn't until 2004 that Brian Deer, an investigative reporter for London's Sunday Times, discovered damaging evidence against him. Despite what Wakefield claimed in his paper, his hospital's ethics committee never approved his experiments to put children to sleep under general anesthesia, do spinal taps on them, take biopsies of their intestines (one of the children was hospitalized after his colon perforated in several places) and take volumes of blood from their veins. Deer also discovered serious conflicts of interest: Wakefield's research was secretly bankrolled by a personal injury lawyer whose clients were suing MMR makers. Wakefield himself was given close to a million dollars to prove that the MMR caused autism. He had filed a patent for a new MMR vaccine at the same time he was doing his research. Upon learning this, Lancet retracted his paper, and he was charged with professional misconduct in 2005. If he is found guilty of misconduct, he will never practice medicine in the U.K. again.

The last nail in the coffin came in 2007 during an "autism omnibus proceeding" in the United States. (This is a federal hearing for several thousand parents who claim their children developed autism because of vaccines. Those parents are seeking compensation from the federal government.) Wakefield's former research assistant testified that his discovery about the MMR vaccine was, in reality, the result of contaminated lab equipment and that Wakefield knew this about but ignored it. In other words, as Offit writes, "Wakefield had crossed the line from ill-conceived, poorly performed science to fraud."

Eleven studies now show that the MMR vaccine doesn't cause autism (the most recent just came out). Six have shown that thimerosal doesn't cause autism; three have shown thimerosal doesn't cause neurological problems. Studies showing the opposite, like Wakefield's, use flawed methods, have serious conflicts of interest or have been conducted in animals whose results can't be extrapolated to humans.

... the father-and-son team of Mark and David Geier, one a doctor and the other with a college degree in biology. The elder, Mark, opened a homemade lab in his basement, where, under the patronage of anti-vaccine advocates, he works on his theories. They include prescribing Lupron to autistic children, a drug that several states use to chemically castrate sex offenders. The son, David, runs a medical-legal consulting firm, where he offers up expert witnesses for vaccine-injury trials. The two work hand in hand to make money both selling treatments and testifying as expert witnesses in vaccine-autism cases...

In addition to the obvious harm caused by falls in vaccination rates, these 17 research studies were a necessary but huge waste of time, money, and talent. I'd rather one of them had been spent on strategies for helping autistic children learn more effectively ...

Autism and ADHD are not so different after all

More evidence that our current categorization of early onset cognitive disorders needs a rewrite.

Evidence for overlapping genetic influences on aut...[J Child Psychol Psychiatry. 2008] - PubMed Result

BACKGROUND: High levels of clinical comorbidity have been reported between autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). This study takes an individual differences approach to determine the degree of phenotypic and aetiological overlap between autistic traits and ADHD behaviours in the general population.

METHODS: The Twins Early Development Study is a community sample born in England and Wales. Families with twins born in 1994-6 were invited to join; 6,771 families participated in the study when the twins were 8 years old. Parents completed the Childhood Asperger Syndrome Test and the Conners' DSM-IV subscales....

RESULTS: Significant correlations were found between autistic and ADHD traits in the general population (.54 for parent data, .51 for teacher data). In the bivariate models, all genetic correlations were >.50, indicating a moderate degree of overlap in genetic influences on autistic and ADHD traits...

CONCLUSIONS: These results suggest there are some common genetic influences operating across autistic traits and ADHD behaviours throughout normal variation and at the extreme. This is relevant for molecular genetic research, as well as for psychiatrists and psychologists, who may have assumed these two sets of behaviours are independent.

I suspect all clinicians with significant experience with autism are accustomed to children who have features of both ADHD and autism. So no surprises there. Unfortunately, most studies of ADHD or autism focus on "pure" subjects, so they exclude children who have features of both.

That means there's very little research about children with both ADHD and autism spectrum disorder -- we don't know what medications, behavioral or educational interventions are most effective.

These results may justify research on the large number of children and adults who aren't "pure" examples.

A breakthrough in understanding the genetics of schizophrenia -- and perhaps of autism too

A major publication in Science on the genetics of schizophrenia is summarized in Gordon's Notes

Gordon's Notes: What is schizophrenia? Not what we thought.

... note only 15% percent of "schizophrenics" fit this pattern. I'll summarize the key implications:

• Schizophrenia is not a disease. It's the name given a fairly large number of unique disorders of brain development that have, among their endpoints, social withdrawal, hallucinations, and fixed beliefs.
• A good number of cases of "autism" and "schizophrenia" are different manifestations of overlapping sets of mutations.
• There may be"no genes for most instances autism and schizophrenia". There are sets of large scale mutations that are similar between close genetic relatives, but similar appearances are resulting from disorders of quite different components of brain development.
• One in twenty seemingly normal people have big, ugly looking mutations that ought to be messing up their brain development. Yet they seem "normal". Seventeen in twenty persons with "schizophrenia" do NOT have these nasty scattered "sledgehammer" mutations. (So called because it's as though something took a sledgehammer to the genome.)
• The age onset of schizophrenia is determined by when the disordered developmental genes are activated. There's a lot of this going on in late teen years. The implication is that the same thing explains why "autism" presents around ages 2-3, and why it can seem to appear fairly suddenly. This may also explain why some conditions seem to improve at other ages. Schizophrenia syndromes often improves in middle age, for example.
• If every person with autism has a somewhat unique disorder, then treatments and prognosis are also unique. This validates the age old practice of asking someone with a cognitive/psychiatric disorder what treatments have worked for relatives.

I'm seeing a growing consensus that "autism" will turn out to have a similar picture. The trend is clear, autism is also going to turn out to be a diverse collection of disorders of brain development and injury response with diverse genetic causes. These as yet unnamed disorders will turn out to have different prognoses and different therapies.

Interactive Autism Network Research: Johns Hopkins and the Kennedy Krieger Institute

I came across this one at a scientific meeting I was attending.

The Kennedy Krieger Institute claims to be America's largest facility for the care and study of children with autism and other developmental disorders. Together with Autism Speaks they're sponsoring the IAN Project, a national project to study the natural history and characteristics of the the complex array of syndromes and disabilities now awkwardly lumped together as "autism":

Interactive Autism Network Research

...IAN Research allows parents of children diagnosed with an Autism Spectrum Disorder (ASD) to participate in research over the Internet. Parents provide information about their child's diagnosis, behavior, family, environment, and services received. Parents may also report on their child's progress over time.

Who can participate in IAN Research?

To register and answer research questions in IAN Research, you must live in the United States and be a biological or adoptive parent of a child under the age of 18 who is diagnosed professionally with one of the following disorders:

• Autism Spectrum Disorder (ASD)
• Autism
• Asperger Syndrome
• Autistic Disorder
• Pervasive Developmental Disorder (PDD)
• Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS)
• Childhood Disintegrative Disorder (CDD)

The child should not have a diagnosis of Rett Syndrome.

What are the benefits of joining?

You will be able to participate in important research on ASDs. IAN will provide tools that help you monitor your child's progress over time and explore how your child is similar to (or different than) other children affected by this disorder.

I suspect there's some work involved and that the benefits will not accrue to this generation of autistic children, but we will consider entering the study.

The IAN Project has a related community component to recruit study participants and connect interested persons to their research developments (though they're not going to reveal anything interesting prior to publication - that's just the way academia works). It includes discussion groups and articles like this one:

What are the behaviors and ways of taking in the outside world that distinguish a person with an ASD from his or her “typical” peers? Although these will vary according to the severity of a person’s autism and where they are in the lifespan, there are core issues that impact most people with an Autism Spectrum Disorder. In this section we explore each of these overlapping topics...

The Community component is very much secondary to the research component. The articles all end on the same note "we don't know much, please join our study". A bit disappointing but also true -- we really don't know much about cognitive disorders.

The Discussion Groups are focused on the IAN research project. It will be tough to keep them on topic -- they'd need heavy moderation to survive. I'll take a look at them later and comment on how well that's working out.

Vaccine payment for a mitochondrial disorder?

It's a weird story. The feds paid out a vaccine injury claim for a child with a mitochondrial disorder.

Deal in an Autism Case Fuels Debate on Vaccine - New York Times

...Hannah’s father, Dr. Jon Poling, was a neurology resident at Johns Hopkins Hospital at the time, and she underwent an intensive series of tests that found a disorder in her mitochondria, the energy factories of the cells...

Since the formal definition of autism doesn't exclude brain injury from other causes Hannah does technically have autism, but she'd be excluded from any research study of the disorder. She apparently has a well defined and extremely rare disorder of her mitochondria...

...symptoms of mitochondrial myopathies include muscle weakness or exercise intolerance, heart failure or rhythm disturbances, dementia, movement disorders, stroke-like episodes, deafness, blindness, droopy eyelids, limited mobility of the eyes, vomiting, and seizures. The prognosis for these disorders ranges in severity from progressive weakness to death. Most mitochondrial myopathies occur before the age of 20, and often begin with exercise intolerance or muscle weakness. During physical activity, muscles may become easily fatigued or weak. Muscle cramping is rare, but may occur. Nausea, headache, and breathlessness are also associated with these disorders....

I wonder what the legal basis of the claim was? Are vaccines known to precipitate a crisis in mitochondrial disorders? They are thought to be exceedingly rare, so I suppose that's possible.

I hope this gets covered in more detail in a major medical or science journal. Based on what I've read so far I think this has no relevance to 99.99% of the children and adults who have some form of idiopathic autism. I think this does emphasize that the definition of autism is impossibly broad.

Update 3/18/2008: Dr Rahul Parikh, writing for Salon, is the only writer on this topic I've read who bothered to include the Judge's statement:

the court "concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations CHILD received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder. Therefore, respondent recommends that compensation be awarded to petitioners."

The vaccine court is predisposed to pay if there's any chance of injury. So they paid out, even though the expected course of some mitochondrial disorders includes, tragically, regressive encephalopathy.

The confusion in this case arises because the technical (DSM IV) definition of autism is exceedingly broad, and says nothing about the underlying cause. This story is yet another indicator that we need better ways to describe disorders of cognition.

Berate, Guggenheim and ABC: three slimy entities

There's no good reason today to believe that autism spectrum disorders are related to immunization.

Science in general, and clinical science in particular, is very imperfect. Even so, it's all we've got. There are no credible competitors to science for guiding health care and health related decisions.

The answer from the best science we've got is that there's no connection. The strong beliefs of many people has meant that the topic has been very well studied -- probably to the detriment of more promising investigations. Today what was once a plausible hypothesis has become a waste of time and resources. We have better things to do now.

Maybe that situation will change, but today that's what it is.

So, like all scientists and most clinicians, I was very annoyed when I heard about a television show promoting an autism/immunization link. Still, that's what one gets from television. There's a reason I don't watch it.

What took me from annoyance to blogging, however, was this quote from the creators of the TV show:

ABC defends show against outcry by pediatricians: Scientific American:

....ABC said it plans to broadcast the episode without changes, but would run a disclaimer at the opening of the show stating the story is fictional. A message at the end will refer viewers to a CDC Web site for information about autism.

The show's two creators, Greg Berate and Marc Guggenheim, disputed the notion that their show would frighten parents away from vaccines.

'We actually share the concern of the American Academy of Pediatrics. We believe that children should be vaccinated,' Berate told Reuters. But he also said, 'We hope that people do watch the episode and draw their own conclusions.'...

That's slimy. If they really believe that immunizations lead to autism, they should have the courage to say so. If they believe otherwise, then they're cynical slimeballs to have created the show. "Disputing" the notion that the show discourages immunization makes my head explode.

Whatever the explanation, whether they're believers or not, they are definitely slimy -- and so is their network.

I'd boycott ABC, but I already mentioned I don't watch television. Maybe I should watch NBC so I can say I'm boycotting ABC, but that's too terrible to consider.

A mouse model for schizophrenia

This was announced in July of 2007, but I completely missed it. I only read of it in a recent 'top 10 science stories' article.

Hopkins team develops first mouse model of schizophrenia

Johns Hopkins researchers have genetically engineered the first mouse that models both the anatomical and behavioral defects of schizophrenia, a complex and debilitating brain disorder that affects over 2 million Americans.

In contrast to current animal studies that rely on drugs that can only mimic the manifestations of schizophrenia, such as delusions, mood changes and paranoia, this new mouse is based on a genetic change relevant to the disease. Thus, this mouse should greatly help with understanding disease progression and developing new therapies.

Animal models of schizophrenia have been hard to design since many different causes underlie this disease. However, Akira Sawa, M.D., Ph.D., associate professor of psychiatry and neuroscience and director of the program in molecular psychiatry and his colleagues took advantage of the recent discovery of a major risk factor for this disease: the DISC1 gene (short for disrupted in schizophrenia), which makes a protein that helps nerve cells assume their proper positions in the brain.

As reported online this week in Proceedings of the National Academy of Sciences, the researchers generated mice that make an incomplete, shortened form of the DISC1 protein in addition to the regular type. The short form of the protein attaches to the full-length one, disrupting its normal duties.

As these mice matured, they became more agitated when placed in an open field, had trouble finding hidden food, and did not swim as long as regular mice; such behaviors parallel the hyperactivity, smell defects and apathy observed in schizophrenia patients. Magnetic resonance imaging (MRI), taken in collaboration with Susumu Mori, Ph.D., professor of radiology, also revealed characteristic defects in brain structure, including enlarged lateral ventricles, a region that circulates the spinal fluid and helps protect against physical trauma.

Sawa notes that the defects in these mice were not as severe as those typically seen in people with schizophrenia, because more than one gene is required to trigger the clinical disease. “However, this mouse model will help us fill many gaps in schizophrenia research,” he says. “We can use them to explore how external factors like stress or viruses may worsen symptoms. The animals can also be bred with other strains of genetically engineered mice to try to pinpoint additional schizophrenia genes.”

Mouse models for human disorders of the mind are hugely important. In 2006 I wished for a murine autism model (twice, actually) and in 2007 there were hints of some models (MECP2 based). I didn't realize that a DISC1 model also existed for schizophrenia.

Of course as I always mention, autism and schizophrenia are fuzzy labels we apply to what's likely to turn out to be many diverse neurologic disorders.

A mouse model is to thought disorders as the telescope was to learning about the universe. It's progress we can celebrate.

Vaccines and autism: stop betting on the horse that always loses

Many people believe in things for which there is no evidence. A smaller, but still large, number of people believe in things for which there is not only no evidence, but for which there is great evidence to the contrary. Immunization as a cause for autism is one of those things ...

Why there's no dispelling the vaccines-cause-autism myth. - By Arthur Allen - Slate Magazine

.... People who study irrational beliefs have a variety of ways of explaining why we cling to them. In rational choice theory, what appear to be crazy choices are actually rational, in that they maximize an individual's benefit—or at least make him or her feel good.

Blaming vaccines can promise benefits. Victory in a lawsuit is an obvious one, especially for middle-class parents struggling to care for and educate their unruly and unresponsive kids. Another apparent benefit is the notion, espoused by a network of alternative-medical practitioners and supplement pushers, that if vaccines are the cause, the damage can be repaired, the child made whole. In the homes of autistic children it is not unusual to find cabinets filled with 40 different vitamins and supplements, along with casein-free, gluten-free foods, antibiotics, and other drugs and potions. Each is designed to fix an aspect of the "damage" that vaccines or other "toxins" caused.

"Hope is a powerful drug," says Jim Laidler, a Portland scientist and father of two autistic boys who jumped ship from the vaccine conspiracy a few years ago. In reality, autism has no cure, nor even a clearly defined cause. Science takes its time and often provides no definitive answers. That isn't medicine that's easy to swallow.

Another explanation for the refusal to face facts is what cognitive scientists call confirmation bias. Years ago, when writing an article for the Washington Post Magazine about the Tailwind affair, a screwy piece of journalism about a nonexistent attack on American POWs with sarin gas, I concluded that the story's CNN producers had become wedded to the thesis after interviewing a few unreliable sources. After that, they unconsciously discounted any facts that interfered with their juicy story. They weren't lying—except, perhaps, to themselves. They had brain blindness—confirmation bias.

The same might be said of crusading journalists like David Kirby, author of Evidence of Harm, a book that seemed to corroborate the beliefs of hundreds of parents of autistic children, and UPI reporters Dan Olmsted and Mark Benjamin (the latter now with Salon).

Systems of belief such as religion and even scientific paradigms can lock their adherents into confirmation biases. And then tidbits of fact or gossip appear over the Internet to shore them up. There's a point of no return beyond which it's very hard to change one's views about an important subject.

Then, too, the material in discussion is highly technical and specialized, and most parents aren't truly able to determine which conclusions are reasonable. So they go with their gut, or the zeitgeist message that it makes more sense to trust the "little guy"—the maverick scientist, the alt-med practitioner—than established medicine and public health. "History tells us that a lot of ground-breaking discoveries are made by mavericks who don't follow the mainstream," says Laidler. "What is often left out is that most of the mavericks are just plain wrong. They laughed at Galileo and Edison, but they also laughed at Bozo the Clown and Don Knotts."

And to be sure, there was some basis for suspecting vaccines several years ago, before definitive studies had discounted a link. When the first vaccine theory was proposed in 1998, it appeared in the prestigious British medical journal Lancet and was published by an established London gastroenterologist, Andrew Wakefield. Two years later at a congressional hearing, Wakefield and an Irish virologist, John O'Leary, announced they had found measles viral RNA in the guts of autistic kids with severe bowel problems.

The air of respectability fell away over the years as we learned that Wakefield had serious conflicts of interest (including a 1997 patent application on a measles vaccine to replace the potentially soon-to-be-avoided MMR shot) and that a subsequent publication on measles RNA was probably an artifact of false positives, a common problem in polymerase chain-reaction technology.

The thimerosal theory emerged in a different context. The Centers for Disease Control and Prevention, concerned about cumulative mercury exposures in young children, asked manufacturers in 1999 to phase out thimerosal-containing vaccines. In other countries, such as Denmark and Canada, thimerosal was removed because of new vaccine combinations that either didn't require thimerosal or would be damaged by it. Nowhere was thimerosal removed because of evidence of harm.

But the first CDC study of children's exposures to thimerosal-containing vaccines was difficult to interpret. And anti-mercury activists jumped on the transcript of a 2000 meeting at which the study was scrutinized to argue that something improper was going on. The transcript shows no such thing. But the activists unleashed a public-relations campaign alleging a government and "big pharma" coverup.

That, in turn, proved to be eye candy for environmental groups already enraged by the Bush administration's enlistment of former industry officials in the squashing of environmental regulations. Anti-pollution lawyer Robert F. Kennedy zealously jumped on the thimerosal bandwagon in an "expose" published in Salon and Rolling Stone.

No surprise there. What editor or writer doesn't want to "reveal" that drugmakers and the government conspired to poison a generation of innocent kids. (Kirby's book won a 2005 Investigative Reporters and Editors award.) Where's the passion in the story that some public-health bureaucrats quietly moved to blunt a danger that turned out to be nonexistent?

In the pre-Internet days, the parents of an autistic child living in a small city might have found a handful of other parents in their predicament. Now, they instantly find thousands online. The denominator—healthy children—has disappeared. This is a good thing if you're looking for answers. But the answers may not be good ones. Joined together on the Internet, these actors create a climate of opinion that functions as an echo chamber for conspiracy dittoheads. Even the women's division of the Methodist Church has gotten in on the act, presumably on the grounds that it is fighting for social justice by decrying mercury poisoning, although there was no mercury poisoning, and social justice would be better met by promoting confidence in vaccines.

Kennedy, who wrote blithely in the Huffington Post during the trial that "overwhelming science" had confirmed the link, continues to believe it. So does Rep. Dan Burton, R-Ind., whose circuslike hearing room aired many such claims. Neither cites any solid studies, because they do not exist...

It makes no sense to keep doubling down on the three legged horse that's finished last in the past twenty races. It's long past time for the hard core loyalists to bet on a a new nag.

Years ago it was arguably reasonable to look for a connection between thimerasol and autism, or immunization and autism, but those days have passed. Now it's a waste of precious time and precious energy. Every week brings new insights into cognitive disorders of every kind, including parts of the diverse collection currently labeled "autism" -- that's where we should put our effort.