Stephen Barrie, ND: Child Autism Epidemic Firmly Linked to Environment

Stephen Barrie, ND: Child Autism Epidemic Firmly Linked to Environment

Neonatal Administration of Thimerosal Causes Persistent Changes in Mu Opioid Receptors in the Rat Brain

Full study.

http://groups.google.com/group/gryffins-tail/web/2010thimerosalstudy.pdf

Family win 18 year fight over MMR damage to son: �90,000 payout is first since concerns over vaccine surfaced | Mail Online

Family win 18 year fight over MMR damage to son: �90,000 payout is first since concerns over vaccine surfaced | Mail Online

Flu vaccination ban goes national after fever, convulsions in children

Flu vaccination ban goes national after fever, convulsions in children

Autism: Military's Tricare balks at covering autism therapy - latimes.com

Autism: Military's Tricare balks at covering autism therapy - latimes.com

'New Scientific Evidence Links Autism to Vaccines and Mercury'

'New Scientific Evidence Links Autism to Vaccines and Mercury'

Two new papers published this week in the peer-reviewed neuroscience journal Acta Neurobiologiae Experimentalis point to vaccines and heavy metal toxins including mercury as causes of the alarming rise in autism. The Centers for Disease Control now estimate autism to affect one in 110 children, up 40% from just a few years ago.

"The rapid increase in autism cannot be explained solely by changes in diagnostic practices and awareness," said Sallie Bernard, president of SafeMinds. "We must look at what babies and pregnant women are being exposed to that has created this epidemic and take immediate steps to protect our children from these hazardous substances."

In the first study, researchers from the University of Pittsburgh and Thoughtful House in Austin, Texas compared two sets of macaque infant monkeys. One set of monkeys was unvaccinated while the second set received vaccines identical to the 1990s pediatric vaccine schedule, most of which contained mercury. Infant macaques were used due to their similarity to human infants. Macaques share 93.5% of the DNA found in the human genome.

The contrasting results were remarkable. The vaccinated monkeys showed increased brain growth, which the authors theorize may arise from the inability to prune neurons. Larger head size is a hallmark of human infants who later develop autism. The vaccinated primates also showed a different rate of maturation of the amygdala section of the brain than the non-vaccinated monkeys. Amygdala dysfunction has been long implicated in autism. The amygdala region is responsible for emotions, memory and learning. Individuals with autism often struggle in these areas.

In the second paper, two scientists from the University of Northern Iowa made a critical appraisal of research that has been used to disprove a link between autism and heavy metals, and mercury in particular. They found statistical errors in several studies so that a re-analysis of the data demonstrated a greater presence of metals in autistic children than controls. The authors calculated that 43 out of 58 scientific reports suggest some link between heavy metals and autism may be present, while 13 reports suggest no link. They concluded that while questions remain, "the weight of evidence favor[s] a connection."

SafeMinds is calling for the United States government to pass legislation banning mercury in vaccines as has been done already by many states, based upon these two new significant articles and the growing scientific literature casting doubt on the safety of the infant vaccine schedule and of exposures to heavy metals including mercury. Most influenza vaccines contain mercury. SafeMinds also asks Congress to pass the Safe Chemicals Act of 2010 so that harmful chemical substances like mercury in medical products will be discontinued when proof of safety is absent.

"While we wait for the government to act, the public can take steps to limit their exposures to toxicants which can alter fetal and infant development leading to developmental disabilities like autism," said Ms. Bernard. "The public can refuse vaccines made with mercury, can make choices for their child's vaccine schedule, and can create homes that are largely mercury-free."

Let's say it again: Genes Don't Cause Autism

July 07, 2010

New Autism Consortium Study Proves (Again) that Inherited Genes Don’t Cause Autism

By Mark Blaxill

The Autism Genome Project Consortium (AGPC) deserves credit for at least one thing. They know how to make a public relations mountain out of a scientific molehill.

The AGPC was all over the news last month, leading a celebration that went global. “Genes breakthrough in autism study” proclaimed a UK headline. “Genetic link to autism found”, announced the Sydney Morning Herald, while the Los Angeles Times told us with only bit more circumspection that a “Big study identifies new genes that may be involved in autism.” The publicity blitz included the suggestion of practical applications, with a report from the Daily Mirror in London promising that an “Autism find could lead to a new test” whileBusiness Week picked up more directly on the commercial opportunity, “Autism’s genetic ties may lead to early detection, treatment.”

We’ve seen this movie before. No really, not just the metaphorical repetition of the autism genetics script, but a real movie. It’s calledGroundhog Day. Like Bill Murray’s character waking up every morning on the same day, the autism gene hunters relive this same public relations routine over and over again with full awareness of their past failures. Meanwhile the media, like Murray’s fellow travelers in the movie, remain blessedly free of any long term memory and go willingly along for every ride.

Genetic analysis once again finds…not very much

So what, you might ask, was all the excitement about? In brief, the AGPC reported evidence that a particular type of rare, inherited mutation (called a CNV, or copy number variant) was more frequent in the DNA of autistic cases than controls. Unlike past autism-CNV studies, the authors did not report that the total number of mutations per individual was more frequent in autism. Instead, according to the AGPC, the specific mutations found in autism cases were more frequently located on active genes. In the eyes of the study authors, this “higher global burden of rare, genic CNVs” suggests that the location rather than the frequency of CNVs on the autistic genome made them likely to be disruptive in their biological effect.

One thing to know about CNVs is that they come in two flavors. They can include either missing DNA—deletions, or extra stretches of a DNA sequence—duplications. The AGPC study attempted to tie both flavors to autism. In the AGPC account, however, the coherence of the argument around these two CNV flavors mattered far less than their ability to report encouraging progress in the decades-long hunt for autism genes.

Not surprisingly, there was little encouraging news for families affected by autism in the fine print, nor was there much clarity over the CNV specifics. Notably, the AGPC authors couldn’t quite pinpoint which flavor of CNV--deletions or duplications-- was at the root of the problem in autism. Across all genes, they calculated that the DNA of autistic cases harbored more deletions but not duplications; in terms of the subset of so-called “ASD-implicated” genes (more on these below), the deletions weren’t the problem it was the duplications; yet when it came down to extracting causal insight from all these CNVs, duplications were out and deletions were in.

So here’s a simple question for the AGPC. Which is it, are deletions or duplications associated with autism?

Well, and again not surprisingly, the answer depends on what argument they’re trying to make. And the flip from deletions to duplications and back again reveals the AGPC’s progressive retreat, a retreat away from objective findings and towards questionable and therefore manipulable constructs.

The most compelling part of their evidence, the finding that is featured most actively, points to the deletion evidence. This finding emerges from the AGPC’s exhaustive analysis examining how frequently CNVs show up on the autism genome relative to unaffected controls. They report their single positive finding with great fanfare, but if one reads the study carefully (including the 74 pages of supplemental materials), one learns quickly that the vast majority of the results are actually negative. Most astonishing is that there was essentially no difference at all in the mutation rate between autistic subjects and controls, a finding that goes against several prior studies. In fact, along just about every dimensions, the AGPC team found no difference in CNVs between cases and controls: no excess of CNVs in terms of the number of CNVs per sample, the percentage of samples with CNVs, the total amount of affected DNA, or the average size of CNVs. This was true for deletions and duplications and for small and large CNVs. Nor were there any differences between families with a single child (simplex) or multiple affected (multiplex) children.

The single finding of significance relied on specifying the location of the CNVs in autism cases, i.e. that they were on active genes, the small fraction of the genome that actually encodes for proteins. And here, the AGPC found that the autistic genome more frequently demonstrated stretches of lost DNA—deletions--on such genes.  This is an interesting, if hardly revolutionary, finding but one that goes essentially nowhere in explaining causation. Even though the suggestion of a different mutation rate of just the genic regions of the autism genome narrows the range of biology under inspection, we’re still talking about the entire set of protein-coding human genes, roughly 21,000 of them according to recent estimates.

So, although the suggestion of an elevated rate of missing genic DNA in autism is interesting, the AGPC obviously needed to look for something more specific. And here, their deletion evidence failed them, because although there appeared to be more deletions in allgenic regions, there weren’t really any differences in deletion rates on the genes of highest interest. Over 170 orthodox autism researchers were listed as co-authors on the study. For years, these researchers have been working overtime to specify “autism genes.” And over that period they’ve accumulated long lists of faint signals (rarely replicated with any consistency and often abandoned): genes they believe they’ve connected to autism. But when it came time to zoom in on their putative “global burden of rare, genic” deletions, the AGPC wasn’t able to connect that burden of deletions to the long list of genes they’ve been trying to implicate in autism for so long.

In fact, upon closer inspection, the deletion findings were downright embarrassing for the authors. Deletion rates in cases and controls were virtually identical on all kinds of genes that have been connected to autism. So despite a purportedly “breakthrough” finding on of an increased rate of missing genic DNA in autism, the authors had to turn to the other flavor of CNVs—duplications--to salvage some kind of biological case from their data.

For this purpose, they turned to a second analysis based on three different short lists of genes:

1) Markers of genetic syndromes like Fragile X, neurofibromatosis, Smith-Lemli-Opitz and tuberous sclerosis that are known to increase susceptibility to autism (“ASD-implicated”);

2) Genes that have been suggested in previous autism research (“ASD candidates”); and

3) Genes that have never been connected to autism but are involved in other intellectual disabilities (“ID”).

In this second analysis, they reported a small, but significant increase in the duplication rate in “ASD implicated” genes. That’s about it. (Neither deletions nor duplications showed up significant on the ID gene list, but when added together a small ID effect was just barely significant).

But in a shocking setback for decades of autism research, the findings on over 100 “ASD candidate” genes were completely negative. Anyone with fond Groundhog Day memories of earlier publicity blitzes for the HOXA1 gene, Cadherin 10, the serotonin transporter gene?  There’s not even a hint of a positive in this long list of previously ballyhooed genes that made up the AGPC’s “ASD candidate list.”

What’s more, although the AGPC’s duplication findings were positive, their effect was trivial. For the only significant finding--duplications on the ASD-implicated genic regions--the “population attributable risk” (PAR) came out to less than 2%. Under the best possible scenario (one in which they take credit for individually insignificant effects in ID deletions and duplications and ASD-Implicated deletions), the PAR was 3.3%.

Of course, the headlines never read, “after years of effort, a multi-million dollar AGPC study connects gene mutations to less than 2% of autism cases.” But the raw truth in the fine print reveals that this weak finding has no right to be called a “breakthrough”: most of the genetic defects involved in these ASD or ID implicated syndromes are vanishingly rare; none of them “cause” autism, they merely create susceptibility; and the suggested biological mechanisms are as diverse as the many syndromes lumped together as “ASD-implicated” and “ID.” This is just the kind of constructed, tortured finding that falls apart on closer inspection. Will this molehill of a scientific finding ever be replicated? We’ll have to wait and see.

Moving beyond their second analysis based on these somewhat arbitrary lists, the researchers turned to a third approach in order to investigate possible biological mechanisms in their faint CNV signal. This last approach looked at cluster of genes that have been assembled by other groups into “gene sets” (clusters of between 5 to 700 genes) based on known metabolic connections between the proteins these genes sets produce. In this last analysis the AGPC researchers asked whether the mutations they saw in their autism cases showed any tendency to cluster in certain subsets of connected genes.

In this third go around, the AGPC team turned away from their brief infatuation with duplications and returned to deletions. In their analysis of how the mutations clustered in identifiable biological pathways, “only deletions were found to be significantly enriched in gene sets in cases over controls.”

So was there anything of value that might come from this gene set finding, any insights on the altered metabolism of autism that might provide clues to its cause, prevention or treatment? Reporting their findings without much interpretation, the authors merely offered the hope that their work might “lead to final connected pathways.” Let’s hope that some good may ultimately be extracted from all this investment. But is it even remotely conceivable that any of these pathways supposedly “enriched in deletions” going to lead us to viable insight about prevention or targets for treatment of autism anytime soon?

I wouldn’t hold your breath.

The devil in the details

So far in this critique, I’ve made the assumption that, hype aside, the basic evidence in the AGPC paper is reliable as far as it goes. After all, with dozens of authors, presumably rigorous peer review and the imprimatur of the prestigious journal Nature, one can at least expect to rely on the integrity of the methods the AGPC authors used and the validity of the results obtained thereby. Right?

Well…

Although, I wouldn’t make the case that Nature has fallen to the level of Pediatrics in terms of de minimus quality standards (ahhPediatrics! the refuge of such airtight study designs as Verstraeten et al, 2003, Madsen/Thorsen et al, 2003 and Fombonne, 2000) it’s hard not to raise your eyebrows at a number of aspects of the AGPC’s study design. At the most basic level, a few notable concerns jump out.

• The controls aren’t matched to the cases. It’s a fundamental principle of any quality case-control study that the case group should resemble the control group as closely as possible. Here, and oddly, the demographic profile of the AGPC’s autism subjects is not reported at all.

Yet it’s almost certain that their case population differs sharply from controls, a profile of which is provided. For one thing, the control population is 69% female, while the case population is almost certainly disproportionately male. In addition, this heavily female group was, on average, 39 years old at the time of sample collection; the age of the autism subjects was almost certainly younger than that. This profound mismatch of gender and age in the study population raises all kinds of interesting questions. What if the female controls were less prone to mutagenic damage and carried lower mutation rates? What if birth date is a key risk factor for CNVs? What if some other unreported population mismatch underlies the faint difference in CNVs the group reported? Suffice it to say, when cases and controls aren’t rigorously matched, any report of a significant difference between the two groups is suspect.

• The autism samples are thrown out more often. As in all CNV research, quality control issues abound when it comes to detecting the minute changes in DNA that qualify as deletions or duplications. Indeed, one need only scan the methods sections of any CNV study to discern the importance of quality control in the interpretation of CNV “calls.” In the case of the AGPC report, despite manifestly rigorous efforts to ensure the reliability of their CNV findings, the possibility remains that the results are simply artifacts. Why? Because the case and control samples come from completely different sources: the autism samples from the various consortium members and the control samples from the Study on Addiction, Genetics, and the Environment. And were there differences in the handling of samples between these two sources? It’s hard to know but certainly possible. If one reads the methods section closely, one can calculate that the rate of autism samples thrown out for quality reasons was nearly twice (11.2%) as high as the rejection rate for controls (6.2%).

• Duplicate reporting perpetuates possibly random findings.  There’s one issue that’s hard to sort out from the methods described: the possibility of duplicate reporting of results within the autism group. The AGPC autism sample relies at least in part autism cases derived from the AGRE repository. The AGRE cases have been deployed multiple times, and at least some of the replication of CNV findings in the AGPC report occurs because the same samples are included in more than one study.

More important than these three basic concerns, however, is the possibility of more subtle design errors, especially in the parts of the study where the authors have developed original conceptual frameworks in their quest for biological relevance. For example, a key part of the AGPC analysis relies on a bucketing of genes into three categories: “ASD-implicated” genes, “ASD candidate” genes and “intellectual disability” genes. But these are categories created by the authors for the first time. They carry no special legitimacy or significance beyond what the authors claim for them. And since the results of the AGPC analysis differ significantly across the three categories, the possibility that these categories are (at best) artefacts or (at worst) targets for data manipulation must be considered.

At first glance, the “ASD-implicated” gene category seems quite reasonable. This set of “genes” (actually a list of 36 genes and 10 loci) includes known genes for several disorders that have shown high susceptibility to autism: conditions like tuberous sclerosis, neurofibromatosis, and syndromes such as Angelman’s, Rett, Fragile X and Smith-Lemli-Opitz.

On the surface, that all seems reasonable. But upon closer inspection, it’s not at all clear how the researchers made their choices between the genes that made it on to the “ASD-implicated” list and the genes that were merely “ASD candidates.” Upon what basis did they draw the line between these two categories? Indeed, they promote their ASD-implicated list as a group of active genes, yet over 20% of their DNA regions are “loci” rather than identified genes. Within the listed genes, while a number of the ASD implicated genes seem to fit their description, quite a few seem arbitrary. For example, why is the NRXN 1 gene “ASD-implicated” and not merely an ASD-candidate? Perhaps because the AGPC is quite favorably inclined to accept the NRXN1 a “known autism gene” (after all, they were the first to suggest it might be an important CNV), but that hardly puts it in the same category as the gene for Fragile X syndrome. And at least one other group found no support for this gene as significant in autism.

This is no trivial matter, with 103 “ASD candidates” providing no significant support for a CNV role in autism and 46 “ASD-implicated” genes and loci providing modest support, the question of whether there is any valid distinction between these two groups is critical. If the AGPC team had analyzed all 149 “genes” as a single group, would there have been a significant finding? I suspect not.  Would the subset of the 46 ASD-implicated genes that drove the significance of the result increase the credibility of the group as a whole if identified by name? One wonders. Indeed, the simple assertion that these categories carry biological significance raises questions over how and whether this framework was qualified and tested. Even more troubling, without rigorous criteria for selection of these categories (none are provided in the 74 page supplement) one wonders whether the three lists were created before or after the analysis began. Needless to say, any ex post categorization creates huge potential for bias and even for abuse, with the investigators “tuning” the respective lists to cull out a subset around which they can conjure up a favorable finding. Did the AGPC team hold themselves to a rigorous standard of ex ante hypothesis formulation and empirical testing? One would certainly hope so, but no insight into how this design work was conceived or carried out is described in the methods.

Association is not causation

There is also a basic logic problem in the entire autism-CNV literature that bears emphasizing. It’s one thing to find evidence of differences in CNV rates, either inherited or de novo, in a sample of autistic subjects and quite another thing to draw extravagant conclusions. More specifically, if an exhaustive data mining exercise like the AGPC project can succeed in extracting a faint signal of significance from the vast swath of base pairs that make up the human genome, it’s one thing to report that there might be evidence of a small excess in mutation rates. But to suggest that any constellation of these mutations actually cause autism is a conceptual leap that’s actually quite risky.

As the watchdogs of scientific rigor so frequently remind us, association is not the same as causation.  

What does that mean for the interpretation of autism-CNV research? The one glaringly obvious possibility that none of the genetic researchers can bring themselves to admit is that their painstaking genetic findings could simply be an effect and not a cause. Indeed, why wouldn’t it be the case that a population of pregnant women and infants that is under higher environmental stress than a control population would have a higher rate of DNA damage? Isn’t it more likely that the environmental exposures that have provoked the autism epidemic are also mutagenic in their own right? 

Mercury, for example, is a well-know mutagen. Many other toxins have similarly genotoxic effects. So instead of assuming a straight line of causality from the genome to autism based on a meandering pattern of findings from the CNV analyses of the AGPC and others, there’s a far more parsimonious interpretation. Any kind of elevated CNV rate in autism (to the extent that any such pattern endures, more on this below) could simply be a benign outcome of causal environmental factors.

And all of this expensive number-crunching could amount to much ado about nothing.

Fire and fall back: gene hunters in a strategic retreat

With methods and designs as creative as these, it shouldn’t surprise anyone that there has been a veritable parade of autism gene studies that have not only failed to reinforce one another, they have consistently repudiated the findings and (often grandiose) theories of previous investigations. The CNV parade has rolled out in just a few short years. In 2007, a group from Cold Spring Harbor (1) reported that de novo CNVs appeared in 10% of their ASD cases and only 2% in controls. Soon after, a group called The Autism Consortium (not the AGPC), based at Harvard, looked for support for a higher rate of de novo mutations in autism (4). Although they reported a “hot spot” of genetic instability on chromosome 16, they found no evidence of the pervasive pattern the Cold Spring Harbor group proposed. Meanwhile, and publishing before the Harvard group, the first AGPC report jumped on the CNV bandwagon as well and pointed loudly to a de novo deletion on the NRXN1 gene (3). Shortly thereafter, however, the Harvard group found no evidence for a significant rate of de novo NRXN1 deletion in autism. In addition, yet another 2008 analysis found that NRXN1 deletions might not be such a big deal after all; controls could have the NRXN1 deletion too--so it wasn’t really causal (6)--and although some affected families had the same deletion (this time it wasn’t de novo but rather in the parents), the inheritance pattern showed that the NRXN1 deletion did little to explain the autism risk (6). Not long after these two 2008 publications poked holes in the 2007 CNV claims, a 2009 study from The Children’s Hospital of Philadelphia (CHOP) threw out the Harvard group’s 2008 “breakthrough,” finding no evidence for any excess of de novo mutations in autism and no “hot spot of genetic instability” on 16p11.2. Instead, the CHOP group turned the focus back to inherited CNVs, proposing several new candidate regions (7). Unfortunately for CHOP, the two most recent analyses (8,9), have rejected their most prominent proposals.

And the beat goes on with the new AGPC report. You’d never know it from the publicity blitz, but the latest AGPC study was bad news for almost all of its predecessors’ CNV findings as it failed to replicate almost all of their most prominent predictions.  For one, although the AGPC paper stretched to find a high rate of inherited CNVs, they found no evidence for a higher rate of de novo mutations in autism. They also found no support for elevated CNV rates on a long list of “ASD candidate” genes, regions that include many of the CHOP areas, not to mention others from the list of 103 genes in these regions that have been raised in previous studies. And the faint signals they so aggressively promoted in their public relations program have yet to face a major replication test.

If the past provides any lesson, the latest AGPC claims will likely prove ephemeral, and turn into yet another casualty in a long parade of failed autism gene studies. As the table below demonstrates graphically, the specific pattern of proposing CNV abnormalities in autism (the green shaded areas) only to find that the evidence contradicts the proposed abnormality (the red shaded areas) as new data comes in, has repeated itself multiple times.

 

(Click table to enlarge.)

So instead of being a startling new breakthrough in autism science, the latest AGPC report is actually just the opposite: yet anotherGroundhog Day repetition of the futility of autism gene science unaccompanied by any acknowledgement of that sad reality. Instead, the strategic retreat is masked by a sharp volley of new claims, with the gene science enterprise firing as it falls back.

To make this point even more clear than I have so far, it’s worth elaborating a bit on how a few specific theories of CNV causation in autism have been forced into retreat. Four of them (most notably represented by the four blue boxes in the table above) make this case most clearly.

1. The unified genetic theory. The 2007 report from the Cold Spring Harbor (CSH) group that first focused attention on CNVs in autism brought with it both an ambitious theory and strong predictions. Unlike most previous genetic work in autism that focused on inheritance, the CSH group brought forth a new and largely environmental theory, calling it a “unified theory for sporadic and inherited autism.” Based on provocative results from a small sample, they argued for a specific pattern of genetic mutations in autism: that rare CNVs occurred at a higher overall rate in autism families (implicitly, this rate reflected environmental pressure and explained the increased rate of autism); that families with multiple affected children (called multiplex families) harbored CNVs that first emerged in the parental germ line and that these parental mutations were passed on, largely through genetically protected females (this was a new variant of mother blaming, the “mutant mom” theory) to multiple male children; and that families with a single affected child (or simplex families) would show an especially high rate of de novo mutations, not present in the parents. According to some private accounts, this bold new theory was all the rage for a short while. It offered a creative new synthesis of genetic transmission patterns and environmental causation (via mutagenesis) that both explained old facts and was sustained by new data in a pilot analysis (2).

Unfortunately for the CSH group, however, their bold predictions failed to hold up under close inspection with larger samples. Relatively few subsequent analyses have examined the rate of de novo mutation in a control group, but the one study that did found no support for a higher mutation rate in autism families (4). One study found a higher de novo mutation rate in simplex families (6), but the new AGPC analysis showed the two rates to be virtually identical (9). More importantly, virtually none of the later evidence supported the unified model of autism gene acquisition or transmission, either from “mutant moms” to multiple affected children or de novo in simplexfamilies. As one study conceded, their results were “consistent with the idea that true risk loci show…imperfect segregation with disease, a reality that will complicate gene finding efforts.” (8)  So much for mutant moms.

2. The hot spot theory. Following the fashion of seeking de novo CNVs, the Harvard-based Autism Consortium published their 2008 study suggesting that despite a lack of general de novo risk, as the Cold Spring Harbor theory went, there were specific areas of “genetic instability” on the genome that could be tied to autism risk. Like Cold Spring Harbor, the Harvard group’s theory was consistent with environmental factors playing a role in producing CNVs. Elaborating on this idea, an editorial accompanying the consortium’s paper in The New England Journal of Medicine spun a new grandiose theory of autism based on faint signals from Harvard’s CNV study: that “from an evolutionary standpoint, autism may be a relatively ‘young’ disease’”; that the de novo mutations on chromosome 16p11.2 might represent “a hot spot of genetic instability” in autism; and that these hot spots of de novo CNVs in “rapidly evolving gene families” might “highlight a different paradigm for the genetic basis of autism.”  The editorial writers went on to theorize that “each new objective finding expands the number of forms, or ‘autisms,’ like layers of an onion,” making them among the first autism geneticist to blame the failure of their work on the semantics of the disease’s describers rather than the shortcomings of their own theory.

Beyond the obvious extravagance of this leap (that autism is not the singular disorder first observed by Leo Kanner, rather it is thousands of different ones) the hot spot theory failed at a more basic level. Its own purported onion layer, evidence of deletions on 16p11.2, was not a stable finding. The Harvard group’s deletion evidence depended on the idea that the presence of 13 deletions in their cases was significantly higher than the 5 deletions they found in controls. But just a year after their widely publicized finding of a hot spot on 16p11.2, the CHOP group found “the CNV frequency in the control subjects at this locus was…comparable to the cases.” (7) So much for the hot spot.

3. Specific pathways rather than genes. The failure of the de novo mutation theory led the CNV theorists to a new retreat. Out went both the emphasis on genetic instability (inherited CNVs were back in the game) and on specific DNA regions, hot spots or otherwise. In came a broader search for defective biological pathways. In this new model, it didn’t matter whether specific genes could be shown consistently to have mutated in autism families. Instead the goal was to find defects in any numbers of genes that coded instead forbiologically connected proteins. And since the genes no longer held the key, but instead gene clusters, a whole new gene hunting strategy could be deployed.  Moving from long lists of genes to short list of pathways got the rhetorical juices flowing. One 2008 paper from the Harvard group theorized that the cause of autism could be traced to metabolic pathways surrounding “the autistic neuron” (10) and proposed that such pathways could be tied to autism by investigating targets such as “synaptic protein synthesis.” Following this idea, the CHOP group made a splash early last year with a report suggesting that  both “ubiquitin degradation” and “neuronal gene” pathways (7) were enriched with CNVs

It wasn’t long, however, before the first of these findings bit the dust.  Late last year, yet another consortium joined the quest and reported that “no evidence for…overrepresentation was found for genes in the ubiquitin degradation pathway and neither term was highlighted as overrepresented among [deletions] or [duplications].” (8) So much for the short list of pathways.

4. Pathways here, pathways there, defective pathways are everywhere. Not surprisingly, as neither specific genes, nor hot spots, nor specific pathways have held up under scrutiny, the next move of the autism gene hunters has been to retreat to the last refuge they can find, any pathway that offers the hope for a clustering of autism defects. Seen in the context of these successive retreats, it becomes clearer just how the latest AGPC paper fits in. Offering no theory of environmental interaction with the genome while also gliding by a remarkable repudiation of decades of autism gene candidates, they proposed a new retreat. The evidence for their substitute theory? An undifferentiated collection of mutations only in “genic regions” that are traceable only to an unspecified collection of “gene sets.” This is an explanation for a disorder so specific that Leo Kanner memorably described its victims as “children whose condition differs so markedly and uniquely from anything reported so far, that each case merits…a detailed consideration of its fascinating peculiarities”?

In the absurdity of the latest retreat, perhaps we might dare to ask whether it’s time. Could this new paper--a grand mush of random, rare, multiple inherited gene mutations that at best can explain only a tiny fraction of autism cases—be the last stand of the rare CNV theory?

There’s a bigger game being played

As we consider this question, it’s important to remember, however, that in all the storm and fury surrounding the latest AGPC findings there is more at stake than the mere collapse of autism gene science. The larger failure of genetic research goes well beyond autism and has far more serious consequences for the greatest hope of 20th century biology. Indeed, one reason autism gene studies get so much attention is that autism was always supposed to be an early victory, one of the easiest targets in the broader search for the genetic roots of human disease. If genetic research can’t prove its value in autism, then the prospects for the larger enterprise are bleak indeed. The New York Times, hardly a harsh critic of the great autism gene hunt over the years, wrote about this problem on June 12th, in an article titled, “A Decade Later, Genetic Map Yields Few New Cures.”  (see HERE)

“For biologists, the genome has yielded one insightful surprise after another. But the primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.”

This failure has been particularly acute in the effort to find common (mostly inherited) disease genes, including any involved in autism (for a related discussion, see HERE).

“With the catalog [of common variants] in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009. The upshot is that hundreds of common genetic variants have now been statistically linked with various diseases. But with most diseases, the common variants have turned out to explain just a fraction of the genetic risk.“

That failure has forced a retreat that goes beyond those we’re seeing in autism, but one that helps explain the recent infatuation with autism CNV research; it’s a retreat from the specification of the catalog of common genes to a search for rare mutations, or CNVs. According to The New York Times report, “It now seems more likely that each common disease is mostly caused by large numbers of rare variants, ones too rare to have been cataloged.”

Seen from a larger perspective, then, the AGPC celebration was all about the struggle with this looming specter of failure: an attempt to avoid the shame of yet another defeat, to loudly claim victory in what is in truth another losing skirmish in a war the gene hunters are losing badly. On the autism front, once thought easily winnable, the larger genetics enterprise is now scattering backward after absorbing multiple blows to their theory and is beating several different paths of retreat all at once: a retreat from linkage studies that aimed to find common inherited genes; a retreat from grand, unified theories of de novo mutation; a retreat from hot spots of genetic instability; and (latest) a retreat from short lists of candidate pathways to an undifferentiated mush of 75 gene sets representing a multitude of only dimly connected pathways.

Despite this historic sequence of failure, the AGPC group understands their need to defend the millions of dollars of investment in the great autism gene hunt, and so again they have positioned this latest publication as a celebration when an incoherent mush of findings offered no support whatever for decades of prior work, “explained” only 2% of autism with a questionable clustering of (at least some) known risk genes and stretched that claim to 3.3% with a brand new list that had nothing to do with autism.

Then, in an astonishing bit of hubris, the AGPC went on to double down on their bets, pitching parents directly for more money and more community support. In an Autism Speaks blog post written shortly after the paper’s publication, AGPC member Stanley Nelson made a plea to the autism parent community (see HERE) to invest even more time and more money in gene hunting research. His idea? That chasing down all of these faint signals would require sample populations that were many times larger than those assembled for past work, populations that already number in the thousands

You have to hand it to these guys; they sure know how to sell a losing war.

Keep in mind that this long, slow collapse of the great autism gene hunt is no cause for celebration in its own right. This tragic waste of time and money is both surprising and unfortunate. It shouldn’t have been this hard to gain genetic insight into the biology of autism. Everyone knows there is familial clustering in autism. Everyone concedes that there ought to be genetic susceptibility factors. And moving faster to learn the lessons of autism’s underlying biology is something all of us should be rooting for. Yet, autism is teaching us another lesson instead: about the futility of looking to our genes for explanations of the cause of human disease. That’s a painful lesson for many.

But when it comes to autism, it should also be clear that the massive hype surrounding the new AGPC study was out of all proportion to the importance of its scientific findings, not to mention any benefits it offered autism families. The AGPC report found almost nothing yet claimed almost everything. Worse, they succeeded in attracting millions of dollars on speculative work that has generated zero value to date and in the process crowded out more promising avenues of research. Optimistic headlines aside, no predictive genetic tests are in sight and nor is there much prospect for new treatment targets. Even if there were a faint hope of new drug target targets tied to the putative list of target gene clusters, any drug development that might stem from this work lies years, if not decades, in the future.  For the foreseeable future, there will be no magic pill for autism. The best one might hope for is a ruthless plan for prevention via genetic counseling, i.e. abortion.

It’s time. Time to put an end to the great autism gene hunt. Time to turn resources over to the investigation of environmental risk factors. Time to turn from delusion to rationality. Time, in the words of Bernard Rimland, to defeat autism.

Time for our children (and an exploding number of young adults) is growing short. Let’s not waste any more of it.

References:

1: Sebat J, Lakshmi B, Malhotra D, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316(5823):445-9.

2: Zhao X, Leotta A, Kustanovich V, et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci U S A. 2007;104(31):12831-6.

3. Szatmari P, Paterson AD, Zwaigenbaum L, et al. (Autism Genome Project Consortium) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39(3):319-28.

4. Weiss LA, Shen Y, Korn JM, et al. (Autism Consortium) Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358(7):667-75.

5. Eichler EE, Zimmerman AW. A hot spot of genetic instability in autism. N Engl J Med. 2008;358(7):737-9.

6. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477-88.

7: Glessner JT, Wang K, Cai G, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459(7246):569-73.

8. Bucan M, Abrahams BS, Wang K, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009;5(6):e1000536.

9. Pinto D, Pagnamenta AT, Klei L, et al. (Autism Genome Project Consortium) Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010 Jun 9. [Epub ahead of print]

10. Kelleher RJ 3rd, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135(3):401-6

Autism on the Seas

If you were wondering what kind of family vacation you could possibly take with a child on the spectrum, look no further!  Autism on the Seas has packages that cater specifically to autism families.

 

http://www.alumnicruises.org/Autism/Autism_Home.htm

How to talk to a child with autism

Thimerasol Causing Brain Problems in Rats

Vaccine Adjuvant Alters Neurological Function in Rat Experiment, Symptoms Identical to Autism -- Lourdes Salvador November 30, 2009 Autism is a neurodevelopmental disability characterized by social withdrawal, communication deficits, and repetitive behaviors. Both genetic and environmental factors have been implicated as causes of autism, moreover a high body burden of mercury and other toxic metals from vaccinations and environmental exposures has been increasingly given more attention.   Thimerosal is mercury containing vaccine preservative added to many childhood vaccines. It is widely suspected as a cause of an increasing widespread epidemic of childhood neurodevelopmental disorders such as autism. Now, a new study shows that administration of thimerosal leads to long lasting neurological impairment in rats, specifically by altering the neural process of handling noxious stimuli. Analysis also shows that significant amounts of mercury from thimerosal accumulates in the rat brain and remains long term. The mercury is not readily cleared, as was previously believed. Though mercury readily leaves the blood stream, it does not leave the body. It is now recognized to accumulate in brain tissue.   Additionally, this research is supported by various prior studies which show that children with autism suffer from a weak ability to excrete mercury and that the weaker the ability, the more severe the symptoms of autism.   Now, two new research studies investigating the effects of chelation therapy on the health and behavior of children with autism spectrum disorders have discovered that children receiving chelation to reduce mercury levels had significant improvements. It appears that mercury may produce the symptom set recognized in the autism spectrum disorders as a form of autism.   References Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr J. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part A--medical results. BMC Clin Pharmacol. 2009 Oct 23;9:16. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr J. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results. BMC Clin Pharmacol. 2009 Oct 23;9:17. Olczak M, Duszczyk M, Mierzejewski P, Majewska MD. Neonatal administration of a vaccine preservative, thimerosal, produces lasting impairment of nociception and apparent activation of opioid system in rats. Brain Res. 2009 Dec 8;1301:143-51. Epub 2009 Sep 9. This article originally appeared in the MCS America News, December 2009 Issue http://mcs-america.org/december2009.pdf . For more articles on this topic, see: MCSA News. Copyrighted 2009 Lourdes Salvador & MCS America

Utah scientist makes breakthrough in mental illness research

 

http://www.ksl.com/?nid=148&sid=10947928&autostart=y <<< CLICK HERE to Watch Video Intreview!!!   Utah scientist makes breakthrough in mental illness research   By Jennifer Stagg   SALT LAKE CITY -- It is heartbreaking to see someone you love suffer from mental illness. Now a famous Utah scientist says he's made a big breakthrough in the research to find a cure. Doctors have traditionally treated mental illness with drugs to alter the brain's chemistry, but the University of Utah's Nobel Prize-winning geneticist Dr. Mario Capecchi tried a new approach on a lab mouse. He treated the animal for the illness the same way you would many other illnesses -- by treating its immune system.   Capecchi says compulsive behavior doesn't just affect people. In fact, he had a lab mouse who was suffering from the condition trichotillomania, where one pulls their own hair out. Scientists say it was the mouse that led to the ground-breaking discovery as they found a way to cure him. "There's a direct correlation, in essence, between the immune system and behavior," Capecchi says. He says scientists have known for years that there is a connection between behavior and the immune system, but they didn't quite understand it. Now he and his team have discovered it all has to do with a tiny cell called microglia. Microglia were believed to be "scavenger cells" that would clean up damage in the brain, but Capecchi says the cells are much more powerful than they were letting on. "What we're saying is microglia are much more sophisticated and are actually controlling behavior, and they have to do it by interacting the nerve cells in your brain," Capecchi says.   They found people and animals afflicted with behavior disorders have deformed microglia cells. So, instead of treating mental illness the way doctors traditionally have -- with medication to alter brain chemistry -- they tried a new approach by treating the immune system. The researchers used a procedure on the mouse that's commonly practiced on cancer patients -- a bone marrow transplant. "That cured the disease permanently," Capecchi says. "All the hair grew back, all the lesions were healed, and the mouse no longer removes the body hair." Capecchi says this new discovery could lead to cures for mental disorders from autism to schizophrenia. "The book is just opened, and so there are many, many possibilities; and hopefully not only will we pursue it, but also hopefully it will interest other researchers, other investigators, to pursue similar experiments," Capecchi says.   What are... microglia? Microglia are immune system cells that originate in bone marrow and migrate from blood to the brain acting as the first and main form of active immune defense in the central nervous system (CNS) defending the brain and spinal cord, constantly excavating the CNS and attacking and engulfing infectious agents.   E-mail: jstagg@ksl.com

Dr. Wakefield Removed from the United Kingdom’s Medical Register

Statement prepared by: Rebecca Estepp
Contact # (949) 640-4401 ext. 106

May 24, 2010

The General Medical Council (GMC) erased Dr. Andrew Wakefield from Britain’s Medical Register earlier today. TACA is deeply saddened by these unnecessary and vindictive actions. We will continue to support Dr. Wakefield.

Repealing Dr. Wakefield’s license does not erase the last 12 years of his work for children and their families. The GMC cannot revise history with this action. There are thousands of families that witnessed their children regress into autism after childhood vaccinations. Dr. Wakefield is a hero to these families.

TACA is very grateful that Dr. Wakefield will continue his much needed research into vaccine safety, autism and bowel disease.  Dr. Wakefield’s research is not a threat to vaccine programs world wide. The real threat comes from the cozy relationships between vaccine regulators and industry.

One in four parents already believes that vaccines can cause autism in children. The autism community has been asking for independent research and transparency in the vaccine program for more than ten years. Until this happens, parents will continue to lose confidence in this program. Revoking Dr. Wakefield’s medical license will only cause parents to become more leery of the medical establishment and the vaccine program as a whole.

The following studies replicated Dr. Wakefield's original findings:

Gonzalez, L. et al., "Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with gastro-Intestinal Symptoms." Arch Venez Pueric Pediatr, 2005;69:19-25.

Balzola, F., et al., "Panenteric IBD-like disease in a patient with regressive autism shown for the first time by wireless capsule enteroscopy: Another piece in the jig-saw of the gut-brain syndrome?" American Journal of Gastroenterology, 2005. 100(4): p. 979- 981.

S. Walker, K. Hepner, J. Segal, A. Krigsman "Persistent Ileal Measles Virus in a Large Cohort of Regressive Autistic Children with Ileocolitis and Lymphonodular Hyperplasia: Revisitation of an Earlier Study" [IMFAR May 2007]

Balzola F et al. "Autistic enterocolitis: confirmation of a new inflammatory bowel disease in an Italian cohort of patients." Gastroenterology 2005;128(Suppl. 2);A-303.

Madsen KM et al. A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism (2002). N Engl J Med 347 (19): 1477–82 http://content.nejm.org/cgi/content/short/347/19/1477?query=prevarrow

More Information

Watch Today show featuring Dr. Andrew Wakefield





Dr. Wakefield’s GMC Findings (January 28, 2010)


About TACA

Talk About Curing Autism (TACA) provides information, resources, and support to families affected by autism. For families who have just received the autism diagnosis, TACA aims to speed up the cycle time from the autism diagnosis to effective treatments. TACA helps to strengthen the autism community by connecting families and the professionals who can help them, allowing them to share stories and information to help people with autism be the best they can be.

DISCLAIMER: TACA provides general information regarding medical research, treatment options, therapies and nutrition to the autism community. The information comes from a variety of sources, and TACA does not independently verify any of it. Nothing presented at meetings, emails or in print should be construed as medical or legal advice. Always consult your child's doctor regarding his or her individual needs.

Dr. Bob Sears' Response to Hyman Diet Study

Allergen free Diet Can, and Does, Help Many Children with Autism

I've seen over 500 children with autism in my pediatric practice over the past 10 years, and in my experience the majority have benefited from the diet. Children with chronic GI symptoms, such as loose stools or constipation, seem to benefit the most, which would make sense. But I've seen some children without any GI symptoms improve on the diet.

So when I see a study come out that conflicts with my extensive clinical experience, I take a very close look at the study before I decide whether or not it should influence my medical decision-making. This new study, published by Dr Susan Hyman on May 19, 2010 from the University of Rochester definitely does not change my opinion of the possible effectiveness of the diet for children with autism. First, this was a tiny study of 14 children. The medical community rarely considers such a small study clinically useful. A much larger study would have more weight. Second, the study didn't allow for enough time to pass for the diet to create enough improvement to be clinically significant. In my experience, parents often see results from casein elimination within a few weeks. But gluten often takes longer, up to several months before benefits can be seen. Third, gluten and casein aren't the only allergens that children have to eliminate. In my practice, I eliminate all allergic foods at the same time to allow for maximum healing. A very common allergen on the diet is soy. It is possible that some children in this study had other foods that needed to be eliminated and weren't. Finally, two children in the study were excluded because they tested extremely allergic to gluten (positive TTG test). Such kids would be virtually guaranteed to benefit from the diet. It is likely the researchers wanted to determine if the diet would help the general population of kids with autism and not just those with severe gluten allergy. But including those two children in the study could have resulted in an outcome more in favor of the diet.

The mainstream medical community looks for treatments with a very high success rate. For example, if an antibiotic only improves half of kids with an ear infection, such an antibiotic wouldn't be approved. A drug or treatment needs to work very well in most patients in order for it to be adopted. Autism is unique, however, in that many treatments work extremely well, but not always in a high percentage of children. Does that mean we shouldn't offer such treatments? Not at all. If I have a particular treatment that would help even 20% of children with autism, I would offer it to all children. Those that do benefit can be blessed by improvement they wouldn't otherwise have. When it comes to the diet, my success rates are much higher than 20%. I would say that at least 75% of parents report positive results, and many of those report amazing results.

I'm not going to let a very small study such as this one prevent me from offering the hope of healing to parents, and I hope that parents everywhere consider trying the GFCF diet for their child.

Additional studies that are positive for Autism and dietary invention can be found at
http://gfcf-diet.talkaboutcuringautism.org/dietary-research-in-asd.htm

Sincerely
Dr Bob Sears - Sears Pediatrics
And TACA Physician Advisory Board

Popular Autism Diet Does Not Demonstrate Behavioral Improvement

You decide:  What do you think of this study?  Let me know what you think.

ScienceDaily (May 20, 2010) — A popular belief that specific dietary changes can improve the symptoms of children with autism was not supported by a tightly controlled University of Rochester study, which found that eliminating gluten and casein from the diets of children with autism had no impact on their behavior, sleep or bowel patterns.

The study is the most controlled diet research in autism to date. The researchers took on the difficult yet crucial task of ensuring participants received needed nutrients, as children on gluten-free, casein-free diets may eat inadequate amounts of vitamin D, calcium, iron and high quality protein. Unlike previous studies, they also controlled for other interventions, such as what type of behavioral treatments children received, to ensure all observed changes were due to dietary alterations. Past studies did not control for such factors. And although no improvements were demonstrated, the researchers acknowledged that some subgroups of children, particularly those with significant gastrointestinal (GI) symptoms, might receive some benefit from dietary changes.

"It would have been wonderful for children with autism and their families if we found that the GFCF diet could really help, but this small study didn't show significant benefits," said Susan Hyman, M.D., associate professor of Pediatrics at Golisano Children's Hospital at the University of Rochester Medical Center (URMC) and principal investigator of the study which will be presented on May 22 at the International Meeting for Autism Research in Philadelphia. "However, the study didn't include children with significant gastrointestinal disease. It's possible those children and other specific groups might see a benefit."

In response to widespread parent-reported benefits, URMC initiated the trial in 2003 to scientifically evaluate the effects of the gluten-free and casein-free diet, which eliminates wheat, rye, barley and milk proteins. Parent observation has played an important role in earlier treatment discoveries in children with autism, such as melatonin's benefits for sleep.

Hyman's study enrolled 22 children between 2 ½- and 5 ½-years-old. Fourteen children completed the intervention, which was planned for 18 weeks for each family. The families had to strictly adhere to a gluten-free and casein-free diet and participate in early intensive behavioral intervention throughout the study. Children were screened for iron and vitamin D deficiency, milk and wheat allergies and celiac disease. One child was excluded because of a positive test for celiac disease and one was excluded for iron deficiency. Other volunteers who were excluded were unable to adhere to the study requirements. The children's diets were carefully monitored throughout the study to make sure they were getting enough vitamin D, iron, calcium, protein and other nutrients.

After at least four weeks on the strict diet, the children were challenged with either gluten, casein, both or placebo in randomized order. They were given a snack once weekly with either 20 grams of wheat flour, 23 grams of non fat dried milk, both, or neither until every child received each snack three times. The type of snack was given in randomized order and presented so that no one observing -- including the family, child, research staff and therapy team -- knew what it contained. The snacks were carefully engineered to look, taste and feel the same, which was an exercise in innovative cooking. In addition, the nutrition staff worked closely with the families to make a snack that met their child's preferences. Casein was disguised in pudding, yogurt or smoothies and gluten in banana bread, brownies, or cookies depending on the child's food preferences.

Parents, teachers and a research assistant filled out standardized surveys about the child's behavior the day before they received the snack, at two and 24 hours after the snack. (If the child's behavior wasn't usual at the scheduled snack time, the snack would be postponed until the child was back to baseline.) In addition, the parents kept a standard diary of food intake, sleep and bowel habits. Social interaction and language were evaluated through videotaped scoring of a standardized play session with a research assistant.

Following the gluten and casein snacks, study participants had no change in attention, activity, sleep or frequency or quality of bowel habits. Children demonstrated a small increase in social language and interest in interaction after the challenges with gluten or casein on the Ritvo Freeman Real Life Rating Scale; however, it did not reach statistical significance. That means because of the small difference and the small number of participants in the study, the finding may be due to chance alone.

The investigators note that this study was not designed to look at more restrictive diets or the effect of nutritional supplements on behavior. This study was designed to look at the effects of the removal of gluten and casein from the diet of children with autism (without celiac disease) and subsequent effect of challenges with these substances in a group of children getting early intensive behavioral intervention.
Hyman said, "This is really just the tip of the iceberg. There are many possible effects of diet including over- and under-nutrition, on behavior in children with ASD that need to be scientifically investigated so families can make informed decisions about the therapies they choose for their children."

This study was funded by the NIH's National Institutes of Mental Health Studies to Advance Autism Treatment Research and National Center for Research Resources (NCRR).

More successes!

Never again!

Second, no more diapers!  He has been day trained for years but we have never been able to get rid of the night diapers.  He hated that he wore them, often telling me he's not a baby, but they were necessary.  We tried several times to just let him go without and every time it was a wet, urine filled disaster. Not so anymore!  He has been diaper free for about three weeks now and has only had 4 accidents.  They seem to be coming on faster as I haven't chelated since spring break where I chelated the entire week and brought about these wondrous changes.  I intend to return to our regularly scheduled chelation program this weekend and hopefully, we'll be able to banish the accidents to the fiery inferno of hell to which they belong.

I'll keep you posted on what happens!

We started AC chelation several months ago and couldn't be more pleased with the results.

Since chelating, we have had two very beautiful successes happen.

My son now eats what we give him.  Yes, sometimes I have to make him and feed him myself but he does it with very little complaint.  This is huge!  I'm sure you can all relate to the dilemma of picky eaters.

The Peer Review "Fig Leaf": Vera Hassner Sharav

Thursday, 01 April 2010, 6:45 pm Column: Suzan Mazur

The Peer Review "Fig Leaf": Vera Hassner Sharav

By SUZAN MAZUR

Vera Hassner Sharav

While the chief of the US National Institute of Mental Health this week stopped short of saying scientists are corrupt because of their ties to industry, as AP reported -- Vera Hassner Sharav does not give scientists a similar pass, partly because the testimonies she organized on unethical research on the mentally ill before the National Bioethics Advisory Committee in 1997 led to the shut down of 29 clinical trials at NIMH. Hassner Sharav is founder and president of the Alliance for Human Research Protection, a public interest watch dog group based in New York that aims to "unlock the walls of secrecy in biomedical research and to bring accountability to that endeavor". As a human rights champion, she has opposed experiments on children such as the EPA's CHEERS pesticide tests and pushed for a federal investigation into foster care children being used in AIDS drug experiments. She has appeared before various national advisory panels addressing her concerns about experiments on prisoners, about the use of antidepressants and the risk of suicide, among other issues. Hassner Sharav is also a former law librarian and has developed a database that tracks unethical research practices and the failure to disclose information on drug hazards.

I spoke with Vera Hassner Sharav earlier this week by phone about peer-reviewed science journals.

Suzan Mazur: Science peer review is regarded as censorship. That's the issue David Noble and I explored in my recent interview with him . . .

Vera Hassner Sharav: That's clearly not how peer review was originally supposed to work. Once reviewers are selected based on what's good for industry, they are not independent peers. But the process is so much more corrupt than even censorship. For example, Elsevier published propaganda favoring Vioxx as "peer-reviewed" inarticles in a phony journal paid for by Merck.

When reviewers are under contract and financially tied to industry, articles that get approved for publication, say in medical journals, are those that promote newly patented drugs or medical devices.

Suzan Mazur: What is the concern with peer review at the Alliance for Human Research Protection.

Vera Hassner Sharav: The concern is that this corruption of the peer review process leads to the promotion of defective drugs that cause harm and even kill people, whether it's Vioxx, Avandia, Zyprexa or the like -- toxic, dangerous drugs that were promoted within peer review. Independent scientists do not have access to the complete data on these newly patented drugs being promoted in scientific journals and elsewhere in the media. We should be able to ask authors for the actual data about which they are reporting.

Industry controls the process and the data, it controls the clinical trials, the selection and design of the trials. It controls what is disclosed and what is concealed. What gets published and what gets put in the so-called "drawer". Peer review has become a fig leaf covering up make-believe peer review. It's not rigorous, not independent and not honest. It's rubberstamp, paid for and controlled by the pharmaceutical industry.

The integrity of the scientific literature has been compromised. The clinical practice of medical doctors is jeopardized because physicians think these articles in influential journals have been vetted (i.e., peer reviewed). They then unwittingly prescribe to patients dangerous drugs that are being marketed widely. And people are harmed.

Suzan Mazur: With the passage of the Obama health care bill, do you see the beginning of a clean up of the peer review process?

Vera Hassner Sharav: No it doesn't touch corrupt practices at all. Obama health care is totally silent on this. The assumption is that science professions are policing themselves. But if science is under the influence of industry, receiving huge money from industry, then there is a disincentive to police.

Suzan Mazur: Can you tell me about the controversy surrounding the public being kept out of sessions at the upcoming American Psychiatric Association conference in New Orleans?

Vera Hassner Sharav: The American Psychiatric Association is having its annual meeting in New Orleans in May. Science journal publishers -- Wiley, Elsevier, etc. -- and pharmaceutical companies will be attending as well as psychiatrists.

Dr. Charles Schulz, chairman of psychiatry at the University of Minnesota Medical School, who has received hundreds of thousands of dollars as a paid consultant to AstraZeneca and Eli Lilly, whose favorable report about the antipsychotic Seroquel -- presented at an APA conference in 2000 -- was contradicted by an analysis of the drug's manufacturer AstraZeneca, is holding a session at the APA 2010 conference: "How to help parents of a first psychotic episode patient". A parent whose son committed suicide in a clinical trial conducted by Schulz wants to attend but was told the meeting is closed to all but APA members.

[NOTE Schulz office 3/29/2010 email to me: "He [Dr. Schulz] has been thinking about her [the parent Hassner Sharav refers to above is Mary Weiss, whose child died in a Schulz clinical trial] and is glad she wants to obtain more information. If you wanted to provide her name and address, Dr. Schulz would like to send her his book on the Early Stages of Schizophrenia, which is published by the APA and has chapters about psychotherapy and family therapy.]

So the question arises -- if this meeting is geared toward helping parents, what is it Schulz is going to say that he doesn't want parents to know? This is serious. This is peer review at its maximum corruption. These meetings are a commercial circus.

Suzan Mazur: Is the public completely barred?

Vera Hassner Sharav: Some meetings are open, but it costs a lot of money that individuals can't afford. [NOTE: APA advises admission is $860 - $950 for non-APA members.] But the Schulz session is closed.

Robert Whittaker, author of the forthcoming book Anatomy of an Epidemic, wanted to attend last year's APA meeting. The APA didn't want to let him in. His publisher, Crown, intervened to get him in. Whittaker attended and recorded quite a few of the sessions. They were humdingers. What's discussed at these APA meetings is information that does not reach the public.

[NOTE: -- APA has emailed me stating the following:

"Charles Schulz's Case Conference is only open to residents. Case conferences are closed to nonmembers because of the clinical nature of the discussions and the patient confidentiality restrictions inherent in presenting cases. Members are bound by ethics confidentiality and nonmembers are not, which is why nonmembers are restricted.

A few sessions are only open to residents to allow residents to have a more hands-on experience with less people, but all other sessions are open to members and nonmembers."]

Suzan Mazur: Regarding Wiley, one of the major science journal publishers attending the APA meeting -- it's been around for over 200 years but apparently just became profitable in the 1990s. Do you have any insight into that?

Vera Hassner Sharav: What this shows is that when industry began to influence the content of journals by paying Wiley hefty fees, Wiley became profitable.

Suzan Mazur: Advertising?

Vera Hassner Sharav: There are many ways to influence publishers, but two things especially. Advertising is one but at least with advertising you know an ad when you see one. And doctors are perhaps less influenced by ads than the public. Maybe.

What is even more insidious is the articles that are published as peer-reviewed scientific articles facing those ads. The reports are promotional pieces, not independently and rigorously reviewed. They are masquerading as scientific articles. That's deception of the worst kind.

Suzan Mazur: You have a Masters degree in Library Science.

Vera Hassner Sharav: Yes.

Suzan Mazur: Is there a movement on the part of libraries to challenge this corruption?

Vera Hassner Sharav: No they have no power, no say.

Suzan Mazur: Do they have any interest in dealing with it?

Vera Hassner Sharav: I don't know if they've even been asked about it. The librarians have been pretty much bypassed in the information explosion age. It was their own fault.

Suzan Mazur: They have to know about the bogus information.

Vera Hassner Sharav: They simply transmit it. You ask for an article, they'll fetch it for you. And now with the Internet, librarians are used less and less.

Suzan Mazur: One recent open-access journal called Philosophy and Theory in Biology, "a product of the Scholarly Publishing Office of the University of Michigan Library and DLXS" has come under criticism as a reflection of the gaming of the system. Here's a complaint from an independent investigator whose article was rejected by the journal after 36 hours. The journal editors include a half dozen Altenberg 16 cronies (esteemed cell biologist Stuart Newman is not among them):

"But the most insulting rejection came from Philosophy and Theory in Biology, a relatively new publication (started in August) whose senior editor is none other than Massimo Pigliucci. It took his team of editors only 36 hours to reject the paper on the grounds that it was not appropriate. The science and math in the paper, unless examined by specialists in the field, could not possibly have been understood by the editors in that amount of time. . . . I don't think Massimo ever saw the paper, trusting instead to his editorial scriveners to do their duty. In an embarrassing rant, presented in two emails, I raged that not only was his journal the most appropriate one, given its stated objectives, but also his editorial linemen were stultifying in their ignorance not just of current trends in the biosciences, but of the philosophy of science and the physical sciences. . . . [D]espite his posturing as a man of science and a skeptic, [he] is an obstacle to scientific progress although chief editor of a journal alleged to advance that very thing." -- Gregory O'Kelly

Any idea how that library affiliation works?

Vera Hassner Sharav: I'm not familiar with that particular arrangement. But many of the journals have university affiliation. Little journals. . . . What would make a huge difference would be if academia started to penalize faculty members who sell their name and append it to ghost-written articles. Simply fire them because it's unprofessional conduct.

Suzan Mazur: Here are five questions I submitted to Wiley that they refused to answer. I emailed the questions to Eric Swanson, who is the Wiley point person there in Hoboken in charge of science journals I was told by Susan Spilka in their press office that Swanson was "pondering" responding. I assume he found the questions too challenging. He emailed the Wiley template on ethics via his press office.

"1. As one of the top publishers of science journals and a public corporation, is Wiley aware that the public knows the science peer-reviewed journal system is a major factor corrupting science?

2. Is Wiley concerned that science peer review is increasingly viewed by the public as censorship -- a way of keeping out the public, who actually fund science?

3. Why does Wiley approve of anonymous peer review of journal articles? There are complaints that too often when a paper is submitted that exposes the errors of science journal editors, the paper is simply rejected and there is no avenue of appeal regarding such unethical publication practices. A psychologist complained this happened in submitting to a Blackwell, now- Wiley psychology journal. In the case of your anatomy journals, there are complaints about a possible conflict of interest regarding what is acceptable content because many of the journal editors [and the journals themselves] are based on the University of Utah campus where the LDS church has a significant presence and a gene-centered approach to science is favored.

4. Is Wiley at all concerned by lack of operational financial transparency on the part of its science journals? For example, Wiley Evolution and Development journal editor-in-chief Rudy Raff told me each of his editors gets an allowance FOR an editorial assistant (he wouldn't say how much) but that the editors do not get paid nor do the anonymous referees. Raff says it's "traditional community service" -- but the public increasingly sees the practice as a gaming of the system. What is your response?

5. Does Wiley see a serious disconnect between its corporate board of directors who endorse the Wiley journal product and pass it on to the public -- but may not understand the science -- and the scientists who actually write the anonymously-reviewed journal articles for publication?"

Vera Hassner Sharav: The arrogance of Wiley is overwhelming. No Swanson wouldn't respond because to answer would put him and Wiley in jeopardy. Yet they have a public responsibility.

Suzan Mazur: Wiley's got on its board of directors the current CEO of Moody's and the former CFO of Dow Jones.

Vera Hassner Sharav: Elsevier is intertwined with pharmaceutical companies such as Merck and GlaxoSmithKline -- whose board includes James Murdoch and Elsevier's former CEO Sir Crispin Davis. The challenge is, the way the corruption can be halted is if under Obama health care reform, if the publicly-financed reimbursement uses its muscle to not reimburse for drugs where it has been shown in court that they were illegally marketed, that the hazards were concealed and the benefits were made up. Medicare -- Medicaid should not reimburse for them. If that would happen, things would change very fast. The whole system would be shaken. Cutting off the money is the only way to get out of it.

Suzan Mazur: What about the drugs being produced now that may be detrimental to our health? How do you stop that process? Are you in favor of revoking the Bayh-Dole Act.

Vera Hassner Sharav: Bayh-Dole is what started it by encouraging corporate-academic collaboration. By removing the firewall between academia and industry, academic ethics and the integrity of science gave way to corporate ethics -- which above all, seeks to maximize profit. Since academia is far too dependent on industry money, they won't police corrupt practices. Stopping reimbursement in health care for harmful drugs illegally marketed is the way to go. As government gets more involved, they'll have more leverage. When government Medicare - Medicaid stops paying for these drugs and it involves tens of millions of prescriptions, you will see change. Once you cut the profit margin, industry will have no interest. The cycle can't continue without government subsidy.